Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Blumen, Helena M. | Schwartz, Emily | Allali, Gilles | Beauchet, Olivier | Callisaya, Michele | Doi, Takehiko | Shimada, Hiroyuki | Srikanth, Velandai | Verghese, Joe

Article Type: Research Article

Abstract: Background: The motoric cognitive risk (MCR) syndrome is a pre-clinical stage of dementia characterized by slow gait and cognitive complaint. Yet, the brain substrates of MCR are not well established. Objective: To examine cortical thickness, volume, and surface area associated with MCR in the MCR-Neuroimaging Consortium, which harmonizes image processing/analysis of multiple cohorts. Methods: Two-hundred MRIs (M age 72.62 years; 47.74%female; 33.17%MCR) from four different cohorts (50 each) were first processed with FreeSurfer 6.0, and then analyzed using multivariate and univariate general linear models with 1,000 bootstrapped samples (n-1; with resampling). All models adjusted for …age, sex, education, white matter lesions, total intracranial volume, and study site. Results: Overall, cortical thickness was lower in individuals with MCR than in those without MCR. There was a trend in the same direction for cortical volume (p  = 0.051). Regional cortical thickness was also lower among individuals with MCR than individuals without MCR in prefrontal, insular, temporal, and parietal regions. Conclusion: Cortical atrophy in MCR is pervasive, and include regions previously associated with human locomotion, but also social, cognitive, affective, and motor functions. Cortical atrophy in MCR is easier to detect in cortical thickness than volume and surface area because thickness is more affected by healthy and pathological aging. Show more

Keywords: Cognitive complaint, cortical thickness, gait, motoric cognitive risk

DOI: 10.3233/JAD-201576

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Choi, Joon Yul | Lee, Seunghyun | Lee, Wanhyung

Article Type: Research Article

Abstract: Background: Dementia and cognitive impairment were significantly associated with hearing loss. The impact of hearing loss on dementia and cognitive impairment is understudied, particularly for different effect on cognitive impairment according to types of hearing loss. Objective: The present study was conducted to elucidate the association between clinically diagnosed dementia and hearing loss with consideration of the type of hearing loss among an elderly population, and to explore the effects of different types of hearing loss on preclinical cognitive impairment. Methods: Data (n  = 59,675) from the Korean National Health Insurance Service–Health Screening were used to calculate …odds ratios (OR) for cognitive impairment according to type of hearing loss (conductive, sensorineural, mixed, and noise-induced hearing losses, and presbycusis). Cognitive impairment was assessed using the Korean Dementia Screening Questionnaire-Prescreening (KDSQ-P). Results: Cognitive impairment was significantly associated with conductive (OR: 1.45, 95% confidence interval (CI): 1.20–1.77), sensorineural (OR: 1.23, CI: 1.12–1.36), and noise-induced hearing loss (OR: 1.32, CI: 1.12–1.56), and presbycusis (OR: 1.53, CI: 1.25–1.87). Among participants scoring positive on the KDSQ-P (score≥4), the KDSQ-P score was significantly elevated in the mixed and noise-induced hearing loss groups. Conclusion: This study revealed a significant correlation between different types of hearing loss and cognitive impairment. Noise-induced hearing loss is especially important because it occurs earlier than other types of hearing loss and has large effects on cognitive impairment. Show more

Keywords: Cognitive function, cognitive impairment, dementia, hearing loss, National Health Insurance Service in Korea, noise

DOI: 10.3233/JAD-210074

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Jaul, Efraim | Meiron, Oded

Article Type: Review Article

Abstract: There is an urgent need in advanced dementia for evidence-based clinical prognostic predictors that could positively influence ethical decisions allowing health provider and family preparation for early mortality. Accordingly, the authors review and discuss the prognostic utility of clinical assessments and objective measures of pathological brain states in advanced dementia patients associated with accelerated mortality. Overall, due to the paucity of brain-activity and clinical-comorbidity predictors of survival in advanced dementia, authors outline the potential prognostic value of brain-state electroencephalography (EEG) measures and reliable clinical indicators for forecasting early mortality in advanced dementia patients. In conclusion, two consistent risk-factors for predicting …accelerated mortality in terminal-stage patients with advanced dementia were identified: pressure ulcers and paroxysmal slow-wave EEG parameters associated with cognitive impairment severity and organic disease progression. In parallel, immobility, malnutrition, and co-morbid systemic diseases are highly associated with the risk for early mortality in advanced dementia patients. Importantly, the authors’ conclusions suggest utilizing reliable quantitative-parameters of disease progression for estimating accelerated mortality in dementia patients entering the terminal disease-stages characterized by severe intellectual deficits and functional disability. Show more

Keywords: Disease comorbidity, electroencephalography, pressure ulcers, prognostic predictors, terminal stage

DOI: 10.3233/JAD-201563

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Pais, Marcos Vasconcelos | Cunha Loureiro, Júlia | Santigado do Vale, Vagner | Radanovic, Marcia | Talib, Leda Leme | Stella, Florindo | Vicente Forlenza, Orestes

Article Type: Research Article

Abstract: Background: Decreased cerebrospinal fluid (CSF) concentrations of the amyloid-β (Aβ), along with increased total (T-tau) and phosphorylated tau protein (P-tau), are widely accepted as core biomarkers of Alzheimer’s disease (AD) pathology. Nonetheless, there are a few remaining caveats that still preclude the full incorporation of AD biomarkers into clinical practice. Objective: To determine the frequency of clinical-biological mismatches in a clinical sample of older adults with varying degrees of cognitive impairment. Methods: 204 participants were enrolled for a cross-sectional assessment and allocated into diagnostic groups: probable AD (n  = 60, 29.4%); MCI (n  = 84, 41.2%); or normal …cognition (NC, n  = 60, 29.4%). CSF concentrations of Aβ 42 , T-tau, and 181 Thr-P-tau were determined, and Aβ 42 /P-tau ratio below 9.53 was used as a proxy of AD pathology. The AT(N) classification was further used as a framework to ascertain the biological evidence of AD. Results: The majority (73.7%) of patients in the AD group had the Aβ 42 /P-tau ratio below the cut-off score for AD, as opposed to a smaller proportion in the MCI (42.9%) and NC (23.3%) groups. In the latter, 21 subjects (35%) were classified as A +, 28 (46.7%) as T +, and 23 (38.3%) as N + . In the AD group, 66.7%of the cases were classified as A +, 78.3%as T +, and 80%as N+. Conclusion: Analysis of CSF biomarkers was able to discriminate between AD, MCI, and NC. However, clinical-biological mismatches were observed in a non-negligible proportion of cases. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, dementia, mild cognitive impairment

DOI: 10.3233/JAD-210144

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Müller, Luisa | Kirschstein, Timo | Köhling, Rüdiger | Kuhla, Angela | Teipel, Stefan

Article Type: Research Article

Abstract: Transgenic mouse models serve a better understanding of Alzheimer’s disease (AD) pathogenesis and its consequences on neuronal function. Well-known and broadly used AD models are APPswe/PS1dE9 mice, which are able to reproduce features of amyloid-β (Aβ) plaque formations as well as neuronal dysfunction as reflected in electrophysiological recordings of neuronal hyperexcitability. The most prominent findings include abnormal synaptic function and synaptic reorganization as well as changes in membrane threshold and spontaneous neuronal firing activities leading to generalized excitation-inhibition imbalances in larger neuronal circuits and networks. Importantly, these findings in APPswe/PS1dE9 mice are at least partly consistent with results of electrophysiological …studies in humans with sporadic AD. This underscores the potential to transfer mechanistic insights into amyloid related neuronal dysfunction from animal models to humans. This is of high relevance for targeted downstream interventions into neuronal hyperexcitability, for example based on repurposing of existing antiepileptic drugs, as well as the use of combinations of imaging and electrophysiological readouts to monitor effects of upstream interventions into amyloid build-up and processing on neuronal function in animal models and human studies. This article gives an overview on the pathogenic and methodological basis for recording of neuronal hyperexcitability in AD mouse models and on key findings in APPswe/PS1dE9 mice. We point at several instances to the translational perspective into clinical intervention and observation studies in humans. We particularly focus on bi-directional relations between hyperexcitability and cerebral amyloidosis, including build-up as well as clearance of amyloid, possibly related to sleep and so called glymphatic system function. Show more

Keywords: Alzheimer’s disease, amyloid-β, APPswe/PS1dE9 mice, neuronal hyperexcitability, sleep-wake cycle

DOI: 10.3233/JAD-201540

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2021

Authors: Norins, Leslie C.

Article Type: Research Article

Abstract: Substantial evidence, composed of drug mechanisms of action, in vivo testing, and epidemiological data, exists to support clinical testing of FDA-approved drugs for repurposing to the treatment of Alzheimer’s disease (AD). Licensed compound investigation can often proceed at a faster and more cost-effective manner than un-approved compounds moving through the drug pipeline. As the prevalence of AD increases with life expectancy, the current rise in life expectancy amalgamated with the lack of an effective drug for the treatment of AD unnecessarily burdens our medical system and is an urgent public health concern. The unfounded reluctance to examine repurposing existing …drugs for possible AD therapy further impedes the possibility of improving the quality of patient lives with a terminal disease. This review summarizes some evidence which exists to suggest certain already-approved drugs may be considered for the treatment of AD and will perhaps encourage physicians to off-label prescribe these safe therapeutics. Show more

Keywords: Alzheimer’s disease, amyloid-β, amyloid-β protein precursor, cognitive dysfunction

DOI: 10.3233/JAD-210080

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Johnstone, Daniel M. | Hamilton, Catherine | Gordon, Luke C. | Moro, Cecile | Torres, Napoleon | Nicklason, Frank | Stone, Jonathan | Benabid, Alim-Louis | Mitrofanis, John

Article Type: Research Article

Abstract: In recent times, photobiomodulation has been shown to be beneficial in animal models of Parkinson’s disease, improving locomotive behavior and being neuroprotective. Early observations in people with Parkinson’s disease have been positive also, with improvements in the non-motor symptoms of the disease being evident most consistently. Although the precise mechanisms behind these improvements are not clear, two have been proposed: direct stimulation, where light reaches and acts directly on the distressed neurons, and remote stimulation, where light influences cells and/or molecules that provide systemic protection, thereby acting indirectly on distressed neurons. In relation to Parkinson’s disease, given that the major …zone of pathology lies deep in the brain and that light from an extracranial or external photobiomodulation device would not reach these vulnerable regions, stimulating the distressed neurons directly would require intracranial delivery of light using a device implanted close to the vulnerable regions. For indirect systemic stimulation, photobiomodulation could be applied to either the head and scalp, using a transcranial helmet, or to a more remote body part (e.g., abdomen, leg). In this review, we discuss the evidence for both the direct and indirect neuroprotective effects of photobiomodulation in Parkinson’s disease and propose that both types of treatment modality, when working together using both intracranial and extracranial devices, provide the best therapeutic option. Show more

Keywords: Animal models, behavior, mitochondrial activity, neuroprotection, neurotrophic factors

DOI: 10.3233/JAD-210052

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2021

Authors: Bernstein, John P.K. | Dorociak, Katherine E. | Mattek, Nora | Leese, Mira | Beattie, Zachary T. | Kaye, Jeffrey A. | Hughes, Adriana

Article Type: Research Article

Abstract: Background: Computer use is a cognitively complex instrumental activity of daily living (IADL) that has been linked to cognitive functioning in older adulthood, yet little work has explored its capacity to detect incident mild cognitive impairment (MCI). Objective: To examine whether routine home computer use (general computer use as well as use of specific applications) could effectively discriminate between older adults with and without MCI, as well as explore associations between use of common computer applications and cognitive domains known to be important for IADL performance. Methods: A total of 60 community-dwelling older adults (39 cognitively …healthy, 21 with MCI) completed a neuropsychological evaluation at study baseline and subsequently had their routine home computer use behaviors passively recorded for three months. Results: Compared to those with MCI, cognitively healthy participants spent more time using the computer, had a greater number of computer sessions, and had an earlier mean time of first daily computer session. They also spent more time using email and word processing applications, and used email, search, and word processing applications on a greater number of days. Better performance in several cognitive domains, but in particular memory and language, was associated with greater frequency of browser, word processing, search, and game application use. Conclusion: Computer and application use are useful in identifying older adults with MCI. Longitudinal studies are needed to determine whether decreases in overall computer use and specific computer application use are predictors of incident cognitive decline. Show more

Keywords: Aging, computer use, mild cognitive impairment, technology

DOI: 10.3233/JAD-210049

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Feldman, Robin

Article Type: Research Article

Abstract: Background: US direct-to-consumer advertising spending for medicine has soared in recent decades. Advertising has been shown to impact drug utilization. Most Alzheimer’s disease patients are above age 65 and may take a range of prescription medications for various disease states. Objective: To investigate how direct-to-consumer advertising is associated with the drug utilization of patients ≥65 years old. Methods: Using advertising expenditure data and Medicare Part D drug purchase claims, we performed regression analyses for each of the highest-spending drugs and age group, with cumulative monthly spending as the predictor variable and drug utilization as the response …variable. For each drug, we ran a second set of regression analyses to determine if the spending-utilization correlation showed a significant difference between the two patient age groups (older than 65, younger than 65). Results: For all 14 drugs in our study, advertising spending is positively correlated with utilization (p  <  0.01) in both age groups. For seven of the 14 drugs studied, the difference in the utilization of patients older than 65 and the utilization of patients younger than 65 is statistically significant at a p  <  0.01 level. The 65-and-older age bracket exhibits significantly greater utilization for all seven of these drugs. Conclusion: We find televised advertising for certain drugs to be associated with significantly stronger drug utilization among seniors, as compared to younger patients. Alzheimer’s disease physicians should be aware of this result, in light of the medications that patients may take for other disease states, particularly mood and mental health medications. Show more

Keywords: Aged, direct-to-consumer advertising, drug utilization, health services for the aged, prescription drugs, public health, television

DOI: 10.3233/JAD-210294

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Beuckmann, Carsten T. | Suzuki, Hiroyuki | Musiek, Erik S. | Ueno, Takashi | Sato, Toshitaka | Bando, Masahiro | Osada, Yoshihide | Moline, Margaret

Article Type: Research Article

Abstract: Background: Many patients with Alzheimer’s disease (AD) display circadian rhythm and sleep-wake disturbances. However, few mouse AD models exhibit these disturbances. Lemborexant, a dual orexin receptor antagonist, is under development for treating circadian rhythm disorders in dementia. Objective: Evaluation of senescence-accelerated mouse prone-8 (SAMP8) mice as a model for sleep-wake and rhythm disturbances in AD and the effect of lemborexant by assessing sleep-wake/diurnal rhythm behavior. Methods: SAMP8 and control senescence-accelerated mouse resistant-1 (SAMR1) mice received vehicle or lemborexant at light onset; plasma lemborexant and diurnal cerebrospinal fluid (CSF) orexin concentrations were assessed. Sleep-wake behavior and running …wheel activity were evaluated. Results: Plasma lemborexant concentrations were similar between strains. The peak/nadir timing of CSF orexin concentrations were approximately opposite between strains. During lights-on, SAMP8 mice showed less non-rapid eye movement (non-REM) and REM sleep than SAMR1 mice. Lemborexant treatment normalized wakefulness/non-REM sleep in SAMP8 mice. During lights-off, lemborexant-treated SAMR1 mice showed increased non-REM sleep; lemborexant-treated SAMP8 mice displayed increased wakefulness. SAMP8 mice showed differences in electroencephalogram architecture versus SAMR1 mice. SAMP8 mice exhibited more running wheel activity during lights-on. Lemborexant treatment reduced activity during lights-on and increased activity in the latter half of lights-off, demonstrating a corrective effect on overall diurnal rhythm. Lemborexant delayed the acrophase of activity in both strains by approximately 1 hour. Conclusion: SAMP8 mice display several aspects of sleep-wake and rhythm disturbances in AD, notably mistimed activity. These findings provide some preclinical rationale for evaluating lemborexant in patients with AD who experience sleep-wake and rhythm disturbances. Show more

Keywords: Alzheimer’s disease, animal models, dual orexin receptor antagonist, E2006, in vivo , irregular sleep-wake rhythm disorder, lemborexant, mouse, orexin, running wheel, sleep

DOI: 10.3233/JAD-201054

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2021

Authors: Li, Jennifer | Bur, Andres M. | Villwock, Mark R. | Shankar, Suraj | Palmer, Gracie | Sykes, Kevin J. | Villwock, Jennifer A.

Article Type: Research Article

Abstract: Background: Olfactory dysfunction (OD) is an early symptom of Alzheimer’s disease (AD). However, olfactory testing is not commonly performed to test OD in the setting of AD. Objective: This work investigates objective OD as a non-invasive biomarker for accurately classifying subjects as cognitively unimpaired (CU), mild cognitive impairment (MCI), and AD. Methods: Patients with MCI (n  = 24) and AD (n  = 24), and CU (n  = 33) controls completed two objective tests of olfaction (Affordable, Rapid, Olfactory Measurement Array –AROMA; Sniffin’ Sticks Screening 12 Test –SST12). Demographic and subjective sinonasal and olfaction symptom information was also obtained. Analyses …utilized traditional statistics and machine learning to determine olfactory variables, and combinations of variables, of importance for differentiating normal and disease states. Results: Inability to correctly identify a scent after detection was a hallmark of MCI/AD. AROMA was superior to SST12 for differentiating MCI from AD. Performance on the clove scent was significantly different between all three groups. AROMA regression modeling yielded six scents with AUC of the ROC of 0.890 (p  <  0.001). Random forest model machine learning algorithms considering AROMA olfactory data successfully predicted MCI versus AD disease state. Considering only AROMA data, machine learning algorithms were 87.5%accurate (95%CI 0.4735, 0.9968). Sensitivity and specificity were 100%and 75%, respectively with ROC of 0.875. When considering AROMA and subject demographic and subjective data, the AUC of the ROC increased to 0.9375. Conclusion: OD differentiates CUs from those with MCI and AD and can accurately predict MCI versus AD. Leveraging OD data may meaningfully guide management and research decisions. Show more

Keywords: Alzheimer’s disease, machine learning, mild cognitive impairment, olfaction, olfactory dysfunction

DOI: 10.3233/JAD-210175

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Damron, Lisa | Litvan, Irene | Bayram, Ece | Berk, Sarah | Siddiqi, Bernadette | Shill, Holly

Article Type: Research Article

Abstract: Background: Hispanics are under-represented in Parkinson’s disease (PD) research despite the importance of diversity for results to apply to a wide range of patients. Objective: To investigate the perspective of Hispanic persons with Parkinson disease (PWP) regarding awareness, interest, and barriers to participation in research. Methods: We developed and administered a survey and qualitative interview in English and Spanish. For the survey, 62 Hispanic and 38 non-Hispanic PWP linked to a tertiary center were recruited in Arizona. For interviews, 20 Hispanic PWP, 20 caregivers, and six physicians providing service to Hispanic PWP in the community were …recruited in California. Survey responses of Hispanic and non-Hispanic PWP were compared. Major survey themes were identified by applying grounded theory and open coding. Results: The survey found roughly half (Q1 54%, Q2 55%) of Hispanic PWP linked to a tertiary center knew about research; there was unawareness among community Hispanic PWP. Most preferred having physician recommendations for research participation and were willing to participate. Hispanics preferred teams who speak their native language and include family. Research engagement, PD knowledge, role of family, living with PD, PD care, pre-diagnosis/diagnosis emerged as themes from the interview. Conclusion: Barriers exist for participation of Hispanic PWP in research, primarily lack of awareness of PD research opportunities. Educating physicians of the need to encourage research participation of Hispanic PWP can address this. Physicians need to be aware of ongoing research and should not assume PWP disinterest. Including family members and providing research opportunities in their native language can increase research recruitment. Show more

Keywords: Health services research, hispanic, minority health, Parkinson’s disease, research access, research barriers

DOI: 10.3233/JAD-210231

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Michaelian, Johannes C. | Duffy, Shantel L. | Mowszowski, Loren | Guastella, Adam J. | McCade, Donna | McKinnon, Andrew C. | Naismith, Sharon L.

Article Type: Research Article

Abstract: Background: Older adults living with amnestic mild cognitive impairment (aMCI) not only demonstrate impairments in Theory of Mind (ToM), relative to adults with non-amnestic MCI (naMCI), but are also at a higher risk of developing dementia. Objective: Our primary objective was to ascertain whether default mode network (DMN) functional connectivity was differentially associated with ToM abilities between MCI subgroups. Methods: Using functional magnetic resonance imaging, we investigated alterations in resting-state functional connectivity within the brain’s DMN in a sample of 43 older adults with aMCI (n  = 19) and naMCI (n  = 24), previously reported to demonstrate poorer …ToM abilities. Results: Compared to naMCI, the aMCI subgroup revealed a significant association between poorer ToM performance and reduced functional connectivity between the bilateral temporal pole (TempP) and the left lateral temporal cortex (LTC) (LTC_L-TempP_L : b  = –0.06, t(33) = –3.53, p  = 0.02; LTC_L-TempP_R : b  = –0.07,t(33) = –3.20, p  = 0.03); between the right TempP and the dorsal medial prefrontal cortex (dMPFC) (b  = –0.04, t(33) = –3.02, p  = 0.03) and between the left and right TempP (b  = –0.05, t(33) = –3.26, p  = 0.03). In the naMCI subgroup, the opposite relationship was present between the bilateral TempP and the left LTC (Combined correlation: r  = –0.47, p  = 0.02), however, not between the right TempP and the dMPFC (r  = –0.14, p  = 0.51) or the left and right TempP (r  = –0.31, p  = 0.14). Conclusion: Our findings suggest that alterations in functional connectivity within the DMN involving temporal and frontal lobe regions are associated with ToM deficits in aMCI. Show more

Keywords: Amnestic mild cognitive impairment, default mode network, functional connectivity, functional magnetic resonance imaging, theory of mind

DOI: 10.3233/JAD-201284

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Sakurai, Keita | Kaneda, Daita | Inui, Shohei | Uchida, Yuto | Morimoto, Satoru | Nihashi, Takashi | Kato, Takashi | Ito, Kengo | Hashizume, Yoshio

Article Type: Research Article

Abstract: Background: The differentiation of Alzheimer’s disease (AD) from age-related limbic tauopathies (LT), including argyrophilic grain disease (AGD) and senile dementia of the neurofibrillary tangle type (SD-NFT), is often challenging because specific clinical diagnostic criteria have not yet been established. Despite the utility of specific biomarkers evaluating amyloid and tau to detect the AD-related pathophysiological changes, the expense and associated invasiveness preclude their use as first-line diagnostic tools for all demented patients. Therefore, less invasive and costly biomarkers would be valuable in routine clinical practice for the differentiation of AD and LT. Objective: The purpose of this study is …to develop a simple reproducible method on magnetic resonance imaging (MRI) that could be adopted in daily clinical practice for the differentiation of AD and other forms of LT. Methods: Our newly proposed three quantitative indices and well-known medial temporal atrophy (MTA) score were evaluated using MRI of pathologically-proven advanced-stage 21 AD, 10 AGD, and 2 SD-NFT patients. Results: Contrary to MTA score, hippocampal angle (HPA), inferior horn area (IHA), and ratio between HPA and IHA (i.e., IHPA index) demonstrated higher diagnostic performance and reproducibility, especially to differentiate advanced-stage AD patients with Braak neurofibrillary tangle stage V/VI from LT patients (the area under the receiver-operating-characteristic curve of 0.83, 089, and 0.91; intraclass correlation coefficients of 0.930, 0.998, and 0.995, respectively). Conclusion: Quantitative indices reflecting hippocampal deformation with ventricular enlargement are useful to differentiate advanced-stage AD from LT. This simple and convenient method could be useful in daily clinical practice. Show more

Keywords: Alzheimer’s disease, argyrophilic grain disease, hippocampal angle, limbic tauopathy, magnetic resonance imaging, senile dementia of the neurofibrillary tangle type, ventricular enlargement

DOI: 10.3233/JAD-210043

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Article Type: Research Article

DOI: 10.3233/JAD-219318

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-1, 2021

Authors: Habeych, Miguel E. | Falcone, Tatiana | Dagar, Anjali | Ford, Lisa | Castilla-Puentes, Ruby

Article Type: Research Article

Abstract: Background: Seizure disorders have been identified in patients suffering from different types of dementia. However, the risks associated with the seizure subtypes have not been characterized. Objective: To compare the occurrence and risk of various seizure subtypes (focal and generalized) between patients with and without a dementia diagnosis. Methods: Data from 40.7 million private insured patient individual electronic health records from the U.S., were utilized. Patients 60 years of age or more from the Optum Insight Clinformatics-data Mart database were included in this study. Using ICD-9 diagnoses, the occurrence of generalized or focal seizure disorders was …identified. The risk of new-onset seizures and the types of seizures associated with a dementia diagnosis were estimated in a cohort of 2,885,336 patients followed from 2005 to 2014. Group differences were analyzed using continuity-adjusted chi-square and hazard ratios with 95%confidence intervals calculated after a logistic regression analysis Results: A total of 79,561 patient records had a dementia diagnosis, and 56.38%of them were females. Patients with dementia when compared to those without dementia had higher risk for seizure disorders [Hazard ratio (HR) = 6.5 95%CI = 4.4–9.5]; grand mal status (HR = 6.5, 95%CI = 5.7–7.3); focal seizures (HR = 6.0, 95%CI = 5.5–6.6); motor simple focal status (HR = 5.6, 95%CI = 3.5–9.0); epilepsy (HR = 5.0, 95%CI = 4.8–5.2); generalized convulsive epilepsy (HR = 4.8, 95%CI = 4.5–5.0); localization-related epilepsy (HR = 4.5, 95%CI = 4.1–4.9); focal status (HR = 4.2, 95%CI = 2.9–6.1); and fits convulsions (HR = 3.5, 95%CI = 3.4–3.6). Conclusion: The study confirms that patients with dementia have higher risks of generalized or focal seizure than patients without dementia. Show more

Keywords: Databases, dementia, epilepsy, new-onset seizures

DOI: 10.3233/JAD-210028

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2021

Authors: Tsamou, Maria | Pistollato, Francesca | Roggen, Erwin L.

Article Type: Research Article

Abstract: The worldwide prevalence of sporadic (late-onset) Alzheimer’s disease (sAD) is dramatically increasing. Aging and genetics are important risk factors, but systemic and environmental factors contribute to this risk in a still poorly understood way. Within the frame of BioMed21, the Adverse Outcome Pathway (AOP) concept for toxicology was recommended as a tool for enhancing human disease research and accelerating translation of data into human applications. Its potential to capture biological knowledge and to increase mechanistic understanding about human diseases has been substantiated since. In pursuit of the tau-cascade hypothesis, a tau-driven AOP blueprint toward the adverse outcome of memory loss …is proposed. Sequences of key events and plausible key event relationships, triggered by the bidirectional relationship between brain cholesterol and glucose dysmetabolism, and contributing to memory loss are captured. To portray how environmental factors may contribute to sAD progression, information on chemicals and drugs, that experimentally or epidemiologically associate with the risk of AD and mechanistically link to sAD progression, are mapped on this AOP. The evidence suggests that chemicals may accelerate disease progression by plugging into sAD relevant processes. The proposed AOP is a simplified framework of key events and plausible key event relationships representing one specific aspect of sAD pathology, and an attempt to portray chemical interference. Other sAD-related AOPs (e.g., Aβ-driven AOP) and a better understanding of the impact of aging and genetic polymorphism are needed to further expand our mechanistic understanding of early AD pathology and the potential impact of environmental and systemic risk factors. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, environmental impact, memory loss, neurotoxicity, tauopathy

DOI: 10.3233/JAD-201418

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-27, 2021

Authors: Halminen, Olli | Vesikansa, Aino | Mehtälä, Juha | Hörhammer, Iiris | Mikkola, Teija | Virta, Lauri J. | Ylisaukko-oja, Tero | Linna, Miika

Article Type: Research Article

Abstract: Background: Dementia is one of the strongest predictors of admission to a 24-hour care facility among older people, and 24-hour care is the major cost of Alzheimer’s disease (AD). Objective: The aim of this study was to evaluate the association of early start of anti-dementia medication and other predisposing factors with 2-year risk of transition to 24-hour care in the nationwide cohort of Finnish AD patients. Methods: This was a retrospective, non-interventional study based on individual-level data from Finnish national health and social care registers. The incident cohort included 7,454 AD patients (ICD-10, G30) comprised of …two subgroups: those living unassisted at home (n  = 5,002), and those receiving professional home care (n  = 2,452). The primary outcome was admission to a 24-hour care facility. Exploratory variables were early versus late anti-dementia medication start, sociodemographic variables, care intensity level, and comorbidities. Results: Early anti-dementia medication reduced the risk of admission to 24-hour care both in patients living unassisted at home, with a hazard ratio (HR) of 0.58 (p  <  0.001), and those receiving professional home care (HR, 0.84; p  = 0.039). Being unmarried (HR, 1.69; p  <  0.001), having an informal caregiver (HR, 1.69; p  = 0.003), or having a diagnosis of additional neurological disorder (HR, 1.68; p  = 0.006) or hip fracture (HR, 1.61; p  = 0.004) were associated with higher risk of admission to 24-hour care in patients living unassisted at home. Conclusion: To support living at home, early start of anti-dementia medication should be a high priority in newly diagnosed AD patients. Show more

Keywords: Alzheimer’s disease, cholinesterase inhibitors, dementia, finland, healthcare, institutionalization, memantine, nursing homes, register

DOI: 10.3233/JAD-201502

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Eeza, Muhamed N.H. | Singer, Rico | Höfling, Corinna | Matysik, Jörg | de Groot, Huub J.M. | Roβner, Steffen | Alia, A.

Article Type: Research Article

Abstract: Background: Circadian rhythm disturbance is commonly observed in Alzheimer’s disease (AD). In mammals, these rhythms are orchestrated by the superchiasmatic nucleus (SCN). Our previous study in the Tg2576 AD mouse model suggests that inflammatory responses, most likely manifested by low GABA production, may be one of the underlying perpetrators for the changes in circadian rhythmicity and sleep disturbance in AD. However, the mechanistic connections between SCN dysfunction, GABA modulation, and inflammation in AD is not fully understood. Objective: To reveal influences of amyloid pathology in Tg2576 mouse brain on metabolism in SCN and to identify key metabolic sensors …that couple SCN dysfunction with GABA modulation and inflammation. Methods: High resolution magic angle spinning (HR-MAS) NMR in conjunction with multivariate analysis was applied for metabolic profiling in SCN of control and Tg2576 female mice. Immunohistochemical analysis was used to detect neurons, astrocytes, expression of GABA transporter 1 (GAT1) and Bmal1 . Results: Metabolic profiling revealed significant metabolic deficits in SCN of Tg2576 mice. Reductions in glucose, glutamate, GABA, and glutamine provide hints toward an impaired GABAergic glucose oxidation and neurotransmitter cycling in SCN of AD mice. In addition, decreased redox co-factor NADPH and glutathione support a redox disbalance. Immunohistochemical examinations showed low expression of the core clock gene, Bmal1 , especially in activated astrocytes. Moreover, decreased expression of GAT1 in astrocytes indicates low GABA recycling in this cell type. Conclusion: Our results suggest that redox disbalance and compromised GABA signaling are important denominators and connectors between neuroinflammation and clock dysfunction in AD. Show more

Keywords: Alzheimer’s disease, GABA dysfunction, 1H high-resolution magic angle spinning NMR, metabolic deficit, suprachiasmatic nucleus, Tg2576 mouse model

DOI: 10.3233/JAD-201575

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Wang, Ziqi | Zhang, Yige | Dong, Li | Zheng, Zihao | Zhong, Dayong | Long, Xunqin | Cai, Qingyan | Jian, Wei | Zhang, Songge | Wu, Wenbin | Yao, Dezhong

Article Type: Research Article

Abstract: Background: Given that there is no specific drug to treat Alzheimer’s disease, non-pharmacologic interventions in people with subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI) are one of the most important treatment strategies. Objective: To clarify the efficacy of blue-green (500 nm) light therapy on sleep, mood, and physiological parameters in patients with SCD and aMCI is an interesting avenue to explore. Methods: This is a monocentric, randomized, and controlled trial that will last for 4 weeks. We will recruit 150 individuals aged 45 years or older from memory clinics and divide them into 5 …groups: SCD treatment (n  = 30), SCD control (n  = 30), aMCI treatment (n  = 30), aMCI control (n  = 30), and a group of healthy adult subjects (n  = 30) as a normal control (NC). Results: The primary outcome is the change in subjective and objective cognitive performance between baseline and postintervention visits (4 weeks after baseline). Secondary outcomes include changes in performance assessing from baseline, postintervention to follow-up (3 months after the intervention), as well as sleep, mood, and physiological parameters (including blood, urine, electrophysiology, and neuroimaging biomarkers). Conclusion: This study aims to provide evidence of the impact of light therapy on subjective and objective cognitive performance in middle-aged and older adults with SCD or aMCI. In addition, we will identify possible neurophysiological mechanisms of action underlying light therapy. Overall, this trial will contribute to the establishment of light therapy in the prevention of Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, low-level light therapy, non-pharmacologic interventions, phototherapy

DOI: 10.3233/JAD-201560

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2021

Authors: Mizuno, Akiko | Karim, Helmet T. | Ly, Maria J. | Cohen, Ann D. | Lopresti, Brian J. | Mathis, Chester A. | Klunk, William E. | Aizenstein, Howard J. | Snitz, Beth E.

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) may be an early manifestation of pre-clinical Alzheimer’s disease. Elevated amyloid-β (Aβ) is a correlate of SCD symptoms in some individuals. The underlying neural correlates of SCD symptoms and their association with Aβ is unknown. SCD is a heterogeneous condition, and cognitive reserve may explain individual differences in its neural correlates. Objective: We investigated the association between brain activation during memory encoding and SCD symptoms, as well as with Aβ, among older individuals. We also tested the moderating role of education (an index of cognitive reserve) on the associations. Methods: We …measured brain activation during the “face-name” memory-encoding fMRI task and Aβ deposition with Pittsburgh Compound-B (PiB)-PET among cognitively normal older individuals (n = 63, mean age 73.1 ± 7.4 years). We tested associations between activation and SCD symptoms by self-report measures, Aβ, and interactions with education. Results: Activation was not directly associated with SCD symptoms or Aβ. However, education moderated the association between activation and SCD symptoms in the executive control network, salience network, and subcortical regions. Greater SCD symptoms were associated with greater activation in those with higher education, but with lower activation in those with lower education. Conclusion: SCD symptoms were associated with different patterns of brain activation in the extended memory system depending on level of cognitive reserve. Greater SCD symptoms may represent a saturation of neural compensation in individuals with greater cognitive reserve, while it may reflect diminishing neural resources in individuals with lower cognitive reserve. Show more

Keywords: Amyloid, cognitive reserve, functional MRI, PiB-PET, preclinical dementia, subjective cognitive decline

DOI: 10.3233/JAD-201087

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Wan Suh, Seung | Kim, You Joung | Kwak, Kyung Phil | Kim, Kiwon | Kim, Moon-Doo | Kim, Byung-Soo | Jo Kim, Bong | Gyeom Kim, Shin | Kim, Jeong Lan | Kim, Tae Hui | Moon, Seok Woo | Park, Kyung Won | Park, Jong-Il | Park, Joon Hyuk | Bae, Jae Nam | Seo, Jiyeong | Seong, Su Jeong | Son, Sang Joon | Shin, Il-Seon | Ryu, Seung-Ho | Lee, Kang Joon | Lee, Nam-Jin | Lee, Dong Young | Lee, Dong Woo | Lee, Seok Bum | Lee, Chang Uk | Chang, Sung Man | Jeong, Hyun-Ghang | Cho, Maeng Je | Cho, Seong-Jin | Jhoo, Jin Hyeong | Choe, Young Min | Han, Ji Won | Kim, Ki Woong

Article Type: Research Article

Abstract: Background: In many high-income Western countries, the prevalence of dementia had been reduced over the past decades. Objective: We investigated whether the prevalence of all-cause dementia, Alzheimer’s disease, vascular dementia, and mild cognitive impairment (MCI) had changed in Korea from 2008 to 2017. Methods: Nationwide Survey on Dementia Epidemiology of Korea (NaSDEK) in 2008 and 2017 was conducted on representative elderly populations that were randomly sampled across South Korea. Both surveys employed a two-stage design (screening and diagnostic phases) and diagnosed dementia and MCI according to the fourth edition of the Diagnostic and Statistical Manual of …Mental Disorders and the consensus criteria from the International Working Group, respectively. The numbers of participants aged 65 years or older in the screening and diagnostic phases were 6,141 and 1,673 in the NaSDEK 2008 and 2,972 and 474 in the NaSDEK 2017, respectively. Results: The age- and sex-standardized prevalence of all-cause dementia and Alzheimer’s disease showed nonsignificant decrease (12.3% to 9.8%, odds ratio [OR] = 0.89, 95% confidence interval [CI] = 0.54–1.48 for all-cause dementia; 7.6% to 6.8%, OR [95% CI] = 0.91 [0.58–1.42] for Alzheimer’s disease). Vascular dementia decreased in the young-old population aged less than 75 years (2.7% to 0.001%, OR [95% CI] = 0.04 [0.01–0.15]) and in women (1.9% to 0.5%, OR [95% CI] = 0.27 [0.10–0.72]) while MCI remained stable (25.3% to 26.2%, OR [95% CI] = 1.08 [0.67–1.73]). Conclusion: We found that the prevalence of dementia in Korea showed a nonsignificant decrease between 2008 and 2017. Show more

Keywords: Alzheimer’s disease, dementia, mild cognitive impairment, prevalence, vascular dementia

DOI: 10.3233/JAD-201588

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Williams, Victoria J. | Carlsson, Cynthia M. | Fischer, Anne | Johnson, Sterling C. | Lange, Kate | Partridge, Eileen | Roan, Carol | Asthana, Sanjay | Herd, Pamela

Article Type: Research Article

Abstract: Background: There is growing consensus that non-genetic determinants of dementia can be linked to various risk- and resiliency-enhancing factors accumulating throughout the lifespan, including socioeconomic conditions, early life experiences, educational attainment, lifestyle behaviors, and physical/mental health. Yet, the causal impact of these diverse factors on dementia risk remain poorly understood due to few longitudinal studies prospectively characterizing these influences across the lifespan. Objective: The Initial Lifespan’s Impact on Alzheimer’s Disease and Related Dementia (ILIAD) study aims to characterize dementia prevalence in the Wisconsin Longitudinal Study (WLS), a 60-year longitudinal study documenting life course trajectories of educational, family, occupational, …psychological, cognitive, and health measures. Methods: Participants are surveyed using the modified Telephone Interview for Cognitive Status (TICS-m) to identify dementia risk. Those scoring below cutoff undergo home-based neuropsychological, physical/neurological, and functional assessments. Dementia diagnosis is determined by consensus panel and merged with existing WLS data for combined analysis. Results: Preliminary findings demonstrate the initial success of the ILIAD protocol in detecting dementia prevalence in the WLS. Increasing age, hearing issues, lower IQ, male sex, APOE4 positivity, and a steeper annualized rate of memory decline assessed in the prior two study waves, all increased likelihood of falling below the TICS-m cutoff for dementia risk. TICS-m scores significantly correlated with standard neuropsychological performance and functional outcomes. Conclusion: We provide an overview of the WLS study, describe existing key lifespan variables relevant to studies of dementia and cognitive aging, detail the current WLS-ILIAD study protocol, and provide a first glimpse of preliminary study findings. Show more

Keywords: Alzheimer’s disease, dementia, epidemiologic determinants, health risk behaviors, prevalence

DOI: 10.3233/JAD-201422

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2021

Authors: Roβmeier, Carola | Hartmann, Julia | Riedl, Lina | Dorn, Bianca | Fischer, Julia | Hartmann, Florentine | Egert-Schwender, Silvia | Kehl, Victoria | Schneider-Schelte, Helga | Jox, Ralf J. | Dinkel, Andreas | Diehl-Schmid, Janine

Article Type: Research Article

Abstract: Background: End of life symptoms and symptom management as well as the quality of dying (QoD) of persons with advanced dementia (PWAD) have not yet been systematically studied in Germany. Objective: 1) To investigate symptoms, treatment and care at the end of life, advance care planning, and circumstances of death of recently deceased PWAD; 2) To determine whether there are differences between young and late onset dementia (YOD and LOD). Methods: The study was performed in the context of the project EPYLOGE (IssuE s in P alliative care for persons in advanced and terminal stages of …Y oung-onset and L ate-O nset dementia in Ge rmany). Closest relatives of recently deceased patients with advanced YOD (N = 46) and LOD (N = 54) living at home or in long term care were interviewed. Results: Circumstances of death, symptoms, and treatment appeared to be similar between YOD and LOD, except that persons with LOD had significantly more somatic comorbidities and were admitted to hospital in the last three months of life more often than persons with LOD. At end of life, 60%of PWAD appeared to be “at peace”. Difficulty swallowing, gurgling, shortness of breath, and discomfort were observed most frequently. Large interindividual differences in suffering and QoD were present. Determinants of QoD were not identified. Conclusion: Our findings suggest that low QoD was caused by inadequate recognition and/or insufficient treatment of burdensome physical and emotional symptoms. PWADs’ needs should be assessed regularly, and strategies focusing on treatment and implementing support for both the patient and caregiver must be established. Show more

Keywords: Dementia, end-of-life symptoms, home care, late onset dementia, long term care, palliative care, quality of dying, young onset dementia

DOI: 10.3233/JAD-210046

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Marra, Camillo | Piccininni, Chiara | Iacobucci, Giovanna Masone | Caprara, Alessia | Gainotti, Guido | Maria Costantini, Emanuele | Callea, Antonio | Venneri, Annalena | Quaranta, Davide

Article Type: Research Article

Abstract: Background: The assessment of semantic memory may be a useful marker to identify individuals with mild cognitive impairment (MCI) who will progress to Alzheimer’s disease (AD) in the early stages of the disease. Objective: The aim of this five-year follow-up longitudinal study is to assess whether semantic assessment could predict progression in MCI. Methods: A population of MCI (N = 251); mild (N = 178) and moderate AD (N = 114); and a sample of healthy participants (HP; N = 262) was investigated. The five-year follow-up of the MCI group was completed by 178 patients. Semantic and episodic memory measures were used, including a …measure of the discrepancy between categorical and phonological verbal fluency, the semantic–phonological delta (SPD). The main outcome was the progression of MCI due to AD to dementia. Results: A general linear model showed a significant effect of diagnosis on SPD (Wilks’ Lambda = 0.591; p  <  0.001). The estimated marginal means were –0.91 (SE = 0.185) in HP, –1.83 (SE = 0.187) in MCI, –1.16 (SE = 0.218) in mild AD, and –1.02 (SE = 0.275) in moderate AD. Post-hoc comparisons showed a significant difference between MCI and HP (p  <  0.001). The follow-up was completed by 178 MCI individuals. SPD in MCI patients who progress to dementia was significantly lower than in MCI that will not progress (p  = 0.003). Together with the Mini-Mental State Examination, the SPD was the only measure with a significant predicting effect at the five-years follow-up (p  = 0.016). Conclusion: The SPD indicate the impairment of semantic memory in individuals with underlying AD at the MCI early stage, reflecting the early involvement of perirhinal and entorhinal cortices in the earliest stages of AD neuropathological process. Show more

Keywords: Alzheimer’s disease, category fluency task, memory, mild cognitive impairment

DOI: 10.3233/JAD-201452

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Hashimoto, Makoto | Ho, Gilbert | Sugama, Shuei | Takenouchi, Takato | Waragai, Masaaki | Sugino, Hiromu | Inoue, Satoshi | Masliah, Eliezer

Article Type: Research Article

Abstract: Accumulating evidence suggests that the adiponectin (APN) paradox might be involved in promoting aging-associated chronic diseases such as Alzheimer’s disease (AD). In human brain, APN regulation of the evolvability of amyloidogenic proteins (APs), including amyloid-β (Aβ) and tau, in developmental/reproductive stages, might be paradoxically manifest as APN stimulation of AD through antagonistic pleiotropy in aging. The unique mechanisms underlying APN activity remain unclear, a better understanding of which might provide clues for AD therapy. In this paper, we discuss the possible relevance of activin, a member of transforming growth factor β (TGFβ) superfamily of peptides, to antagonistic pleiotropy effects of …APN. Notably, activin, a multiple regulator of cell proliferation and differentiation, as well as an endocrine modulator in reproduction and an organizer in early development, might promote aging-associated disorders, such as inflammation and cancer. Indeed, serum activin, but not serum TGFβ increases during aging. Also, activin/TGFβ signal through type II and type I receptors, both of which are transmembrane serine/threonine kinases, and the serine/threonine phosphorylation of APs, including Aβ 42 serine 8 and αS serine 129, may confer pathological significance in neurodegenerative diseases. Moreover, activin expression is induced by APN in monocytes and hepatocytes, suggesting that activin might be situated downstream of the APN paradox. Finally, a meta-analysis of genome-wide association studies demonstrated that two SNPs relevant to the activin/TGFβ receptor signaling pathways conferred risk for major aging-associated disease. Collectively, activin might be involved in the APN paradox of AD and could be a significant therapeutic target. Show more

Keywords: Activin, adiponectin paradox, Alzheimer’s disease, amyloidogenic proteins, antagonistic pleiotropy, evolvability, transforming growth factor β

DOI: 10.3233/JAD-210206

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2021

Authors: Taylor, Morag E. | Toots, Annika | Lord, Stephen R. | Payne, Narelle | Close, Jacqueline C.T.

Article Type: Research Article

Abstract: Background: In older people with cognitive impairment (CI), executive function (EF) has been associated with motor performance including balance and gait. The literature examining and supporting a relationship between balance performance and other cognitive domains is limited. Objective: To investigate the relationship between global cognition and cognitive domain function and balance performance in older people with CI. Methods: The iFOCIS randomized controlled trial recruited 309 community-dwelling older people with CI. Baseline assessments completed before randomization were used for analyses including the Addenbrooke’s Cognitive Examination-III (ACE-III; global cognition) and its individual cognitive domains (attention; memory; verbal …fluency; language; visuospatial ability) and the Frontal Assessment Battery (FAB), a measure of EF. A composite balance score was derived from postural sway and leaning balance tests. Results: In linear regression analyses adjusted for covariates, global cognition and each cognitive domain were significantly associated with balance performance. EF (verbal fluency; β= –0.254, p  <  0.001, adjusted R2  = 0.387) and visuospatial ability (β= –0.258, p  <  0.001, adjusted R2  = 0.391) had the strongest associations with balance performance. In a comprehensively adjusted multivariable model including all of the ACE-III cognitive domains, visuospatial ability and EF (verbal fluency) were independently and significantly associated with balance performance. Conclusion: Poorer global cognition and cognitive domain function were associated with poorer balance performance in this sample of people with CI. Visuospatial ability and EF were independently associated with balance, highlighting potential shared neural networks and the role higher-level cognitive processes and spatial perception/processing play in postural control. Show more

Keywords: Aged, cognition, dementia, executive function, postural control, visuospatial

DOI: 10.3233/JAD-201325

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Halaas, Nathalie Bodd | Zetterberg, Henrik | Idland, Ane-Victoria | Knapskog, Anne-Brita | Watne, Leiv Otto | Blennow, Kaj

Article Type: Research Article

Abstract: Background: Delirium is associated with an increased risk of incident dementia and accelerated progression of existing cognitive symptoms. Reciprocally, dementia increases the risk of delirium. Cerebrospinal fluid (CSF) concentration of the dendritic protein neurogranin has been shown to increase in early Alzheimer’s disease (AD), likely reflecting synaptic dysfunction and/or degeneration. Objective: To elucidate the involvement of synaptic dysfunction in delirium pathophysiology, we tested the association between CSF neurogranin concentration and delirium in hip fracture patients with different AD-biomarker profiles, while comparing them to cognitively unimpaired older adults (CUA) and AD patients. Methods: The cohort included hip …fracture patients with (n  = 70) and without delirium (n  = 58), CUA undergoing elective surgery (n  = 127), and AD patients (n  = 46). CSF was collected preoperatively and diagnostically in surgery and AD patients respectively. CSF neurogranin concentrations were analyzed in all samples with an in-house ELISA. Delirium was assessed pre-and postoperatively in hip fracture patients by trained investigators using the Confusion Assessment Method. Hip fracture patients were further stratified based on pre-fracture dementia status, delirium subtype, and AD fluid biomarkers. Results: No association was found between delirium and CSF neurogranin concentration (main analysis: delirium versus no delirium, p  = 0.68). Hip fracture patients had lower CSF neurogranin concentration than AD patients (p  = 0.001) and CUA (p  = 0.035) in age-adjusted sensitivity analyses. Conclusion: The findings suggest that delirium is not associated with increased CSF neurogranin concentration in hip fracture patients, possibly due to advanced neurodegenerative disease and age and/or because synaptic degeneration is not an important pathophysiological process in delirium. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid proteins, delirium, neurotransmitter agents

DOI: 10.3233/JAD-201341

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Beydoun, May A. | Hossain, Sharmin | MacIver, Peter H. | Srinivasan, Dhivya | Beydoun, Hind A. | Maldonado, Ana I. | Katzel, Leslie I. | Davatzikos, Christos | Gullapalli, Rao P. | Seliger, Stephen L. | Erus, Guray | Evans, Michele K. | Zonderman, Alan B. | Waldstein, Shari R.

Article Type: Research Article

Abstract: Background: Anemia and red cell distribution width (RDW) have been linked to poor cognitive performance, pending studies of underlying mechanisms. Objective: We examined cross-sectional relationships of initial RDW status (v1 ), RDW change (δ ), and anemia with brain structural magnetic resonance imaging (sMRI) markers, including global and cortical brain and hippocampal and white matter lesion (WML) volumes, 5–6 years later. Methods: Data were used from three prospective visits within the Healthy Aging in Neighborhoods of Diversity Across the Life Span (HANDLS) study with complete v1 (2004–2009) and v2 (2009–2013) exposures and ancillary sMRI …data at vscan (2011–2015, n  = 213, mean v1 to vscan time: 5.7 years). Multivariable-adjusted linear regression models were conducted, overall, by sex, by race, and within non-anemics, correcting for multiple testing with q-values. Results: In minimally adjusted models (socio-demographics and follow-up time), anemiav1 and RDWv1 were consistently associated with smaller bilateral hippocampal volumes overall, and among females (q  <  0.05), without significant sex differences. RDWv1 was related to smaller select regional cortical brain gray and white matter volumes in hematological measure-adjusted models; anemiav1 was associated with larger WML volumes only among Whites. Conclusion: In summary, baseline anemia and RDW were consistently associated with smaller bilateral hippocampal volumes, particularly among females, while anemia was linked to larger WML volume among Whites. In hematological measure-adjusted models, baseline RDW was linked to smaller regional gray and white matter volumes. Pending studies with sMRI repeats, randomized controlled trials are needed, demonstrating associations of anemia and elevated RDW with reduced brain volumes and cognitive dysfunction. Show more

Keywords: Aging, anemia, brain volumes, hippocampus, red cell distribution width, white matter lesion

DOI: 10.3233/JAD-201386

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2021

Authors: Manuel Gómez-López, Vıctor | Viramontes-Pintos, Amparo | Ontiveros-Torres, Miguel Ángel | Garcés-Ramírez, Linda | de la Cruz, Fidel | Villanueva-Fierro, Ignacio | Bravo-Muñoz, Marely | Harrington, Charles R. | Martínez-Robles, Sandra | Yescas, Petra | Guadarrama-Ortíz, Parménides | Hernándes-Alejandro, Mario | Montiel-Sosa, Francisco | Pacheco-Herrero, Mar | Luna-Muñoz, José

Article Type: Research Article

Abstract: Background: Transmissible spongiform encephalopathies (TSEs) are rare neurodegenerative disorders that affect animals and humans. Bovine spongiform encephalopathy (BSE) in cattle, and Creutzfeld-Jakob Disease (CJD) in humans belong to this group. The causative agent of TSEs is called “prion”, which corresponds to a pathological form (PrPSc ) of a normal cellular protein (PrPC ) expressed in nerve cells. PrPSc is resistant to degradation and can induce abnormal folding of PrPC , and TSEs are characterized by extensive spongiosis and gliosis and the presence of PrPSc amyloid plaques. CJD presents initially with clinical symptoms similar to Alzheimer’s disease (AD). In …AD, tau aggregates and amyloid-β protein plaques are associated with memory loss and cognitive impairment in patients. Objective: In this work, we study the role of tau and its relationship with PrPSc plaques in CJD. Methods: Multiple immunostainings with specific antibodies were carried out and analyzed by confocal microscopy. Results: We found increased expression of the glial fibrillary acidic protein (GFAP) and matrix metalloproteinase (MMP-9), and an exacerbated apoptosis in the granular layer in cases with prion disease. In these cases, tau protein phosphorylated at Thr-231 was overexpressed in the axons and dendrites of Purkinje cells and the extensions of parallel fibers of the cerebellum. Conclusion: We conclude that phosphorylation of tau may be a response to the toxic and inflammatory environment generated by the pathological form of prion. Show more

Keywords: Cerebellum, neuronal death, prion encephalopathy, prion protein, tau protein

DOI: 10.3233/JAD-201308

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2021

Authors: O’Bryant, Sid | Zhang, Fan | Petersen, Melissa | Johnson, Leigh | Hall, James | Rissman, Robert A.

Article Type: Research Article

Abstract: Background: The REFLECT Trials were conducted to examine the treatment of mild-to-moderate Alzheimer’s disease utilizing a peroxisome proliferator-activated receptor gamma agonist. Objective: To generate a predictive biomarker indicative of positive treatment response using samples from the previously conducted REFLECT trials. Methods: Data were analyzed on 360 participants spanning multiple negative REFLECT trials, which included treatment with rosiglitazone and rosiglitazone XR. Support vector machine analyses were conducted to generate a predictive biomarker profile. Results: A pre-defined 6-protein predictive biomarker (IL6, IL10, CRP, TNFα, FABP-3, and PPY) correctly classified treatment response with 100%accuracy across study arms …for REFLECT Phase II trial (AVA100193) and multiple Phase III trials (AVA105640, AV102672, and AVA102670). When the data was combined across all rosiglitazone trial arms, a global RSG-predictive biomarker with the same 6-protein predictive biomarker was able to accurately classify 98%of treatment responders. Conclusion: A predictive biomarker comprising of metabolic and inflammatory markers was highly accurate in identifying those patients most likely to experience positive treatment response across the REFLECT trials. This study provides additional proof-of-concept that a predictive biomarker can be utilized to help with screening and predicting treatment response, which holds tremendous benefit for clinical trials. Show more

Keywords: Alzheimer’s disease, clinical trial, predictive biomarker, rosiglitazone

DOI: 10.3233/JAD-201610

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Zhou, Yunzhe | Wang, Yan | Quan, Meina | Zhao, Huiying | Jia, Jianping

Article Type: Research Article

Abstract: Background: Gut microbiota can influence human brain function and behavior. Recent studies showed that gut microbiota might play an important role in the pathogenesis of Alzheimer’s disease (AD). Objective: To investigate the composition of gut microbiota in AD patients and their association with cognitive function and neuropsychiatric symptoms (NPS). Methods: The fecal samples from 60 AD patients (30 with NPS and 30 without NPS) and 32 healthy control subjects (HC) were collected and analyzed by 16S ribosomal RNA sequencing. The functional variations of gut microbiota were predicted using Phylogenetic Investigation of Communities by Reconstruction of Unobserved …States. The correlation between different bacterial taxa and cognitive (Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR)), and NPS measures were analyzed. Results: The fecal microbial composition of AD patients was quite distinct from HC. Bifidobacterium, Sphingomonas, Lactobacillus , and Blautia were enriched, while Odoribacter, Anaerobacterium , and Papillibacter were reduced. AD patients with NPS showed decreased Chitinophagaceae, Taibaiella , and Anaerobacterium compared with those without NPS. Functional pathways were different between AD and HC, and between AD patients with and without NPS. Correlation analysis showed that Sphingomonas correlated negatively with MMSE; Anaerobacterium and Papillibacter correlated positively with MMSE and negatively with CDR. Cytophagia, Rhodospirillaceae, and Cellvibrio correlated positively with NPS, while Chitinophagaceae, Taibaiella, and Anaerobacterium correlated negatively with NPS. Conclusion: AD patients have gut microbiota alterations related to cognition, and differential taxa between AD patients with and without NPS associated differently with NPS domains, which helps further understand the pathogenesis of AD and explore potential therapeutic targets. Show more

Keywords: Alzheimer’s disease, cognitive function, gut microbiota, neuropsychiatric symptoms

DOI: 10.3233/JAD-201497

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Schmidt, Sergio L. | Boechat, Yolanda Eliza Moreira | Schmidt, Guilherme J. | Nicaretta, Denise | van Duinkerken, Eelco | Schmidt, Juliana J.

Article Type: Research Article

Abstract: Background: The Clinical Dementia Rating (CDR) scale is commonly used to stage cognitive impairment, despite having educational limitations. In elderly with low education, a previous study has shown that intraindividual variability of reaction time (CV) and commission errors (CE), measured using a culture-free Go/No-Go task, can reliably distinguish early Alzheimer’s disease (AD) from mild cognitive impairment (MCI) and healthy controls. Objective: We aimed to extend the clinical utility of this culture-free Go/No-Go task in a sample with high educational disparity. Methods: One hundred and ten participants with a wide range of years of formal education (0–14 …years) were randomly selected from a geriatric unit and divided based on their CDR scores into cognitively unimpaired (CDR = 0), MCI (CDR = 0.5), and early AD (CDR = 1). All underwent a 90-s reaction-time test that measured the variables previously found to predict CDR in low educated elderly. Here we added years of formal education (educational level) to the model. Multivariate analyses compared differences in group means using educational level as confounding factor. A confirmatory discriminant analyses was performed, to assess if CDR scores could be predicted by the two Go/No-Go variables in a sample with high educational disparity. Results: Over all three groups, differences in both CE and CV reached statistical significance (p  <  0.05). The discriminant analysis demonstrated that CV and CE discriminated cognitively impaired from cognitively normal elderly. These results remained similar when discriminating MCI from cognitively unimpaired elderly. Conclusion: The Go/No-Go task reliably discriminates elderly with MCI from elderly without cognitive impairment independent of educational disparity. Show more

Keywords: Attention, cognitive dysfunction, dementia, neuropsychology, reaction time

DOI: 10.3233/JAD-210151

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2021

Authors: Aitken, William W. | Lombard, Joanna | Wang, Kefeng | Toro, Matthew | Byrne, Margaret | Nardi, Maria I. | Kardys, Jack | Parrish, Abraham | Dong, Chuanhui | Szapocznik, José | Rundek, Tatjana | Brown, Scott C.

Article Type: Research Article

Abstract: Background: Neighborhood greenness (vegetative presence) has been linked to multiple health outcomes, but its relationship to Alzheimer’s disease (AD) and non-Alzheimer’s (non-AD) dementia has been less studied. Objective: This study examines the relationship of greenness to both AD and non-AD dementia in a population-based sample of Medicare beneficiaries. Methods: Participants were 249,405 US Medicare beneficiaries aged >  65 living in Miami-Dade County, FL, from 2010 to 2011. Multi-level analyses examined the relationship of greenness, assessed by mean Census block level Normalized Difference Vegetation Index (NDVI), to odds of each of AD, Alzheimer’s disease and related dementias …(ADRD), and non-AD dementia, respectively. Covariates included age, gender, race/ethnicity, number of comorbid health conditions, and neighborhood income. Results: Higher greenness was associated with reduced risk of AD, ADRD, and non-AD dementia, respectively, adjusting for individual and neighborhood sociodemographics. Compared to the lowest greenness tertile, the highest greenness tertile was associated with reduced odds of AD by 20%(odds ratio, 0.80; 95%CI, 0.75–0.85), ADRD by 18%(odds ratio, 0.82; 95%CI, 0.77–0.86), and non-AD dementia by 11%(odds ratio, 0.89; 95%CI, 0.82–0.96). After further adjusting for number of comorbidities, compared to the lowest greenness tertile, the highest greenness tertile was associated with reduced odds of AD (OR, 0.94; 95%CI, 0.88–1.00) and ADRD (OR, 0.93; 95%CI, 0.88–0.99), but not non-AD dementia (OR, 1.01; 95%CI, 0.93–1.08). Conclusion: High neighborhood greenness may be associated with lower odds of AD and ADRD. Environmental improvements, such as increasing neighborhood vegetation, may be a strategy to reduce risk for AD and possibly other dementias. Show more

Keywords: Alzheimer’s disease, built environment, dementia, health disparities, medicare beneficiaries, natural environment, neighborhood greenness, older adults

DOI: 10.3233/JAD-201179

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Zheng, Yi-Ming | Zhao, Yang-Yang | Zhang, Ting | Hou, Xiao-He | Bi, Yan-Lin | Ma, Ya-Hui | Xu, Wei | Shen, Xue-Ning | Dong, Qiang | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Heart failure has been considered as a potential modifiable risk factor for cognitive impairment and dementia. Left ventricular ejection fraction (LVEF), an indicator of cardiac dysfunction, has also been associated with cognitive aging. However, the effect of LVEF on Alzheimer’s disease (AD) pathology is still less known. Objective: We aimed to investigate the associations of LVEF with cerebrospinal fluid (CSF) biomarkers for AD in cognitively normal elders. Methods: A total of 423 cognitively normal individuals without heart failure were included from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) study. Participants were divided …into low LVEF group (50%≤LVEF <  60%) and high LVEF group (LVEF≥60%). The associations of LVEF with CSF AD biomarkers including CSF amyloid-β 42 (Aβ 42 ), total-tau (t-tau), and phosphorylated tau (p-tau) were analyzed using multivariate linear regression models. Results: Participants with low LVEF had higher levels of CSF t-tau (β= –0.009, p  = 0.006) and t-tau/Aβ 42 ratios (β= –0.108, p  = 0.026). Subgroup analyses showed that the associations only existed in female and middle-aged groups (<  65 years old). Besides, participants with low LVEF had higher levels of CSF p-tau (β= –0.002, p  = 0.043) in middle-aged group. Conclusion: In conclusion, our findings revealed the associations between LVEF and AD pathology, which may provide new insights into AD prevention through maintaining cardiac function. Show more

Keywords: Alzheimer’s disease, biomarker, cerebrospinal fluid, left ventricular ejection fraction

DOI: 10.3233/JAD-201222

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2021

Authors: Wang, Xuewei | Bui, Hai | Vemuri, Prashanthi | Graff-Radford, Jonathan | Jack Jr, Clifford R. | Petersen, Ronald C. | Mielke, Michelle M.

Article Type: Research Article

Abstract: Background: Lipid alterations contribute to Alzheimer’s disease (AD) pathogenesis. Lipidomics studies could help systematically characterize such alterations and identify potential biomarkers. Objective: To identify lipids associated with mild cognitive impairment and amyloid-β deposition, and to examine lipid correlation patterns within phenotype groups Methods: Eighty plasma lipids were measured using mass spectrometry for 1,255 non-demented participants enrolled in the Mayo Clinic Study of Aging. Individual lipids associated with mild cognitive impairment (MCI) were first identified. Correlation network analysis was then performed to identify lipid species with stable correlations across conditions. Finally, differential correlation network analysis was used …to determine lipids with altered correlations between phenotype groups, specifically cognitively unimpaired versus MCI, and with elevated brain amyloid versus without. Results: Seven lipids were associated with MCI after adjustment for age, sex, and APOE4 . Lipid correlation network analysis revealed that lipids from a few species correlated well with each other, demonstrated by subnetworks of these lipids. 177 lipid pairs differently correlated between cognitively unimpaired and MCI patients, whereas 337 pairs of lipids exhibited altered correlation between patients with and without elevated brain amyloid. In particular, 51 lipid pairs showed correlation alterations by both cognitive status and brain amyloid. Interestingly, the lipids central to the network of these 51 lipid pairs were not significantly associated with either MCI or amyloid, suggesting network-based approaches could provide biological insights complementary to traditional association analyses. Conclusion: Our attempt to characterize the alterations of lipids at network-level provides additional insights beyond individual lipids, as shown by differential correlations in our study. Show more

Keywords: Aging, Alzheimer’s disease, amyloid, lipid, lipidomics, mild cognitive impairment, network analysis, systems biology

DOI: 10.3233/JAD-201347

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Rodríguez, Danelly | Ayers, Emmeline | Weiss, Erica F. | Verghese, Joe

Article Type: Research Article

Abstract: Background: Very few studies have explored the utility of subjective cognitive complaints (SCCs) in primary care settings. Objective: We aim to investigate associations between SCCs (item-level), objective cognitive function (across domains and global), and mood in a diverse primary care population, including subjects with mild cognitive impairment. Methods: We studied 199 (75.9%females; 57.8%Hispanics; 42.2%African Americans) older adults (mean age 72.5 years) with memory concerns at a primary care clinic. A five-item SCC questionnaire, and objective cognitive assessments, including the Montreal Cognitive Assessment (MoCA) and the Geriatric Depression Scale, were administered. Results: …Logistic regression analyses showed associations between SCC score and depressive symptoms. A memory-specific (“memory worsening”) SCC predicted scores on the MoCA (p  = 0.005) in Hispanics. Conclusion: SCCs are strongly linked to depressive symptoms in African Americans and Hispanics in a primary care setting; a specific type of SCC is related to global cognitive function in Hispanics. Show more

Keywords: Cognitive function, cross-sectional, depressive symptoms, primary care, subjective health complaint, underserved populations

DOI: 10.3233/JAD-201399

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Manera, Valeria | Galperti, Guenda | Rovini, Erika | Zeghari, Radia | Mancioppi, Gianmaria | Fiorini, Laura | Gros, Auriane | Mouton, Aurélie | Robert, Philippe | Cavallo, Filippo

Article Type: Research Article

Abstract: Background: Social apathy, a reduction in initiative in proposing or engaging in social activities or interactions, is common in mild neurocognitive disorders (MND). Current apathy assessment relies on self-reports or clinical scales, but growing attention is devoted to defining more objective, measurable and non-invasive apathy proxies. Objective: In the present study we investigated the interest of recording action kinematics in a social reach-to-grasp task for the assessment of social apathy. Methods: Thirty participants took part in the study: 11 healthy controls (HC; 6 females, mean age = 68.3±10.5 years) and 19 subjects with MND (13 females, mean age = 75.7±6.3 …years). Based on the Diagnostic Criteria for Apathy, MND subjects were classified as socially apathetic (A-MND, N  = 9) versus non-apathetic (NA-MND, N  = 10). SensRing, a ring-shaped wearable sensor, was placed on their index finger, and subjects were asked to reach and grasp a can to place it into a cup (individual condition) and pass it to a partner (social condition). Results: In the reach-to-grasp phase of the action, HC and NA-MND showed different acceleration and velocity profiles in the social versus individual condition. No differences were found for A-MND. Conclusion: Previous studies showed the interest of recording patients’ level of weekly motor activity for apathy assessment. Here we showed that a 10-min reach-to-grasp task may provide information to differentiate socially apathetic and non-apathetic subjects with MND, thus providing a tool easily usable in the clinical practice. Future studies with a bigger sample are needed to better characterize these findings. Show more

Keywords: Apathy, diagnosis, intention, motivation, motor activity, neurocognitive disorders, social behavior, social isolation

DOI: 10.3233/JAD-200966

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Martínez-Florez, Juan F. | Osorio, Juan D. | Cediel, Judith C. | Rivas, Juan C. | Granados-Sánchez, Ana M. | López-Peláez, Jéssica | Jaramillo, Tania | Cardona, Juan F.

Article Type: Research Article

Abstract: Background: Amnestic mild cognitive impairment (aMCI) is the most common preclinical stage of Alzheimer’s disease (AD). A strategy to reduce the impact of AD is the early aMCI diagnosis and clinical intervention. Neuroimaging, neurobiological, and genetic markers have proved to be sensitive and specific for the early diagnosis of AD. However, the high cost of these procedures is prohibitive in low-income and middle-income countries (LIMCs). The neuropsychological assessments currently aim to identify cognitive markers that could contribute to the early diagnosis of dementia. Objective: Compare machine learning (ML) architectures classifying and predicting aMCI and asset the contribution of …cognitive measures including binding function in distinction and prediction of aMCI. Methods: We conducted a two-year follow-up assessment of a sample of 154 subjects with a comprehensive multidomain neuropsychological battery. Statistical analysis was proposed using complete ML architectures to compare subjects’ performance to classify and predict aMCI. Additionally, permutation importance and Shapley additive explanations (SHAP) routines were implemented for feature importance selection. Results: AdaBoost, gradient boosting, and XGBoost had the highest performance with over 80%success classifying aMCI, and decision tree and random forest had the highest performance with over 70%success predictive routines. Feature importance points, the auditory verbal learning test, short-term memory binding tasks, and verbal and category fluency tasks were used as variables with the first grade of importance to distinguish healthy cognition and aMCI. Conclusion: Although neuropsychological measures do not replace biomarkers’ utility, it is a relatively sensitive and specific diagnostic tool for aMCI. Further studies with ML must identify cognitive performance that differentiates conversion from average MCI to the pathological MCI observed in AD. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, cognitive markers, healthy aging, machine learning

DOI: 10.3233/JAD-201447

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Zhang, Yun | Natale, Ginny | Clouston, Sean

Article Type: Research Article

Abstract: Background: Larger, or more active social networks are estimated to be associated with lower risks of cognitive decline. However, roles of various social relationships in a broad social network in protecting against cognitive decline remain to be elucidated. Objective: We aimed to investigate how social roles within a social network and number of social network members are associated with cognitive decline. Methods: Six waves of National Health and Aging Trends Study (2011-2016, NHATS) were utilized to examine the development of mild cognitive impairment (MCI) and probable dementia determined using validated criteria. Multivariable-adjusted multi-state survival models were …used to model incidences and transitions, jointly with misclassification errors. Results: A total of 6,078 eligible NHATS participants were included (average age: 77.49±7.79 years; female: 58.42%; non-Hispanic white: 68.99%). Multivariable-adjusted analyses revealed that having more social network members was associated with lower hazards of conversion from MCI to probable dementia (adjusted Hazard Ratio; aHR = 0.82; 95%confidence intervals; 95%CI = [0.67–0.99]), meanwhile having at least one college-educated family member within a social network was associated with lower incidence of probable dementia (aHR = 0.37 [0.26–0.51]). Having at least one friend within a social network was associated with a lower hazard of incidence of probable dementia (aHR = 0.48 [0.33–0.71]), but a higher risk of mortality in the MCI group (aHR = 2.58 [1.47–4.51 ]). Conclusion: Having more social network members, having at least one friend, and having at least one college-educated family member within a social network, were associated with lower risks of incidence of dementia or conversion from MCI to dementia. Show more

Keywords: Cognition, dementia, multistate modeling, social networking

DOI: 10.3233/JAD-201196

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Boström, Gustaf | Freyhult, Eva | Virhammar, Johan | Alcolea, Daniel | Tumani, Hayrettin | Otto, Markus | Brundin, Rose-Marie | Kilander, Lena | Löwenmark, Malin | Giedraitis, Vilmantas | Lleó, Alberto | von Arnim, Christine A.F. | Kultima, Kim | Ingelsson, Martin

Article Type: Research Article

Abstract: Background: Neuroinflammatory processes are common in neurodegenerative diseases such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD), but current knowledge is limited as to whether cerebrospinal fluid (CSF) levels of neuroinflammatory proteins are altered in these diseases. Objective: To identify and characterize neuroinflammatory signatures in CSF from patients with AD, mild cognitive impairment (MCI), and FTD. Methods: We used proximity extension assay and ANOVA to measure and compare levels of 92 inflammatory proteins in CSF from 42 patients with AD, 29 with MCI due to AD (MCI/AD), 22 with stable MCI, 42 with FTD, and 49 …control subjects, correcting for age, gender, collection unit, and multiple testing. Results: Levels of matrix metalloproteinase-10 (MMP-10) were increased in AD, MCI/AD, and FTD compared with controls (AD: fold change [FC] = 1.32, 95%confidence interval [CI] 1.14–1.53, q  = 0.018; MCI/AD: FC = 1.53, 95%CI 1.20–1.94, q  = 0.045; and FTD: FC = 1.42, 95%CI 1.10–1.83, q  = 0.020). MMP-10 and eleven additional proteins were increased in MCI/AD, compared with MCI (q  <  0.05). In FTD, 36 proteins were decreased, while none was decreased in AD or MCI/AD, compared with controls (q  <  0.05). Conclusion: In this cross-sectional multi-center study, we found distinct patterns of CSF inflammatory marker levels in FTD and in both early and established AD, suggesting differing neuroinflammatory processes in the two disorders. Show more

Keywords: Alzheimer’s disease, frontotemporal dementia, mild cognitive impairment, neuroinflammation, proteomics

DOI: 10.3233/JAD-201565

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Kanatome, Ayana | Ano, Yasuhisa | Shinagawa, Kazushi | Ide, Yumiko | Shibata, Midori | Umeda, Satoshi

Article Type: Research Article

Abstract: Background: Epidemiological studies have shown that dairy product consumption is beneficial for cognitive function in elderly individuals. β-lactolin is a lacto-tetrapeptide Gly–Thr–Trp–Tyr rich in fermented dairy products that improves memory retrieval, attention, and executive function in older adults with subjective cognitive decline and prevents the pathology of Alzheimer’s disease in rodents. There has been no study on the effects of β-lactolin on neural activity in humans. Objective: We investigated the effects of β-lactolin on neural activity and cognitive function in healthy adults. Methods: In this randomized, double-blind, placebo-controlled study, 30 participants (45–64 years old) consumed β-lactolin …or placebo for 6 weeks. Neural activity during auditory and language tasks was measured through 64-channel electroencephalography. Moreover, verbal fluency tests were performed at baseline and after 6 weeks. Results: The β-lactolin group had a significantly higher P300 amplitude at the Cp2 site (a part of the parietal lobe near the center of brain, p  = 0.008), and C4 site (the area between the frontal and parietal lobe, p  = 0.021) during the auditory tasks after 6 weeks than the placebo group. Thus, β-lactolin supplementation promoted neural activity in the parietal area, which increases attention during auditory cognitive tasks. Compared with the placebo group, the β-lactolin group also showed significant changes in the scores of verbal fluency test after 6 weeks (p  = 0.03). Conclusion: Our findings provide insight into the mechanisms underlying the effects of β-lactolin on attention in healthy adults. Show more

Keywords: Attention, clinical trial, cognitive function, EEG, β-lactoglobulin, β-lactolin, β-lactopeptide, memory, P300, whey

DOI: 10.3233/JAD-201413

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Li, Lin-Lin | Ma, Ya-Hui | Bi, Yan-Lin | Sun, Fu-Rong | Hu, Hao | Hou, Xiao-He | Xu, Wei | Shen, Xue-Ning | Dong, Qiang | Tan, Lan | Yang, Jiu-Long | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Serum uric acid (SUA) affects the reaction of oxidative stress and free radicals in the neurodegenerative processes. However, whether SUA impacts Alzheimer’s disease (AD) pathology remains unclear. Objective: We aimed to explore whether high SUA levels can aggravate the neurobiological changes of AD in preclinical AD. Methods: We analyzed cognitively intact participants (n = 839, age 62.16 years) who received SUA and cerebrospinal fluid (CSF) biomarkers (amyloid-β [Aβ], total tau [t-Tau], and phosphorylated tau [p-Tau]) measurements from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) database using multivariable-adjusted linear models. Results: Levels of …SUA in the preclinical AD elevated compared with the healthy controls (p = 0.007) and subjects with amyloid pathology had higher concentration of SUA than controls (p = 0.017). Roughly, equivalent levels of SUA displayed among cognitively intact individuals with or without tau pathology and neurodegeneration. CSF Aβ1 - 42 (p = 0.019) and Aβ1 - 42 /Aβ1 - 40 (p = 0.027) were decreased and CSF p-Tau/Aβ1 - 42 (p = 0.009) and t-Tau/Aβ1 - 42 (p = 0.043) were increased with the highest (>  75th percentile) SUA when compared to lowest SUA, implying a high burden of cerebral amyloidosis in individuals with high SUA. Sensitivity analyses using the usual threshold to define hyperuricemia and precluding drug effects yielded robust associations. Nevertheless, the quadratic model did not show any U-shaped relationships between them. Conclusion: SUA may aggravate brain amyloid deposition in preclinical AD, which corroborated the detrimental role of SUA. Show more

Keywords: Alzheimer’s disease pathology, biomarkers, cerebrospinal fluid, serum uric acid

DOI: 10.3233/JAD-201192

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Qiu, Hongyan | Zhao, Ruoqi | Fei, Guoqiang | Pan, Xiaoli | Sang, Shaoming | Xu, Yangqi | Jin, Boru | Jin, Lirong | Cheng, Xiaoqin | Zhong, Chunjiu

Article Type: Research Article

Abstract: Background: Microglia play diverse roles in Alzheimer’s disease (AD). Intracellular metabolism has been indicated an important factor in modulating the function of microglia. However, it is not clear whether the intracellular metabolism of microglia changes dynamically in different stages of AD. Objective: To determine whether microglia intracellular metabolism changes dynamically in different stages of AD. Methods: Microglia were extracted from APPSwe /PS1dE9 (APP/PS1) mice and wild-type littermates at 2, 4, and 8 months old by fluorescence-activated cell sorting and used for RNA-sequencing analysis and quantitative PCR. Morphologies of amyloid plaques and microglia were detected by …immunofluorescence staining. Results: Compared with control littermates, the microglia of APP/PS1 mice exhibited significant transcriptional changes at 2-month-old before microglia morphological alterations and the plaque formation. The changes continued drastically following age with defined morphological shift of microglia and amyloid plaque enhancement in brains. Further analysis of those genotype and age dependent transcriptomic changes revealed that differentially expressed genes enriched in pathways related to energy metabolism. Compared with wild-type mice, there were changes of some vital genes related to glucose metabolism and lipid metabolism pathways in APP/PS1 mice at different ages. Glucose metabolism may play a major role in early activation of microglia, and lipid metabolism may be more important in later activation period. Conclusion: Our results showed that microglia actively participate in the pathological progress of AD. The intracellular metabolism of microglia changed significantly in different stages of AD, even preceding amyloid-β deposition. Show more

Keywords: Alzheimer’s disease, metabolism, microglia, transcriptomics

DOI: 10.3233/JAD-210213

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2021

Authors: Liu, Xin | Chen, Ke-Liang | Wang, Yi | Huang, Yu-Yuan | Chen, Shi-Dong | Dong, Qiang | Cui, Mei | Yu, Jin-Tai

Article Type: Short Communication

Abstract: Mutations in ITM2B have been found to be associated with familial Danish dementia (FDD) and familial British dementia (FBD). Here, we describe a patient with dementia caused by a novel ITM2B p. * 267Leuext * 11 mutation. The patient presented with dementia, ataxia, deafness, and paraplegia. Amyloid PET and Tau PET showed abnormal deposition of amyloid and tau protein in brain. Summarized from previous 26 FBD and FDD cases, the clinical phenotype of ITM2B ; p. * 267Leuext * 11 mutation in ITM2B is different from the features of FBD and FDD. Our findings increased genetic knowledge of familial dementia and …extend the ethnic distribution of ITM2B mutations. Show more

Keywords: Bri2, familial British dementia, familial Danish dementia, familial dementia, ITM2B

DOI: 10.3233/JAD-210176

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2021

Authors: Pillai, Jagan A. | Bena, James | Bekris, Lynn M. | Foldvary-Schaefer, Nancy | Heinzinger, Catherine | Rao, Sujata | Rao, Stephen M. | Leverenz, James B. | Mehra, Reena

Article Type: Research Article

Abstract: Sleep dysfunction has been identified in the pathophysiology of Alzheimer’s disease (AD); however, the role and mechanism of circadian rhythm dysfunction is less well understood. In a well-characterized cohort of patients with AD at the mild cognitive impairment stage (MCI-AD), we identify that circadian rhythm irregularities were accompanied by altered humoral immune responses detected in both the cerebrospinal fluid and plasma as well as alterations of cerebrospinal fluid biomarkers of neurodegeneration. On the other hand, sleep disruption was more so associated with abnormalities in circulating markers of immunity and inflammation and decrements in cognition.

Keywords: Alzheimer’s disease, circadian, immunity, inflammation, neurodegeneration, sleep

DOI: 10.3233/JAD-201573

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2021

Authors: Azevedo, Lílian Viana dos Santos | Calandri, Ismael Luis | Slachevsky, Andrea | Graviotto, Héctor Gastón | Vieira, Maria Carolina Santos | Andrade, Caíssa Bezerra de | Rossetti, Adriana Peredo | Generoso, Alana Barroso | Carmona, Karoline Carvalho | Pinto, Ludmilla Aparecida Cardoso | Sorbara, Marcos | Pinto, Alejandra | Guajardo, Tania | Olavarria, Loreto | Thumala, Daniela | Crivelli, Lucía | Vivas, Ludmila | Allegri, Ricardo Francisco | Barbosa, Maira Tonidandel | Serrano, Cecilia M. | Miranda-Castillo, Claudia | Caramelli, Paulo

Article Type: Research Article

Abstract: Background: People with dementia and their family caregivers may face a great burden through social isolation due to the COVID-19 pandemic, which can be manifested as various behavioral and clinical symptoms. Objective: To investigate the impacts of social isolation due to the COVID-19 pandemic on individuals with dementia and their family caregivers. Methods: Two semi-structured questionnaires were applied via telephone to family caregivers of people diagnosed with dementia in three cities in Argentina, Brazil, and Chile, in order to assess clinical and behavioral changes in people with dementia and in their caregivers. …Results: In general, 321 interviews were conducted. A significant decline in memory function has been reported among 53.0%of people with dementia. In addition, 31.2%of individuals with dementia felt sadder and 37.4%had increased anxiety symptoms. These symptoms of anxiety were greater in individuals with mild to moderate dementia, while symptoms of agitation were greater in individuals with severe dementia. Moreover, compulsive-obsessive behavior, hallucinations, increased forgetfulness, altered appetite, and increased difficulty in activities of daily living were reported more frequently among individuals with moderate to severe dementia. Caregivers reported feeling more tired and overwhelmed during this period and these symptoms were also influenced by the severity of dementia. Conclusion: Social isolation during the COVID-19 pandemic triggered a series of negative behavioral repercussions, both for people with dementia and for their family caregivers in these three South American countries. Show more

Keywords: Behavioral symptoms, caregiver, COVID-19, dementia, social isolation

DOI: 10.3233/JAD-201580

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Miyagawa, Naoko | Ohkubo, Takayoshi | Fujiyoshi, Akira | Shiino, Akihiko | Chen, Randi | Ross, George Webster | Willcox, Bradley | Miura, Katsuyuki | Ueshima, Hirotsugu | Masaki, Kamal

Article Type: Research Article

Abstract: Background: Few studies have compared factors related to cognitive function among people with similar genetic backgrounds but different lifestyles. Objective: We aimed to identify factors related to lower cognitive scores among older Japanese men in two genetically similar cohorts exposed to different lifestyle factors. Methods: This cross-sectional study of community-dwelling Japanese men aged 71–81 years included 2,628 men enrolled in the Kuakini Honolulu-Asia Aging Study based in Hawaii and 349 men in the Shiga Epidemiological Study of Subclinical Atherosclerosis based in Japan. We compared participant performance through Cognitive Abilities Screening Instrument (CASI) assessment in Hawaii (1991–1993) …and Japan (2009–2014). Factors related to low cognitive scores (history of cardiovascular disease, cardiometabolic factors, and lifestyle factors) were identified with questionnaires and measurements. Multivariable logistic regression analysis was used to calculate the adjusted odds ratios (ORs) of a low (<  82) CASI score based on different factors. Results: CASI scores were lower in Hawaii than in Japan [21.2%(n  = 556) versus 12.3%(n  = 43), p  <  0.001], though this was not significant when adjusted for age and educational attainment (Hawaii 20.3%versus Japan 17.9%, p  = 0.328). History of stroke (OR = 1.65, 95%confidence interval = 1.19–2.29) was positively associated with low cognitive scores in Hawaii. Body mass index ≥25 kg/m2 tended to be associated with low cognitive scores in Japan; there was a significant interaction between the cohorts. Conclusion: Cognitive scores differences between cohorts were mostly explained by differences in educational attainment. Conversely, cardiovascular diseases and cardiometabolic factors differentially impacted cognitive scores among genetically similar older men exposed to different lifestyle factors. Show more

Keywords: Aged, cognitive decline, community dwelling, Japanese, Japanese Americans, men

DOI: 10.3233/JAD-201084

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Bernier, Francois | Ohno, Kazuya | Katsumata, Noriko | Shimizu, Takashi | Xiao, Jinzhong

Article Type: Short Communication

Abstract: We demonstrated the benefit of the probiotic strain, Bifidobacterium breve MCC1274 (synonym B. breve A1), at improving cognition in our previous double-blind, placebo-controlled clinical study. Analysis of the association of blood parameters changes with the improvement of cognitive function revealed an inverse correlation of HbA1c with total RBANS score amelioration after the study only in the probiotic group (ρ = –0. 4218, p  = 0.0067). A stratified analysis based on baseline HbA1c with a median value showed a more remarkable benefit by the probiotic supplementation in the higher median subgroup. These data support the mechanism of anti-inflammation in improving cognition …by the probiotic strain. Show more

Keywords: Bifidobacterium, clinical trial, HbA1c, dementia, memory, mild cognitive impairment, probiotics

DOI: 10.3233/JAD-201488

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2021

Authors: Nelson, Monica E. | Andel, Ross | Nedelska, Zuzana | Martinkova, Julie | Cechova, Katerina | Markova, Hana | Matuskova, Veronika | Nikolai, Tomas | Lerch, Ondrej | Parizkova, Martina | Laczo, Jan | Vyhnalek, Martin | Hort, Jakub

Article Type: Research Article

Abstract: Background: Identifying modifiable risk factors for cognitive decline can reduce burden of dementia. Objective: We examined whether homocysteine was associated with memory performance, mediated by entorhinal volume, hippocampal volume, total gray matter volume, or white matter lesions, and moderated by APOE ɛ4 allele, B vitamins, creatinine, total cholesterol, or triglycerides. Methods: All 204 members of the Czech Brain Aging Study with subjective cognitive decline (SCD; n  = 60) or amnestic mild cognitive impairment (aMCI; n  = 144) who had valid data were included. Linear regression was used, followed by conditional process modeling to examine mediation and moderation. …Results: Controlling for age, sex, and education, higher homocysteine was related to poorer memory performance overall (b  = –0.03, SE  = 0.01, p  = 0.017) and in participants with SCD (b  = –0.06, SE  = 0.03, p  = 0.029), but less so in aMCI (b  = –0.03, SE  = 0.02, p  = 0.074); though sensitivity analyses revealed a significant association when sample was reduced to aMCI patients with more complete cognitive data (who were also better functioning; b  = –0.04, SE  = 0.02, p  = 0.022). Results were unchanged in fully adjusted models. Neither mediation by markers of brain integrity nor moderation by APOE ɛ4, B vitamins, creatinine, and cardiovascular factors were significant. Memory sub-analyses revealed that results for SCD were likely driven by non-verbal memory. The homocysteine-memory relationship was significant when hippocampal volume was below the median (b  = –0.04, SE = 0.02, p  = 0.046), but not at/above the median (p  = 0.247). Conclusion: Higher homocysteine levels may adversely influence memory performance, particularly in those without cognitive impairment. Results appear to be independent of brain health, suggesting that homocysteine may represent a good target for intervention. Show more

Keywords: Hippocampus, magnetic resonance imaging, mild cognitive impairment, neuropsychological tests

DOI: 10.3233/JAD-201558

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Edlund, Anna K. | Chen, Kewei | Lee, Wendy | Protas, Hillary | Su, Yi | Reiman, Eric | Caselli, Richard | Nielsen, Henrietta M.

Article Type: Research Article

Abstract: Background: Altered cerebral glucose metabolism, especially prominent in APOE ɛ4 carriers, occurs years prior to symptoms in Alzheimer’s disease (AD). We recently found an association between a higher ratio of plasma apolipoprotein E4 (apoE4) over apoE3, and cerebral glucose hypometabolism in cognitively healthy APOE ɛ3/ɛ4 subjects. Plasma apoE does not cross the blood-brain barrier, hence we speculate that apoE is linked to peripheral glucose metabolism which is known to affect glucose metabolism in the brain. Objective: Explore potential associations between levels of plasma insulin and glucose with previously acquired plasma apoE, cerebral metabolic rate of glucose …(CMRgl), gray matter volume, and neuropsychological test scores. Methods: Plasma insulin and glucose levels were determined by ELISA and a glucose oxidase assay whereas apoE levels were earlier quantified by mass-spectrometry in 128 cognitively healthy APOE ɛ3/ɛ4 subjects. Twenty-five study subjects had previously undergone FDG-PET and structural MRI. Results: Lower plasma apoE3 associated with higher plasma glucose but not insulin in male subjects and subjects with a body mass index above 25. Negative correlations were found between plasma glucose and CMRgl in the left prefrontal and bilateral occipital regions. These associations may have functional implications since glucose levels in turn were negatively associated with neuropsychological test scores. Conclusion: Plasma apoE3 but not apoE4 may be involved in insulin-independent processes governing plasma glucose levels. Higher plasma glucose, which negatively affects brain glucose metabolism, was associated with lower plasma apoE levels in APOE ɛ3/ɛ4 subjects. High plasma glucose and low apoE levels may be a hazardous combination leading to an increased risk of AD. Show more

Keywords: APOE, apolipoprotein E, cerebral glucose metabolism, glucose, insulin

DOI: 10.3233/JAD-210065

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2021

Authors: Li, Xuanting | Yuan, Junliang | Qin, Wei | Yang, Lei | Yang, Shuna | Li, Yue | Hu, Wenli

Article Type: Research Article

Abstract: Background: Cerebral microbleed (CMB) is an increasingly important risk factor for cognitive impairment due to population aging. Controversies, however, remain regarding the exact association between CMB and cognitive dysfunction. Objective: We aimed to determine the relationship between CMB burden and cognitive impairment, and also explore the characteristics of cognitive decline in CMB patients for middle-aged and elderly people. Methods: The present cross-sectional study included 174 participants (87 CMB patients and 87 controls) who underwent brain magnetic resonance imaging and a battery of neuropsychological test. Global cognitive function was measured using Mini-Mental State Examination (MMSE) and Montreal …Cognitive Assessment (MoCA). Compound z-scores were calculated for three cognitive subdomains: memory, executive function and processing speed. Results: CMB patients had lower scores of MMSE (p  <  0.001) and MoCA (p  <  0.001). Patients at each category of CMB count had worse performance in global cognitive function and all three cognitive subdomains (p  <  0.001). In multiple linear regression models, CMB patients had significantly greater declines in executive function (p  <  0.001), processing speed (p  <  0.001), and MoCA (p  = 0.003) with increasing number of CMB. We found no relationship between CMB location and cognition (p  <  0.05). Conclusion: CMB is associated with impairment in global cognition as well as for all tested subdomains. Strongest effect sizes were seen for tests which rely on executive functioning, where performance deficits increased in proportion to degree of CMB burden. Prospective studies are needed to evaluate whether the association between CMB and executive dysfunction is causal. Show more

Keywords: Cerebral microbleed, cerebral small vessel disease, cognitive impairment, susceptibility weighted imaging

DOI: 10.3233/JAD-201202

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2021

Authors: Feng Liu, Quan | Kanmani, Suganya | Lee, Jinhyuk | Kim, Geun-Woo | Jeon, Songhee | Koo, Byung-Soo

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most general, chronic, and progressive neurodegenerative senile disorder characterized clinically by progressive cognitive deterioration and memory impairment. Neoline is effective against neuropathic pain models, but the effects of neoline against AD-like phenotypes have not been investigated. Objective: We offer the investigation of the effects of neoline in AD. Methods: In this study, a Tg-APPswe/PS1dE9 AD mouse model was treated orally with neoline at a concentration of 0.5 mg/kg or 0.1 mg/kg starting at 7.5 months and administered for three months, and its anti-AD effects were evaluated. Results: Neoline improved memory …and cognition impairments and reduced the number of amyloid-beta plaque and the amount of amyloid-β in the brain of AD mice. Furthermore, neoline reduced the anxiety behavior in the AD mouse model. The chronic administration of neoline also induced AMPK phosphorylation and decreased tau, amyloid-β, and BACE1 expression in the hippocampus. These findings indicate that chronic administration of neoline has therapeutic effects via AMPK activation, and BACE1 downregulation resulted in a decrease in the amyloid-β levels in the brain of Tg-APPswe/PS1dE9 AD mice. Conclusion: Our results suggest that neoline is a therapeutic agent for the cure of neurodegenerative diseases like AD. Show more

Keywords: Alzheimer’s disease, AMPK, BACE1, cognitive function, neoline, tau

DOI: 10.3233/JAD-201614

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Pan, Danmin | Gu, Jin-Hua | Zhang, Jin | Hu, Yae | Liu, Fei | Iqbal, Khalid | Cekic, Nevena | Vocadlo, David J. | Dai, Chun-Ling | Gong, Cheng-Xin

Article Type: Research Article

Abstract: Background: Abnormal hyperphosphorylation of microtubule-associated protein tau plays a pivotal role in Alzheimer’s disease (AD). We previously found that O-GlcNAcylation inversely correlates to hyperphosphorylation of tau in AD brain, and downregulation of brain O-GlcNAcylation promotes tau hyperphosphorylation and AD-like neurodegeneration in mice. Objective: Herein we investigated the effect of increasing O-GlcNAcylation by using intermittent dosing with low doses of a potent novel O-GlcNAcase (OGA) inhibitor on AD-like brain changes and cognitive function in a mouse model of sporadic AD (sAD) induced by intracerebroventricular (ICV) injection of streptozotocin (STZ). Methods: STZ was injected into the lateral ventricle …of C57BL/6J mice. From the second day, Thiamme2-G (TM2G) or saline, as a vehicle control, was orally administered to the ICV-STZ mice three times per week for five weeks. A separate group of ICV-saline mice treated with saline was used as a baseline control. Behavioral tests, including open field and novel object recognition, were conducted three weeks after the first dose of the TM2G or saline. Protein O-GlcNAcylation, tau hyperphosphorylation, synaptic proteins, and neuroinflammation in the mouse brain were assessed by western blotting. Results: ICV-STZ caused decreased protein O-GlcNAcylation. Enhancement of O-GlcNAcylation to moderate levels by using low-dose OGA inhibitor in ICV-STZ mice prevented STZ-induced body weight loss, rescued cognitive impairments, and restored AD-like pathologies, including hyperphosphorylation of tau and abnormalities in synaptic proteins and neuroinflammation. Conclusion: These findings suggest that moderately increasing protein O-GlcNAcylation by using low doses of OGA inhibitor may be a suitable therapeutic strategy for sAD. Show more

Keywords: Alzheimer’s disease, O-GlcNAcylation, OGA, OGA inhibitor, tau hyperphosphorylation, Thiamme2-G

DOI: 10.3233/JAD-201450

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Olson, Nancy L. | Albensi, Benedict C.

Article Type: Research Article

Abstract: Persons with dementia (PWD) make up a large portion of the long-term care (LTC) population the world over. Before a global pandemic swept the world, governments and healthcare providers struggled with how to best care for this unique population. One of the greatest challenges is a PWD’s tendency to “walk with purpose” and exhibit unsafe wayfinding and elopement, which places them at risk of falls and injury. Past solutions included increased use of restraints and pharmacological interventions, but these have fallen out of favor over the years and are not optimal. These challenges put enormous strain on staff and caregivers, …who are often poorly trained in dementia care, underpaid, overworked, and overstressed. PWD are impacted by these stresses, and unmet needs in LTC places an even greater stress on them and increases their risks of morbidity and mortality. The physical design of their environments contributes to the problem. Old, institutionalized buildings have poor lighting, poor ventilation, long dead-end hallways, poor visual cues, lack of home-like décor, shared bedrooms and bathrooms, and are often dense and overcrowded. These design elements contribute to the four ‘A’s’ of dementia: apathy, anxiety, agitation, and aggression, and they also contributed to the rapid spread of COVID-19 in these facilities the world over. In this review, we present current “dementia friendly” design models in the home, community, and LTC, and argue how they could have saved lives during the pandemic and reduced the stresses on both the dementia resident and the caregiver/staff. Show more

Keywords: Alzheimer’s café, Alzheimer’s disease, butterfly care, COVID-19, dementia, dementia friendly, dementia village, green care, green house, long-term care, wayfinding

DOI: 10.3233/JAD-210017

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-24, 2021

Authors: Teitsdottir, Unnur D. | Halldorsson, Skarphedinn | Rolfsson, Ottar | Lund, Sigrun H. | Jonsdottir, Maria K. | Snaedal, Jon | Petersen, Petur H.

Article Type: Research Article

Abstract: Background: Understanding how dysregulation in lipid metabolism relates to the severity of Alzheimer‘s disease (AD) pathology might be critical in developing effective treatments. Objective: To identify lipid species in cerebrospinal fluid (CSF) associated with signature AD pathology and to explore their relationships with measures reflecting AD-related processes (neurodegeneration, inflammation, deficits in verbal episodic memory) among subjects at the pre- and early symptomatic stages of dementia. Methods: A total of 60 subjects that had been referred to an Icelandic memory clinic cohort were classified as having CSF AD (n  = 34) or non-AD (n  = 26) pathology profiles. …Untargeted CSF lipidomic analysis was performed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) for the detection of mass-to-charge ratio (m/z) features. CSF proteins reflecting neurodegeneration (neurofilament light [NFL]) and inflammation (chitinase-3-like protein 1 [YKL-40], S100 calcium-binding protein B [S100B], glial fibrillary acidic protein [GFAP]) were also measured. Rey Auditory Verbal Learning (RAVLT) and Story tests were used for the assessment of verbal episodic memory. Results: Eight out of 1008 features were identified as best distinguishing between the CSF profile groups. Of those, only the annotation of the m/z feature assigned to lipid species C18 ceramide was confirmed with a high confidence. Multiple regression analyses, adjusted for age, gender, and education, demonstrated significant associations of CSF core AD markers (Aβ 42 : st.β= –0.36, p  = 0.007; T-tau: st.β= 0.41, p  = 0.005) and inflammatory marker S100B (st.β= 0.51, p  = 0.001) with C18 ceramide levels. Conclusion: Higher levels of C18 ceramide associated with increased AD pathology and inflammation, suggesting its potential value as a therapeutic target. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, inflammation, lipidomics

DOI: 10.3233/JAD-200964

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Douros, Antonios | Santella, Christina | Dell’Aniello, Sophie | Azoulay, Laurent | Renoux, Christel | Suissa, Samy | Brassard, Paul

Article Type: Research Article

Abstract: Background: Previous studies suggested a link between various infectious pathogens and the development of Alzheimer’s disease (AD), posing the question whether infectious disease could present a novel modifiable risk factor. Objective: To assess whether infectious disease burden due to clinically apparent infections is associated with an increased risk of AD. Methods: We conducted a population-based nested case-control study using the United Kingdom Clinical Practice Research Datalink. We included all dementia-free subjects ≥50 years of age enrolling in the database between January 1988 and December 2017. Each case of AD identified during follow-up was matched with up …to 40 controls. Conditional logistic regression estimated adjusted odds ratios (ORs) with 95% confidence intervals (CIs) of AD associated with ≥1 infection diagnosed >  2 years before the index date compared with no infection during the study period. We further stratified by time since first infection and cumulative number of infections. Results: The cohort included overall 4,262,092 individuals (mean age at cohort entry 60.4 years; 52% female). During a median follow-up of 10.5 years, 40,455 cases of AD were matched to 1,610,502 controls. Compared with having no burden of infectious disease, having a burden of infectious disease was associated with an increase in the risk of AD (OR, 1.05; 95% CI, 1.02 to 1.08). The risk increased with longer time since first infection, peaking after 12–30 years (OR, 1.11; 95% CI, 1.05–1.17). The risk did not increase with cumulative number of infections. Conclusion: The overall risk of AD associated with infectious disease burden was small but increased gradually with longer time since first infection. Show more

Keywords: Alzheimer’s disease, dementia, epidemiology, infection, neurodegenerative diseases

DOI: 10.3233/JAD-201534

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Ikeda, Shunya | Mimura, Masaru | Ikeda, Manabu | Wada-Isoe, Kenji | Azuma, Mie | Inoue, Sachie | Tomita, Kiyoyuki

Article Type: Research Article

Abstract: Background: Alzheimer’s disease dementia (ADD) is the leading cause of long-term care in Japan. Objective: This study estimates the annual healthcare and long-term care costs in fiscal year 2018 for adults over 65 years of age with ADD in Japan and the informal care costs and productivity loss for their families. Methods: Healthcare and long-term care costs for ADD were estimated according to the disease severity classified by the clinical dementia rating (CDR) score, using reports from a literature review. For the costs of time spent on caregiving activities, productivity loss for ADD family caregivers aged …20–69 and informal care costs for all ADD family caregivers were estimated. Results: The total healthcare cost of ADD was JPY 1,073 billion, of which 86% (JPY 923 billion) was attributed to healthcare costs other than ADD drug costs (JPY 151 billion). The healthcare costs other than ADD drug costs by severity were less than JPY 200 billion for CDR–0.5, CDR-1, and CDR-2, respectively, but increased to JPY 447 billion (48%) for CDR-3. The public long-term care costs were estimated to be JPY 4,783 billion, which increased according to the severity. Total productivity loss for ADD family caregivers aged 20–69 was JPY 1,547 billion and the informal care cost for all ADD family caregivers was JPY 6,772 billion. Conclusion: ADD costs have a significant impact on public-funded healthcare, long-term care systems, and families in Japan. To minimize the economic burden of ADD, prolonging healthy life expectancy is the key factor to address. Show more

Keywords: Alzheimer’s disease dementia, burden of illness, clinical dementia rating, healthcare cost, long-term care cost, productivity cost

DOI: 10.3233/JAD-210075

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Morris, Robert | Luboff, Hunter | Jose, Rahul P. | Eckhoff, Kyle | Bu, Kun | Pham, Minh | Rohlsen-Neal, Dekai | Cheng, Feng

Article Type: Research Article

Abstract: Background: Bradycardia is a physiological condition characterized by a decrease in heart rate and is a side effect of many drug classes. Bradycardia has been reported as an adverse event for patients receiving donepezil for Alzheimer’s disease (AD) treatment. Objective: The purpose of the paper is to systematically investigate the association between the occurrence of bradycardia in adults and the usage of donepezil using clinical data derived from the FDA Adverse Event Reporting System (FAERS) database. Methods: The risk of bradycardia in patients who only took donepezil was compared with those of patients who only took …over-the-counter medications, multiple arrhythmia drugs, or other medications for AD treatment. In addition, this study sought to determine if this heightened bradycardia risk was influenced by sex, age, and dosage. Results: The results indicated that there was a significant greater likelihood of reporting bradycardia in patients administered donepezil than most of the drugs investigated. There was no significant association between age or the dosage of donepezil and the likelihood of reporting bradycardia. However, males were found to be more likely than females to report bradycardia as an adverse event. Tumor necrosis factor inhibition and stimulation of endothelial nitric oxide synthase were proposed to be the primary mechanism of actions which confer elevated bradycardia risk when using donepezil. Conclusion: These findings identified strong association between the usage of donepezil and bradycardia in adults as well as provide insight into the underlying molecular mechanisms that induce bradycardia by donepezil. Show more

Keywords: Acetylcholinesterase inhibitors, AChE, Alzheimer’s disease, bradycardia, donepezil, endothelial nitric oxide synthase

DOI: 10.3233/JAD-201551

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Jitlal, Mark | Amirthalingam, Guru N.K. | Karania, Tasvee | Parry, Eve | Neligan, Aidan | Dobson, Ruth | Noyce, Alastair J. | Marshall, Charles R.

Article Type: Research Article

Abstract: Background: Socioeconomic deprivation may be an important determinant of dementia risk, mortality, and access to diagnostic services. Premature mortality from other causes and under-representation of deprived individuals in research may lead to this effect being overlooked. Objective: We assessed the relationship between deprivation and dementia mortality using comprehensive death certificate data for England and Wales from 2001 to 2017. Methods: We used standardized mortality ratios (SMR) and a Poisson model to compare likelihood of dying from dementia in each deprivation decile. We also examined the associations of deprivation with age at death from dementia, and with …likelihood of receiving a diagnosis of unspecified dementia. Results: Risk of dying from dementia was higher in more deprived deciles (Mean SMR [95% CI] in decile 1 : 0.528 [0.506 to 0.550], decile 10:0.369 [0.338 to 0.400]). In 2017, 14,837 excess dementia deaths were attributable to deprivation (21.5% of all dementia deaths that year). There were dose-response associations of deprivation with likelihood of being older at death with dementia (odds ratio [95% CI] for decile 10 (least deprived): 1.31 [1.28 to 1.33] relative to decile 1), and with likelihood of receiving a diagnosis of unspecified dementia (odds ratio [95% CI] for decile 10:0.78 [0.76 to 0.80] relative to decile 1). Conclusion: Socioeconomic deprivation in England and Wales is associated with increased dementia mortality, younger age at death with dementia, and poorer access to specialist diagnosis. Reducing social inequality may have a role in the prevention of dementia mortality. Show more

Keywords: Age at death, Alzheimer’s disease, dementia, deprivation, diagnosis, mortality, socioeconomic status

DOI: 10.3233/JAD-210089

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2021

Authors: Kleiman, Michael J. | Barenholtz, Elan | Galvin, James E. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Detecting early-stage Alzheimer’s disease in clinical practice is difficult due to a lack of efficient and easily administered cognitive assessments that are sensitive to very mild impairment, a likely contributor to the high rate of undetected dementia. Objective: We aim to identify groups of cognitive assessment features optimized for detecting mild impairment that may be used to improve routine screening. We also compare the efficacy of classifying impairment using either a two-class (impaired versus non-impaired) or three-class using the Clinical Dementia Rating (CDR 0 versus CDR 0.5 versus CDR 1) approach. Methods: Supervised feature selection …methods generated groups of cognitive measurements targeting impairment defined at CDR 0.5 and above. Random forest classifiers then generated predictions of impairment for each group using highly stochastic cross-validation, with group outputs examined using general linear models. Results: The strategy of combining impairment levels for two-class classification resulted in significantly higher sensitivities and negative predictive values, two metrics useful in clinical screening, compared to the three-class approach. Four features (delayed WAIS Logical Memory, trail-making, patient and informant memory questions), totaling about 15 minutes of testing time (∼30 minutes with delay), enabled classification sensitivity of 94.53% (88.43% positive predictive value, PPV). The addition of four more features significantly increased sensitivity to 95.18% (88.77% PPV) when added to the model as a second classifier. Conclusion: The high detection rate paired with the minimal assessment time of the four identified features may act as an effective starting point for developing screening protocols targeting cognitive impairment defined at CDR 0.5 and above. Show more

Keywords: Alzheimer’s disease, data mining, mild cognitive impairment, neuropsychological tests, supervised machine learning

DOI: 10.3233/JAD-201377

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Ashizawa, Takumi | Igarashi, Ataru | Sakata, Yukinori | Azuma, Mie | Fujimoto, Kenichi | Kobayashi, Tsukasa | Takase, Yoshimasa | Ikeda, Shunya

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) increases societal costs and decreases the activities of daily living (ADL) and quality of life (QoL) of the affected individuals. Objective: We assess the impact of AD severity on ADL, QoL, and caregiving costs in Japanese facilities for the elderly. Methods: Patients with AD in facilities for the elderly were included (47 facilities, N = 3,461). The QoL, ADL, and disease severity of patients were assessed using Barthel Index (BI), EuroQoL-5D-5L (EQ-5D-5L), and Mini-Mental State Examination (MMSE), respectively. Annual caregiving costs were estimated using patients’ claims data. The patients were subcategorized into the following …three groups according to the MMSE score: mild (21≤MMSE≤30), moderate (11≤MMSE≤20), and severe (0≤MMSE≤10). Changes among the three groups were evaluated using the Jonckheere-Terpstra test. Results: Four hundred and one participants were on anti-AD medicines, of whom 287 (age: 86.1±6.4 years, 76.7% women) in the mild (n  = 53, 84.0±6.9 years, 71.7%), moderate (n  = 118, 86.6±5.9 years, 76.3%), and severe (n  = 116, 86.6±6.5 years, 79.3%) groups completed the study questionnaires. The mean BI and EQ-5D-5L scores for each group were 83.6, 65.1, and 32.8 and 0.801, 0.662, and 0.436, respectively. The mean annual caregiving costs were 2.111, 2.470, and 2.809 million JPY, respectively. As AD worsened, the BI and EQ-5D-5L scores decreased and annual caregiving costs increased significantly. Conclusion: AD severity has an impact on QoL, ADL, and caregiving costs. Show more

Keywords: Activities of daily living, Alzheimer’s disease, cost of illness, Japan, observational study, quality of life

DOI: 10.3233/JAD-201514

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2021

Authors: Wong, Dickson | Broberg, Dana N. | Doad, Jagroop | Umoh, Joseph U. | Bellyou, Miranda | Norley, Chris J. D. | Holdsworth, David | Montero-Odasso, Manuel | Beauchet, Olivier | Annweiler, Cedric | Bartha, Robert

Article Type: Research Article

Abstract: Background: Vitamin D deficiency and altered body composition are common in Alzheimer’s disease (AD). Memantine with vitamin D supplementation can protect cortical axons against amyloid-β exposure and glutamate toxicity. Objective: To study the effects of vitamin D deprivation and subsequent treatment with memantine and vitamin D enrichment on whole-body composition using a mouse model of AD. Methods: Male APPswe/PS1dE9 mice were divided into four groups at 2.5 months of age: the control group (n  = 14) was fed a standard diet throughout; the remaining mice were started on a vitamin D-deficient diet at month 6. The …vitamin D-deficient group (n  = 14) remained on the vitamin D-deficient diet for the rest of the study. Of the remaining two groups, one had memantine (n  = 14), while the other had both memantine and 10 IU/g vitamin D (n  = 14), added to their diet at month 9. Serum 25(OH)D levels measured at months 6, 9, 12, and 15 confirmed vitamin D levels were lower in mice on vitamin D-deficient diets and higher in the vitamin D-supplemented mice. Micro-computed tomography was performed at month 15 to determine whole-body composition. Results: In mice deprived of vitamin D, memantine increased bone mineral content (8.7% increase, p  <  0.01) and absolute skeletal tissue mass (9.3% increase, p  <  0.05) and volume (9.2% increase, p  <  0.05) relative to controls. This was not observed when memantine treatment was combined with vitamin D enrichment. Conclusion: Combination treatment of vitamin D and memantine had no negative effects on body composition. Future studies should clarify whether vitamin D status impacts the effects of memantine treatment on bone physiology in people with AD. Show more

Keywords: Adipose tissue, Alzheimer’s disease, animal models, body composition, bone and bones, 3-D imaging, memantine, muscle, vitamin D, x-ray micro-CT

DOI: 10.3233/JAD-201137

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Åström, Daniel Oudin | Adolfsson, Rolf | Segersson, David | Forsberg, Bertil | Oudin, Anna

Article Type: Article Commentary

Abstract: Exposure to fine particulate air pollution (PM2.5 ) is emerging as a risk factor for Alzheimer’s disease (AD), but existing studies are still limited and heterogeneous. We have previously studied the association between dementia (AD and vascular dementia) and PM2.5 stemming from vehicle exhaust and wood-smoke in the Betula cohort in Northern Sweden. The aim of this commentary is to estimate the association between total PM2.5 and dementia in the Betula cohort, which is more relevant to include in future meta-estimates than the source-specific estimates. The hazard ratio for incident dementia associated with a 1μ g/m3 increase in …local PM2.5 was 1.38 (95% confidence interval: 0.99 –1.92). The interpretation of our results is that they indicate an association between local contrasts in concentration of PM2.5 at the residential address and incidence of dementia in a low-level setting. Show more

Keywords: Air pollution, Alzheimer’s disease, dementia, particulate air pollution, PM2.5

DOI: 10.3233/JAD-201538

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-3, 2021

Authors: Byeon, Gihwan | Byun, Min Soo | Yi, Dahyun | Lee, Jun Ho | Jeon, So Yeon | Ko, Kang | Jung, Gijung | Lee, Jun-Young | Kim, Yu Kyeong | Lee, Yun-Sang | Kang, Koung Mi | Sohn, Chul-Ho | Lee, Dong Young | for the KBASE research group

Article Type: Research Article

Abstract: Background: Both elevated blood homocysteine and diabetes mellitus (DM) are related to cognitive impairments or dementia. A previous study also demonstrated that the association between homocysteine and cognitive decline was much stronger in individuals with DM than in those without DM. Objective: This study aimed to examine the interactive effect of blood homocysteine and DM on brain pathological changes including brain atrophy, amyloid-β and tau deposition, and small vessel disease (SVD) related to cognitive impairments. Methods: A total of 430 non-demented older adults underwent comprehensive clinical assessment, measurement of serum homocysteine level, [11 C] Pittsburgh …Compound B (PiB) PET, [18 F] AV-1451 PET, and brain MRI. Results: The interactive effect of homocysteine with the presence of DM on brain atrophy, especially in aging-related brain regions, was significant. Higher homocysteine concentration was associated with more prominent brain atrophy in individuals with DM, but not in those without DM. In contrast, interaction effect of homocysteine and DM was found neither on Alzheimer’s disease (AD) pathologies, including amyloid-β and tau deposition, nor white matter hyperintensity volume as a measure of SVD. Conclusion: The present findings suggest that high blood homocysteine level and DM synergistically aggravate brain damage independently of AD and cerebrovascular disease. With regard to preventing dementia or cognitive decline in older adults, these results support the importance of strictly controlling blood glucose in individuals with hyperhomocysteinemia and lowering blood homocysteine level in those with DM. Show more

Keywords: Brain atrophy, diabetes mellitus, homocysteine, magnetic resonance imaging, positron emission tomography

DOI: 10.3233/JAD-210036

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Ni, Ruiqing | Röjdner, Jennie | Voytenko, Larysa | Dyrks, Thomas | Thiele, Andrea | Marutle, Amelia | Nordberg, Agneta

Article Type: Research Article

Abstract: Background: Emerging evidence indicates a central role of gliosis in Alzheimer’s disease (AD) pathophysiology. However, the regional distribution and interaction of astrogliosis and microgliosis in association with amyloid-β (Aβ) still remain uncertain. Objective: Here we studied the pathological profiles in autopsy AD brain by using specific imaging tracers. Methods: Autopsy brain tissues of AD (n  = 15, age 70.4±8.5 years) and control cases (n  = 12, age 76.6±10.9) were examined with homogenate binding assays, autoradiography for Aβ plaques (3 H-florbetaben/3 H-PIB), astrogliosis (3 H-L-deprenyl), and microgliosis (3 H-PK11195/3 H-FEMPA), as well as immunoassays. Results: In vitro …saturation analysis revealed high-affinity binding sites of 3 H-florbetaben, 3 H-L-deprenyl, and 3 H-PK11195/3 H-FEMPA in the frontal cortex of AD cases. In vitro 3 H-florbetaben binding increased across cortical and subcortical regions of AD compared to control with the highest binding in the frontal and parietal cortices. The in vitro 3 H-L-deprenyl binding showed highest binding in the hippocampus (dentate gyrus) followed cortical and subcortical regions of AD while the GFAP expression was upregulated only in the hippocampus compared to control. The in vitro 3 H-PK11195 binding was solely increased in the parietal cortex and the hippocampus of AD compared to control. The 3 H-florbetaben binding positively correlated with the 3 H-L-deprenyl binding in the hippocampus and parietal cortex of AD and controls. Similarly, a positive correlation was observed between 3 H-florbetaben binding and GFAP expression in hippocampal AD and control brain. Conclusion: The use of multi-modal imaging tracers revealed different regional pattern of changes in autopsy AD brain with respect to amyloid plaque pathology versus astrogliosis and microgliosis. Show more

Keywords: Alzheimer’s disease, amyloid-beta peptides, astrocytes, glial fibrillary acid protein, microglia, monoamine oxidase B, positron emission tomography

DOI: 10.3233/JAD-201344

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2021

Authors: Fonseca, Luciana Mascarenhas | Mattar, Guilherme Prado | Haddad, Glenda Guerra | Ekaterina, Burduli | McPherson, Sterling M. | Guilhoto, Laura Maria de Figueiredo Ferreira | Yassuda, Mônica Sanches | Busatto, Geraldo Filho | Bottino, Cassio Machado de Campos | Hoexter, Marcelo Queiroz | Chaytor, Naomi Sage

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms (NPS) are non-cognitive manifestations common to dementia and other medical conditions, with important consequences for the patient, caregivers, and society. Studies investigating NPS in individuals with Down syndrome (DS) and dementia are scarce. Objective: Characterize NPS and caregiver distress among adults with DS using the Neuropsychiatric Inventory (NPI). Methods: We evaluated 92 individuals with DS (≥30 years of age), divided by clinical diagnosis: stable cognition, prodromal dementia, and AD. Diagnosis was determined by a psychiatrist using the Cambridge Examination for Mental Disorders of Older People with Down’s Syndrome and Others with Intellectual Disabilities …(CAMDEX-DS). NPS and caregiver distress were evaluated by an independent psychiatrist using the NPI, and participants underwent a neuropsychological assessment with Cambridge Cognitive Examination (CAMCOG-DS). Results: Symptom severity differed between-groups for delusion, agitation, apathy, aberrant motor behavior, nighttime behavior disturbance, and total NPI scores, with NPS total score being found to be a predictor of AD in comparison to stable cognition (OR for one-point increase in the NPI = 1.342, p  = 0.012). Agitation, apathy, nighttime behavior disturbances, and total NPI were associated with CAMCOG-DS, and 62% of caregivers of individuals with AD reported severe distress related to NPS. Caregiver distress was most impacted by symptoms of apathy followed by nighttime behavior, appetite/eating abnormalities, anxiety, irritability, disinhibition, and depression (R2  = 0.627, F(15,76) = 8.510, p  < 0.001). Conclusion: NPS are frequent and severe in individuals with DS and AD, contributing to caregiver distress. NPS in DS must be considered of critical relevance demanding management and treatment. Further studies are warranted to understand the biological underpinnings of such symptoms. Show more

Keywords: Alzheimer’s disease, dementia, Down syndrome, intellectual disability, Neuropsychiatric Inventory, neuropsychiatric symptoms

DOI: 10.3233/JAD-201009

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2021

Authors: Lee, Cecilia S. | Lee, Michael L. | Gibbons, Laura E. | Yanagihara, Ryan T. | Blazes, Marian | Kam, Jason P. | McCurry, Susan M. | Bowen, James D. | McCormick, Wayne C. | Lee, Aaron Y. | Larson, Eric B. | Crane, Paul K.

Article Type: Research Article

Abstract: Background: Vascular disease is a risk factor for Alzheimer’s disease (AD) and related dementia in older adults. Retinal artery/vein occlusion (RAVO) is an ophthalmic complication of systemic vascular pathology. Whether there are associations between RAVO and dementia risk is unknown. Objective: To determine whether RAVOs are associated with an increased risk of developing vascular dementia or AD. Methods: Data from Adult Changes in Thought (ACT) study participants were analyzed. This prospective, population-based cohort study followed older adults (age ≥65 years) who were dementia-free at enrollment for development of vascular dementia or AD based on research criteria. …RAVO diagnoses were extracted from electronic medical records. Cox-regression survival analyses were stratified by APOE ɛ 4 genotype and adjusted for demographic and clinical factors. Results: On review of 41,216 person-years (4,743 participants), 266 (5.6%) experienced RAVO. APOE ɛ 4 carriers who developed RAVO had greater than four-fold higher risk for developing vascular dementia (Hazard Ratio [HR] 4.54, 95% Confidence Interval [CI] 1.86, 11.10, p  = 0.001). When including other cerebrovascular disease (history of carotid endarterectomy or transient ischemic attack) in the model, the risk was three-fold higher (HR 3.06, 95% CI 1.23, 76.2). No other conditions evaluated in the secondary analyses were found to confound this relationship. There was no effect in non-APOE ɛ 4 carriers (HR 1.03, 95% CI 0.37, 2.80). There were no significant associations between RAVO and AD in either APOE group. Conclusion: Older dementia-free patients who present with RAVO and carry the APOE ɛ 4 allele appear to be at higher risk for vascular dementia. Show more

Keywords: Alzheimer’s disease, cohort study, epidemiology, retinal artery occlusion, retinal vascular occlusion, retinal vein occlusion, vascular dementia

DOI: 10.3233/JAD-201492

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Gaudreault, Roger | Hervé, Vincent | van de Ven, Theo G.M. | Mousseau, Normand | Ramassamy, Charles

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder, responsible for nearly two-thirds of all dementia cases. In this review, we report the potential AD treatment strategies focusing on natural polyphenol molecules (green chemistry) and more specifically on the inhibition of polyphenol-induced amyloid aggregation/disaggregation pathways: in bulk and on biosurfaces. We discuss how these pathways can potentially alter the structure at the early stages of AD, hence delaying the aggregation of amyloid-β (Aβ) and tau. We also discuss multidisciplinary approaches, combining experimental and modelling methods, that can better characterize the biochemical and biophysical interactions between proteins and phenolic ligands. …In addition to the surface-induced aggregation, which can occur on surfaces where protein can interact with other proteins and polyphenols, we suggest a new concept referred as “confinement stability”. Here, on the contrary, the adsorption of Aβ and tau on biosurfaces other than Aβ- and tau-fibrils, e.g., red blood cells, can lead to confinement stability that minimizes the aggregation of Aβ and tau. Overall, these mechanisms may participate directly or indirectly in mitigating neurodegenerative diseases, by preventing protein self-association, slowing down the aggregation processes, and delaying the progression of AD. Show more

Keywords: Alzheimer’s disease, amyloid, blood cells, computer simulation, polyphenols, tau

DOI: 10.3233/JAD-201549

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-23, 2021

Authors: Ma, Ya-Hui | Wang, Ya-Yu | Tan, Lan | Xu, Wei | Shen, Xue-Ning | Wang, Hui-Fu | Hou, Xiao-He | Cao, Xi-Peng | Bi, Yan-Lin | Dong, Qiang | Yang, Jiu-Long | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: Although social networks are deemed as moderators of incident Alzheimer’s disease (AD), few data are available on the mechanism relevant to AD pathology. Objective: We aimed to investigate whether social networks affect metabolism of cerebrospinal fluid (CSF) AD biomarkers during early stage and identify modification effects of genetic factor and subjective cognitive decline (SCD). Methods: We studied participants from the Chinese Alzheimer’s disease Biomarker and Lifestyle (CABLE) database who received cognition assessments and CSF amyloid-β (Aβ 1–42 and Aβ 1–40 ) and tau proteins (total-tau [T-tau] and phosphorylated-tau [P-tau]) measurements. The social networks were …measured using self-reported questionnaires about social ties. Linear regression models were used. Results: Data were analyzed from 886 cognitively intact individuals aged 61.91 years (SD = 10.51), including 295 preclinical AD participants and 591 healthy controls. Social networks were mostly associated with CSF indicators of AD multi-pathologies (low P-tau/Aβ 1–42 and T-tau/Aβ 1–42 and high Aβ 1–42 /Aβ 1–40 ). Significant differences of genetic and cognitive status were observed for CSF indicators, in which associations of social network scores with CSF P-tau and indicators of multi-pathologies appeared stronger in APOE 4 carriers (versus non-carriers) and participants with SCD (versus controls), respectively. Alternatively, more pronounced associations for CSF T-tau (β= –0.005, p  <  0.001), Aβ 1–42 /Aβ 1–40 (β= 0.481, p  = 0.001), and T-tau/Aβ 1–42 (β= –0.047, p  <  0.001) were noted in preclinical AD stage than controls. Conclusion: These findings consolidated strong links between social networks and AD risks. Social networks as a modifiable lifestyle probably affected metabolisms of multiple AD pathologies, especially among at-risk populations. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, lifestyle, social network

DOI: 10.3233/JAD-201426

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Stonnington, Cynthia M. | Wu, Jianfeng | Zhang, Jie | Shi, Jie | Bauer III, Robert J. | Devadas, Vivek | Su, Yi | Locke, Dona E.C. | Reiman, Eric M. | Caselli, Richard J. | Chen, Kewei | Wang, Yalin | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Besides their other roles, brain imaging and other biomarkers of Alzheimer’s disease (AD) have the potential to inform a cognitively unimpaired (CU) person’s likelihood of progression to mild cognitive impairment (MCI) and benefit subject selection when evaluating promising prevention therapies. We previously described that among baseline FDG-PET and MRI measures known to be preferentially affected in the preclinical and clinical stages of AD, hippocampal volume was the best predictor of incident MCI within 2 years (79%sensitivity/78%specificity), using standard automated MRI volumetric algorithmic programs, binary logistic regression, and leave-one-out procedures. Objective: To improve the same prediction by using …different hippocampal features and machine learning methods, cross-validated via two independent and prospective cohorts (Arizona and ADNI). Methods: Patch-based sparse coding algorithms were applied to hippocampal surface features of baseline TI-MRIs from 78 CU adults who subsequently progressed to amnestic MCI in approximately 2 years (“progressors”) and 80 matched adults who remained CU for at least 4 years (“nonprogressors”). Nonprogressors and progressors were matched for age, sex, education, and apolipoprotein E4 allele dose. We did not include amyloid or tau biomarkers in defining MCI. Results: We achieved 92%prediction accuracy in the Arizona cohort, 92%prediction accuracy in the ADNI cohort, and 90%prediction accuracy when combining the two demographically distinct cohorts, as compared to 79%(Arizona) and 72%(ADNI) prediction accuracy using hippocampal volume. Conclusion: Surface multivariate morphometry and sparse coding, applied to individual MRIs, may accurately predict imminent progression to MCI even in the absence of other AD biomarkers. Show more

Keywords: Alzheimer’s disease, magnetic resonance imaging, mild cognitive impairment, prediction, prognosis

DOI: 10.3233/JAD-200821

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Harb, Amro A. | Chen, RuiJun | Chase, Herbert S. | Natarajan, Karthik | Noble, James M.

Article Type: Research Article

Abstract: Background: Patients with dementia are vulnerable during the coronavirus disease 2019 (COVID-19) pandemic, yet few studies describe their hospital course and outcomes. Objective: To describe and compare the hospital course for COVID-19 patients with dementia to an aging cohort without dementia in a large New York City academic medical center. Methods: This was a single-center retrospective cohort study describing all consecutive patients age 65 or older with confirmed COVID-19 who presented to the emergency department or were hospitalized at New York-Presbyterian/Columbia University Irving Medical Center between March 6 and April 7, 2020. Results: A …total of 531 patients were evaluated, including 116 (21.8%) with previously diagnosed dementia, and 415 without dementia. Patients with dementia had higher mortality (50.0%versus 35.4%, p  = 0.006); despite similar comorbidities and complications, multivariate analysis indicated the association was dependent on age, sex, comorbidities, and code status. Patients with dementia more often presented with delirium (36.2%versus 11.6%, p  <  0.001) but less often presented with multiple other COVID-19 symptoms, and these findings remained after adjusting for age and sex. Conclusion: Hospitalized COVID-19 patients with dementia had higher mortality, but dementia was not an independent risk factor for death. These patients were approximately 3 times more likely to present with delirium but less often manifested or communicated other common COVID-19 symptoms. For this high-risk population in a worsening pandemic, understanding the unique manifestations and course in dementia and aging populations may help guide earlier diagnosis and optimize medical management. Show more

Keywords: Advance directives, COVID-19, delirium, dementia, geriatrics, neurology

DOI: 10.3233/JAD-210050

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Yang, Jianwei | Jia, Longfei | Li, Yan | Qiu, Qiongqiong | Quan, Meina | Jia, Jianping

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) research is entering a unique moment in which enormous information about the molecular basis of this disease is being translated into therapeutics. However, almost all drug candidates have failed in clinical trials over the past 30 years. These many trial failures have highlighted a need for the incorporation of biomarkers in clinical trials to help improve the trial design. Fluid biomarkers measured in cerebrospinal fluid and circulating blood, which can reflect the pathophysiological process in the brain, are becoming increasingly important in AD clinical trials. In this review, we first succinctly outline a panel of fluid biomarkers …for neuropathological changes in AD. Then, we provide a comprehensive overview of current and future application of fluid biomarkers in clinical trials for AD. We also summarize the many challenges that have been encountered in efforts to integrate fluid biomarkers in clinical trials, and the barriers that have begun to be overcome. Ongoing research efforts in the field of fluid biomarkers will be critical to make significant progress in ultimately unveiling disease-modifying therapies in AD. Show more

Keywords: Alzheimer’s disease, biomarkers, blood biomarkers, cerebrospinal fluid, clinical trials

DOI: 10.3233/JAD-201068

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Gao, Dandan | Shang, Junkui | Sun, Ruihua | Shi, Yingying | Jiang, Haisong | Ma, Mingming | Zhang, Jiewen

Article Type: Research Article

Abstract: Background: Exosomes are nano-sized extracellular vesicles which are secreted by cells and usually found in body fluids. Previous research has shown that exosomal secretion and autophagy-lysosomal pathway synergistically participates in intracellular abnormal protein elimination. The main pathological manifestations of Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is abnormal accumulation of mutant NOTCH3, and CADASIL vascular smooth muscle cells have been found with autophagy-lysosomal dysfunction. However, whether plasma exosomes change in CADASIL patients is still unclear. Objective: We are aimed to investigate the differences of plasma exosomes between CADASIL patients and healthy controls. Methods: …The subjects included 30 CADASIL patients and 30 healthy controls without NOTCH3 mutation. The severity of white matter lesions (WMLs) of CADASIL patients was quantified by Fazekas score. Transmission electron microscopy and nanoparticle tracking analysis were performed to characterize plasma exosomes. In addition, NOTCH3, Neurofilament light and Aβ42 levels in plasma exosomes were quantified by enzyme-linked immunosorbent assays. Results: We found that exosomes from CADASIL patients were lower in quantity. In addition, CADASIL plasma exosomes had significantly lower levels of NOTCH3 and significantly increased levels of NFL than those of matched healthy subjects. Interestingly, plasma exosome NOTCH3 levels of CADASIL patients significantly correlated with severity of WMLs. Conclusion: The exosome NOTCH3 may be related to the pathological changes of CADASIL, which provides a basis for the pathogenesis research of CADASIL. In addition, plasma exosome NOTCH3 and NFL levels may act as biomarkers to monitor and predict disease progression and measure therapeutic effectiveness in the future clinical trials. Show more

Keywords: CADASIL, exosomes, nanoparticle tracking analysis, neurofilament light, NOTCH3, transmission electron microscopy

DOI: 10.3233/JAD-210101

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Araya, Joaquín | Bello, Felipe | Shivashankar, Gaganashree | Neira, David | Durán-Aniotz, Claudia | Acosta, Mónica L. | Escobar, María José | Hetz, Claudio | Chacón, Max | Palacios, Adrián G.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most prevalent form of dementia worldwide. This neurodegenerative syndrome affects cognition, memory, behavior, and the visual system, particularly the retina. Objective: This work aims to determine whether the 5xFAD mouse, a transgenic model of AD, displays changes in the function of retinal ganglion cells (RGCs) and if those alterations are correlated with changes in the expression of glutamate and gamma-aminobutyric acid (GABA) neurotransmitters. Methods: In young (2–3-month-old) and adult (6-7-month-old) 5xFAD and WT mice, we have studied the physiological response, firing rate, and burst of RGCs to various types of …visual stimuli using a multielectrode array system. Results: The firing rate and burst response in 5xFAD RGCs showed hyperactivity at the early stage of AD in young mice, whereas hypoactivity was seen at the later stage of AD in adults. The physiological alterations observed in 5xFAD correlate well with an increase in the expression of glutamate in the ganglion cell layer in young and adults. GABA staining increased in the inner nuclear and plexiform layer, which was more pronounced in the adult than the young 5xFAD retina, altering the excitation/inhibition balance, which could explain the observed early hyperactivity and later hypoactivity in RGC physiology. Conclusion: These findings indicate functional changes may be caused by neurochemical alterations of the retina starting at an early stage of the AD disease. Show more

Keywords: Alzheimer’s disease, GABA, glutamate, retinal ganglion cells, 5xFAD transgenic mice

DOI: 10.3233/JAD-201195

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Baptista, Maria Alice Tourinho | Kimura, Nathália | Lacerda, Isabel Barbeito | Silva, Felipe de Oliveira | Dourado, Marcia Cristina Nascimento

Article Type: Research Article

Abstract: Background: There is a lack of research investigating whether there are differences in the domains of awareness according to the age at onset of dementia. Objective: This study is designed to investigate differences in awareness of cognitive functioning and health condition, functional activity impairments, emotional state, and social functioning and relationships among people with young onset (YOD) and late onset dementia (LOD); and examine associations between awareness and its domains with cognition, functionality, neuropsychiatric symptoms, social and emotional functioning, and quality of life (QoL) in both groups. Methods: A group of 136 people with dementia and …their respective caregivers (YOD = 50 and LOD = 86) were consecutively selected. We assessed awareness of disease, dementia severity, cognition, functionality, neuropsychiatric symptoms, social and emotional functioning, and QoL. Results: People with YOD had more neuropsychiatric symptoms than people with LOD. People with YOD were more aware of disease (total score), of their cognitive functioning and health condition and of their functional activity impairments, even if this group was more severely cognitive impaired and had a worse level of functionality than LOD group. Multivariate linear regressions showed that functionality has a wide relationship to awareness for people with YOD. While neuropsychiatric symptoms and QoL has a greater relation to awareness for people with LOD. Conclusion: Different clinical variables are associated to different domains in YOD and LOD groups, reinforcing the heterogeneity of awareness in dementia. Show more

Keywords: Awareness of disease, awareness’ domains, dementia, late onset, young onset

DOI: 10.3233/JAD-201603

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Kadey, Kylie R. | Woodard, John L. | Moll, Allison C. | Nielson, Kristy A. | Smith, J. Carson | Durgerian, Sally | Rao, Stephen M.

Article Type: Research Article

Abstract: Background: Body mass index (BMI) has been identified as an important modifiable lifestyle risk factor for dementia, but less is known about how BMI might interact with Apolipoprotein E ɛ4 (APOE ɛ4) carrier status to predict conversion to mild cognitive impairment (MCI) and dementia. Objective: The aim of this study was to investigate the interaction between APOE ɛ4 status and baseline (b BMI) and five-year BMI change (Δ BMI) on conversion to MCI or dementia in initially cognitively healthy older adults. Methods: The associations between b BMI, Δ BMI, APOE ɛ4 status, and …conversion to MCI or dementia were investigated among 1,289 cognitively healthy elders from the National Alzheimer’s Coordinating Center (NACC) database. Results: After five years, significantly more carriers (30.6%) converted to MCI or dementia than noncarriers (17.6%), p  <  0.001, OR  = 2.06. Neither b BMI (OR = 0.99, 95%CI = 0.96–1.02) nor the b BMI by APOE interaction (OR = 1.02, 95%CI = 0.96–1.08) predicted conversion. Although Δ BMI also did not significantly predict conversion (OR = 0.90, 95%CI = 0.78–1.04), the interaction between Δ BMI and carrier status was significant (OR = 0.72, 95%CI = 0.53–0.98). For carriers only, each one-unit decline in BMI over five years was associated with a 27%increase in the odds of conversion (OR = 0.73, 95%CI = 0.57–0.94). Conclusion: A decline in BMI over five years, but not b BMI, was strongly associated with conversion to MCI or dementia only for APOE ɛ4 carriers. Interventions and behaviors aimed at maintaining body mass may be important for long term cognitive health in older adults at genetic risk for AD. Show more

Keywords: Alzheimer’s disease, Apolipoprotein E4, body mass index, cognitive dysfunction, dementia

DOI: 10.3233/JAD-201360

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Miranda, Alvaro | Montiel, Enrique | Ulrich, Henning | Paz, Cristian

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is associated with marked atrophy of the cerebral cortex and accumulation of amyloid plaques and neurofibrillary tangles. Amyloid plaques are formed by oligomers of amyloid-β (Aβ) in the brain, with a length of 42 and 40 amino acids. α-secretase cleaves amyloid-β protein precursor (AβPP) producing the membrane-bound fragment CTFα and the soluble fragment sAβPPα with neuroprotective activity; β-secretase produces membrane-bound fragment CTFβ and a soluble fragment sAβPPβ. After α-secretase cleavage of AβPP, γ -secretase cleaves CTFα to produce the cytoplasmic fragment AICD and P3 in the non-amyloidogenic pathway. CTFβ is cleaved by γ -secretase producing AICD as …well as Aβ in amyloidogenic pathways. In the last years, the study of natural products and synthetic compounds, such as α-secretase activity enhancers, β-secretase inhibitors (BACE-1), and γ -secretase activity modulators, have been the focus of pharmaceuticals and researchers. Drugs were improved regarding solubility, blood-brain barrier penetration, selectivity, and potency decreasing Aβ42 . In this regard, BACE-1 inhibitors, such as Atabecestat, NB-360, Umibecestat, PF-06751979, Verubecestat, LY2886721, Lanabecestat, LY2811376, and Elenbecestat, were submitted to phase I-III clinical trials. However, inhibition of Aβ production did not recover cognitive functions or reverse the disease. Novel strategies are being developed, aiming at a partial reduction of Aβ production, such as the development of γ -secretase modulators or α-secretase enhancers. Such therapeutic tools shall focus on slowing down or minimizing the progression of neuronal damage. Here, we summarize structures and the activities of the latest compounds designed for AD treatment, with remarkable in vitro , in vivo , and clinical phase activities. Show more

Keywords: Alzheimer disease, α-secretase enhancers, β-secretase inhibitors, clinical trials, γ-secretase modulators

DOI: 10.3233/JAD-201027

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2021

Authors: Bai, Dong | Fan, Junting | Li, Mengyue | Dong, Cuixia | Gao, Yiming | Fu, Min | Huang, Guowei | Liu, Huan

Article Type: Research Article

Abstract: Background: The neuroprotective benefits of combined folic acid and docosahexaenoic acid (DHA) on cognitive function in mild cognitive impairment (MCI) patients are suggested but unconfirmed. Objective: To explore the effects of 6-month folic acid + DHA on cognitive function in patients with MCI. Methods: Our randomized controlled trial (trial number ChiCTR-IOR-16008351) was conducted in Tianjin, China. We divided 160 MCI patients aged >  60 years into four regimen groups randomly: folic acid (0.8 mg/day) + DHA (800 mg/day), folic acid (0.8 mg/day), DHA (800 mg/day), and placebo, for 6 months. Cognitive function and blood amyloid-β peptide (Aβ) biomarker levels were measured at baseline and 6 …months. Cognitive function was also measured at 12 months. Results: A total of 138 patients completed this trial. Folic acid improved the full-scale intelligence quotient (FSIQ), arithmetic, and picture complement scores; DHA improved the FSIQ, information, arithmetic, and digit span scores; folic acid + DHA improved the arithmetic (difference 1.67, 95% CI 1.02 to 2.31) and digital span (1.33, 0.24 to 2.43) scores compared to placebo. At 12 months, all scores declined in the intervention groups. Folic acid and folic acid + DHA increased blood folate (folic acid + DHA: 7.70, 3.81 to 11.59) and S-adenosylmethionine (23.93, 1.86 to 46.00) levels and reduced homocysteine levels (–6.51, –10.57 to –2.45) compared to placebo. DHA lower the Aβ40 levels (–40.57, –79.79 to –1.35) compared to placebo (p  <  0.05), and folic acid + DHA reduced the Aβ42 (–95.59, –150.76 to –40.43) and Aβ40 levels (–45.75, –84.67 to –6.84) more than DHA (p  <  0.05). Conclusion: Folic acid and DHA improve cognitive function and reduce blood Aβ production in MCI patients. Combination therapy may be more beneficial in reducing blood Aβ-related biomarkers. Show more

Keywords: Amyloid-β peptide-related biomarkers, docosahexaenoic acid, folic acid, mild cognitive impairment, randomized double-blind placebo-controlled trial

DOI: 10.3233/JAD-200997

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Tong, Qiang | Chen, Liam

Article Type: Research Article

Abstract: Background: Parkinson’s disease (PD) and Alzheimer’s disease (AD) are the two most prevalent neurodegenerative diseases associated with age. Pathological studies have shown that these two diseases share a certain degree of neuropathological overlap. AD neuropathologic change contributes to cognitive impairment in PD. However, the impact of AD pathology on other clinical phenotypes in PD remains largely unknown. Objective: Herein we aimed to assess the impact of co-occurring AD neuropathologic change on the clinical phenotypes of PD. Methods: We examined 46 autopsy brains of PD patients and available clinical information to retrospectively assess the effects of comorbid …AD pathology on dementia, hallucinations, and dyskinesia commonly seen in advanced PD. Results: AD neuropathology significantly increased the risk of hallucinations and dementia, but not dyskinesia in PD patients. Surprisingly, diffuse Lewy body pathology, but not AD pathology, was associated with the occurrence of dementia and hallucinations. Most importantly, we reported that the severity of neuronal loss in the locus coeruleus (LC), but not the severity of neuronal loss in the substantia nigra (SN), was associated with the occurrence of dyskinesia in advanced PD patients, while neither Lewy body scores in SN nor LC had significant effects. Conclusion: We show for the first time that neuronal loss in LC contributes to dyskinesia. Understanding the relationships between the two distinct pathologies and their relevant clinical phenotypes will be crucial in the development of effective disease-modifying therapies for PD. Show more

Keywords: Alzheimer’s disease neuropathologic change, dementia, dyskinesia, hallucination, locus coeruleus, Parkinson’s disease

DOI: 10.3233/JAD-210114

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2021

Authors: Dias, Irundika H.K. | Griffiths, Helen R.

Article Type: Article Commentary

Abstract: Neuroinflammation has been implicated in Alzheimer’s disease onset and progression. Chronic neuroinflammation is initiated by amyloid-β-activated microglial cells that secrete immuno-modulatory molecules within the brain and into the vasculature. Inflammation is normally self-limiting and actively resolves by “switching off” the generation of pro-inflammatory mediators and by non-phlogistic clearance of spent cells and their debris to restore tissue homeostasis. Deficits in these anti-inflammatory/pro-resolution pathways may predispose to the development of chronic inflammation. The synthesis of endogenous lipid mediators from arachidonic acid, lipoxins via cyclooxygenase 2 and lipoxygenases, and conversion of exogenous polyunsaturated fatty acids, namely docosahexaenoic acid and eicosapentaenoic acid, to …resolvins contributes to effective, timely resolution of acute inflammation. Work by Xiuzhe et al., 2020 in the Journal of Alzheimer ’s Disease reported that plasma level of LXA4 is related to cognitive status in ischemic stroke patients suggesting that decreased LXA4 may be a potential risk factor for post post-stroke cognitive impairment. As evident by recent clinical trials and development of drug analogues, there is recent drive to search for lipoxin analogues as therapeutics for inflammatory diseases. Understanding how bioactive lipid signaling is involved in resolution will increase our understanding of controlling inflammation and may facilitate the discovery of new classes of therapeutic pro-resolution agents for evaluation in AD prevention studies. Show more

Keywords: Alzheimer’s disease, Lipoxin A4, lipoxygenase, LXA4 drug analogues, neuroinflammation, pro-resolution, stroke, therapy

DOI: 10.3233/JAD-210121

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2021

Authors: Surya Tjahyo, Alvin | Gandy, Joan | Porter, Judi | Henry, Christiani Jeyakumar

Article Type: Review Article

Abstract: Weight loss, a hallmark feature of dementia, is associated with higher mortality in older people. However, there is a lack of consensus in the literature as to whether the weight loss commonly observed in older people with dementia results from reduced energy intake and/or increased energy expenditure. Understanding the cause of energy imbalance in older people with dementia would allow more targeted interventions to avoid detrimental health effects in this vulnerable group. In this paper, we review studies that have considered weight change, energy intake, and energy expenditure in older people with and without dementia. We critically assess the studies’ …methodology and outline the various factors which may decrease and increase energy intake and expenditure respectively in older people with and without dementia. Current available literature does not support the view that there is a lower energy intake and/or a higher energy expenditure in older people with dementia when compared to those without dementia. The need for more high-quality studies is also highlighted in order to shed more light towards this issue which continues to elude researchers and clinicians alike. Show more

Keywords: Aged, dementia, energy intake, energy metabolism, weight loss

DOI: 10.3233/JAD-201496

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2021

Authors: Yogev-Seligmann, Galit | Eisenstein, Tamir | Ash, Elissa | Giladi, Nir | Sharon, Haggai | Nachman, Shikma | Kodesh, Einat | Hendler, Talma | Lerner, Yulia

Article Type: Research Article

Abstract: Background: Aerobic training has been shown to promote structural and functional neurocognitive plasticity in cognitively intact older adults. However, little is known about the neuroplastic potential of aerobic exercise in individuals at risk of Alzheimer’s disease (AD) and dementia. Objective: We aimed to explore the effect of aerobic exercise intervention and cardiorespiratory fitness improvement on brain and cognitive functions in older adults with amnestic mild cognitive impairment (aMCI). Methods: 27 participants with aMCI were randomized to either aerobic training (n  = 13) or balance and toning (BAT) control group (n  = 14) for a 16-week intervention. Pre- and …post-assessments included functional MRI experiments of brain activation during associative memory encoding and neural synchronization during complex information processing, cognitive evaluation using neuropsychological tests, and cardiorespiratory fitness assessment. Results: The aerobic group demonstrated increased frontal activity during memory encoding and increased neural synchronization in higher-order cognitive regions such as the frontal cortex and temporo-parietal junction (TPJ) following the intervention. In contrast, the BAT control group demonstrated decreased brain activity during memory encoding, primarily in occipital, temporal, and parietal areas. Increases in cardiorespiratory fitness were associated with increases in brain activation in both the left inferior frontal and precentral gyri. Furthermore, changes in cardiorespiratory fitness were also correlated with changes in performance on several neuropsychological tests. Conclusion: Aerobic exercise training may result in functional plasticity of high-order cognitive areas, especially, frontal regions, among older adults at risk of AD and dementia. Furthermore, cardiorespiratory fitness may be an important mediating factor of the observed changes in neurocognitive functions. Show more

Keywords: Brain plasticity, cardiorespiratory fitness, cognition, functional MRI, mild cognitive impairment, physical exercise

DOI: 10.3233/JAD-201429

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-22, 2021

Authors: Graff-Radford, Jonathan | Lesnick, Timothy G. | Mielke, Michelle M. | Constantopoulos, Eleni | Rabinstein, Alejandro | Przybelski, Scott A. | Vemuri, Prashanthi | Botha, Hugo | Jones, David T. | Ramanan, Vijay K. | Petersen, Ronald C. | Knopman, David S. | Boeve, Bradley F. | Murray, Melissa E. | Dickson, Dennis W. | Jack, Clifford R. | Kantarci, Kejal | Ross Reichard, R.

Article Type: Research Article

Abstract: Background: The relationship between cerebral microbleeds (CMBs) on hemosiderin-sensitive MRI sequences and cerebral amyloid angiopathy (CAA) remains unclear in population-based participants or in individuals with dementia. Objective: To determine whether CMBs on antemortem MRI correlate with CAA. Methods: We reviewed 54 consecutive participants with antemortem T2 * GRE-MRI sequences and subsequent autopsy. CMBs were quantified on MRIs closest to death. Autopsy CAA burden was quantified in each region including leptomeningeal/cortical and capillary CAA. By clustering approach, we examined the relationship among CAA variables and performed principal component analysis (PCA) for dimension reduction to produce two scores from …these 15 interrelated predictors. Hurdle models assessed relationships between principal components and lobar CMBs. Results: MRI-based CMBs appeared in 20/54 (37%). 10 participants had ≥2 lobar-only CMBs. The first two components of the PCA analysis of the CAA variables explained 74% variability. The first rotated component (RPC1) consisted of leptomeningeal and cortical CAA and the second rotated component of capillary CAA (RPC2). Both the leptomeningeal and cortical component and the capillary component correlated with lobar-only CMBs. The capillary CAA component outperformed the leptomeningeal and cortical CAA component in predicting lobar CMBs. Both capillary and the leptomeningeal and cortical components correlated with number of lobar CMBs. Conclusion: Capillary and leptomeningeal/cortical scores correlated with lobar CMBs on MRI but lobar CMBs were more closely associated with the capillary component. The capillary component correlated with APOE ɛ 4, highlighting lobar CMBs as one aspect of CAA phenotypic diversity. More CMBs also increase the probability of underlying CAA. Show more

Keywords: Alzheimer’s disease, capillaries, cerebral amyloid angiopathy, neuropathology

DOI: 10.3233/JAD-201536

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Schwertner, Emilia | Zelic, Renata | Secnik, Juraj | Johansson, Björn | Winblad, Bengt | Eriksdotter, Maria | Religa, Dorota

Article Type: Research Article

Abstract: Background: In Sweden, 2,296,000 firearms were legally owned by private persons in 2017 and there were 150,000 persons living with a dementia diagnosis. A proportion of these persons owning a firearm may pose safety concerns. Objective: The aim was to describe firearm ownership in persons with dementia in Sweden and examine which characteristics are explaining physicians’ decision to report a person to the police as unsuitable to possess a firearm. Methods: This was a registry-based observational study. 65,717 persons with dementia registered in the Swedish Dementia Registry were included in the study. Logistic regression was used …to evaluate which of the persons’ characteristics were most important in predicting the likelihood of being reported as unsuitable to possess a firearm. Relative importance of predictors was quantified using standardized coefficients (SC) and dominance analysis (DA). Results: Out of 53,384 persons with dementia, 1,823 owned a firearm and 419 were reported to the police as unsuitable owners. Firearm owners were predominantly younger, males, living alone, and without assistance of homecare. The most important predictors of being reported to the police were: living with another person (SC = 0.23), frontotemporal dementia (SC = 0.18), antipsychotics prescription (SC = 0.18), being diagnosed in a memory/cognitive clinic (SC = –0.27), female gender (SC = 0.18), mild (SC = –0.25) and moderate (SC = –0.21) dementia, and hypnotics prescription (SC = 0.17). Conclusion: Firearm owners with dementia were mostly younger males who were still living more independent lives. The decision to remove a weapon was not solely based on a diagnosis of dementia but a combination of factors was considered. Show more

Keywords: Alzheimer’s disease, behavioral and psychological symptoms of dementia, dementia, firearm, frontotemporal, neuropsychiatric symptoms, risk assessment, vascular, violence

DOI: 10.3233/JAD-201365

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Valotassiou, Varvara | Sifakis, Nikolaos | Tzavara, Chara | Lykou, Evi | Tsinia, Niki | Kamtsadeli, Vasiliki | Sali, Dimitra | Angelidis, George | Psimadas, Dimitrios | Tsougos, Ioannis | Papageorgiou, Sokratis G. | Georgoulias, Panagiotis | Papatriantafyllou, John

Article Type: Research Article

Abstract: Background: Eating disorders (ED) in dementia represent a significant impairment affecting patients’ and caregivers’ lives. In frontotemporal dementia (FTD), ED include overeating, sweet food preference hyperorality, stereotypical eating, and hyperorality, while in Alzheimer’s disease (AD), anorexia and appetite loss are the most common ED. Objective: The aim of our study was to highlight Brodmann areas (BAs) implicated specifically in the appearance of ED in FTD and AD. Methods: We studied 141 patients, 75 with FTD and 66 with AD. We used the NeuroGamTM software on the reconstructed single photon emission computed tomography-SPECT data for the …automated comparison of BAs perfusion on the left (L) and right (R) hemisphere with perfusion in corresponding BAs of a normal database. Results: The FTD group included 27 men and 48 women, age (mean±SD) 65.8±8.5 years, duration of disease 3.4±3.3 years, Mini-Mental State Examination (MMSE) 17.9±8.6, ED score on Neuropsychiatric Inventory (NPI) 4.7±8.5. ED in FTD were correlated with hypoperfusion in right anterior and dorsolateral prefrontal cortices (BAs 10R, 46R), left orbitofrontal cortex (BA 12L), orbital part of the right inferior frontal gyrus (BA 47R), and left parahippocampal gyrus (BA 36L). The AD group included 21 men and 45 women, age (mean±SD) 70.2±8.0 years, duration of disease 3.3±2.4 years, MMSE 20.2±6, ED-NPI score 2.7±3.9. ED in AD were correlated with hypoperfusion in left inferior temporal cortex (BA 20L). Conclusion: SPECT imaging with automated mapping of brain cortex could contribute to the understanding of the neural networks involved in the manifestation of ED in dementia. Show more

Keywords: Alzheimer’s disease, Brodmann areas, eating disorders, frontotemporal dementia, perfusion, SPECT

DOI: 10.3233/JAD-201434

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Drake, Jonathan D. | Chambers, Alison B. | Ott, Brian R. | Daiello, Lori A. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Cerebrovascular dysfunction confers risk for functional decline in Alzheimer’s disease (AD), yet the clinical interplay of these two pathogenic processes is not well understood. Objective: We utilized Alzheimer’s Disease Neuroimaging Initiative (ADNI) data to examine associations between peripherally derived soluble cell adhesion molecules (CAMs) and clinical diagnostic indicators of AD. Methods: Using generalized linear regression models, we examined cross-sectional relationships of soluble plasma vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-Selectin to baseline diagnosis and functional impairment (clinical dementia rating sum-of-boxes, CDR-SB) in the ADNI cohort (n  = 112 AD, n  = 396 mild …cognitive impairment (MCI), n  = 58 cognitively normal). We further analyzed associations of these biomarkers with brain-based AD biomarkers in a subset with available cerebrospinal fluid (CSF) data (n  = 351). p-values derived from main effects and interaction terms from the linear regressions were used to assess the relationship between independent and dependent variables for significance (significance level was set at 0.05 a priori for all analysis). Results: Higher mean VCAM-1 (p  = 0.0026) and ICAM-1 (p  = 0.0189) levels were found in AD versus MCI groups; however, not in MCI versus cognitively normal groups. Only VCAM-1 was linked with CDR-SB scores (p  = 0.0157), and APOE ɛ4 genotype modified this effect. We observed independent, additive associations when VCAM-1 and CSF amyloid-β (Aβ 42 ), total tau, phosphorylated tau (P-tau), or P-tau/Aβ 42 (all <  p = 0.01) were combined in a CDR-SB model; ICAM-1 showed a similar pattern, but to a lesser extent. Conclusion: Our findings indicate independent associations of plasma-based vascular biomarkers and CSF biomarkers with AD-related clinical impairment. Show more

Keywords: Alzheimer’s disease, E-Selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1

DOI: 10.3233/JAD-200759

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Poptsi, Eleni | Tsolaki, Magda | Bergh, Sverre | Cesana, Bruno Mario | Ciccone, Alfonso | Fabbo, Andrea | Frisoni, Giovanni B. | Frölich, Lutz | Lavolpe, Sara | Guazzarini, Anna Giulia | Hugon, Jacques | Fascendini, Sara | Mecocci, Patrizia | Defanti, Carlo Alberto

Article Type: Research Article

Abstract: Background: Behavioral and psychological symptoms of dementia (BPSD) are quite challenging problems during the dementia course. Special Care Units for people with dementia (PwD) and BPSD (SCU-B) are residential medical structures, where BPSD patients are temporarily admitted, in case of unmanageable behavioral disturbances at home. Objective: RECage (REspectful Caring for AGitated Elderly) aspires to assess the short and long-term effectiveness of SCU-Bs toward alleviating BPSD and improving the quality of life (QoL) of PwD and their caregivers. Methods: RECage is a three-year, prospective study enrolling 500 PwDs. Particularly, 250 community-dwelling PwDs presenting with severe BPSD will …be recruited by five clinical centers across Europe, endowed with a SCU-B, for a short period of time; a second similar group of 250 PwD will be followed by six other no-SCU-B centers solely via outpatient visits. RECage’s endpoints include short and long-term SCU-B clinical efficacy, QoL of patients and caregivers, cost-effectiveness of the SCU-B, psychotropic drug consumption, caregivers’ attitude toward dementia, and time to nursing home placement. Results: PwDs admitted in SCU-Bs are expected to have diminished rates of BPSD and better QoL and their caregivers are also expected to have better QoL and improved attitude towards dementia, compared to those followed in no-SCU-Bs. Also, the cost of care and the psychotropic drug consumption are expected to be lower. Finally, PwDs followed in no-SCU-Bs are expected to have earlier admission to nursing homes. Conclusion: The cohort study results will refine the SCU-B model, issuing recommendations for implementation of SCU-Bs in the countries where they are scarce or non-existent. Show more

Keywords: Behavioral disturbances, dementia, special care units

DOI: 10.3233/JAD-201215

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2021

Authors: Zhou, Rui | Liu, Hua-Min | Li, Fu-Rong | Yang, Hai-Lian | Zheng, Jia-Zhen | Zou, Meng-Chen | Zou, Lian-Wu | Wu, Xiao-Xiang | Wu, Xian-Bo

Article Type: Research Article

Abstract: Background: Wealth and income are potential modifiable risk factors for dementia, but whether wealth status, which is composed of a combination of debt and poverty, and assessed by wealth and income, is associated with cognitive impairment among elderly adults remains unknown. Objective: To examine the associations of different combinations of debt and poverty with the incidence of dementia and cognitive impairment without dementia (CIND) and to evaluate the mediating role of depression in these relationships. Methods: We included 15,565 participants aged 51 years or older from the Health and Retirement Study (1992–2012) who were free of …CIND and dementia at baseline. Dementia and CIND were assessed using either the modified Telephone Interview for Cognitive Status (mTICS) or a proxy assessment. Cox models with time-dependent covariates and mediation analysis were used. Results: During a median of 14.4 years of follow-up, 4,484 participants experienced CIND and 1,774 were diagnosed with dementia. Both debt and poverty were independently associated with increased dementia and CIND risks, and the risks were augmented when both debt and poverty were present together (the hazard ratios [95% confidence intervals] were 1.35 [1.08–1.70] and 1.96 [1.48–2.60] for CIND and dementia, respectively). The associations between different wealth statuses and cognition were partially (mediation ratio range: 11.8–29.7%) mediated by depression. Conclusion: Debt and poverty were associated with an increased risk of dementia and CIND, and these associations were partially mediated by depression. Alleviating poverty and debt may be effective for improving mental health and therefore curbing the risk of cognitive impairment and dementia. Show more

Keywords: Cognitive impairment, cohort studies, dementia, depression, mediation analysis, wealth status

DOI: 10.3233/JAD-201239

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Pagen, Linda H.G. | Smeets, Tom | Schmiedek, Lisa | Yassa, Michael A. | Verhey, Frans R.J. | Jacobs, Heidi I.L.

Article Type: Research Article

Abstract: Background: Reductions in memory practice effects have gained interest as risk factor for future cognitive decline. Practice effects vary with age and can be moderated by factors such as individual variability in arousal or stress experience acting as an additional cognitive load. Objective: In the current pilot study, we examined whether sympathetic nervous system activation moderates the relationship between age and practice effects. Methods: Thirty cognitively healthy individuals aged 40–70 years performed a mnemonic discrimination task twice. Salivary alpha amylase (sAA) samples were obtained at different time points as a proxy of sympathetic activity. Spearman correlations …examined the relation between practice effects and sAA. Subsequently, age by sAA interactions on practice scores were explored with bootstrapped linear regression models. Additionally, participants were divided in learners (exhibiting practice effects) and non-learners based on the difference in mnemonic discrimination performance. Results: Higher age and baseline SNS activity were independently related to lower practice effects. The non-learners showed significantly higher sAA scores at all time points compared to learners. Among the learners, baseline-adjusted lower levels of sAA after encoding were associated with greater practice effects, particularly in middle-aged individuals. No such interaction was observed for non-learners. Conclusion: These results show that higher baseline sympathetic activation is associated with worse practice effects independently of age. Additionally, in a subgroup of middle-aged learners practice effects were observed when sympathetic activity remained low during learning. These findings suggest that elevated sympathetic nervous system activation may be a promising indicator of imminent cognitive decline. Show more

Keywords: Aging, memory, pattern separation, practice effects, sympathetic nervous system

DOI: 10.3233/JAD-200783

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Tanner, Jared J. | Hanchate, Shivani | Price, Catherine C. | Garvan, Cynthia | Lai, Song | Staud, Roland | Deshpande, Hrishikesh | Deutsch, Georg | Goodin, Burel R. | Fillingim, Roger B. | Sibille, Kimberly T.

Article Type: Research Article

Abstract: Background: Non-Hispanic black (NHB) individuals have increased risk of Alzheimer’s disease (AD) relative to non-Hispanic whites (NHW). Ethnicity/race can serve as a proxy sociodemographic variable for a complex representation of sociocultural and environmental factors. Chronic pain is a form of stress with high prevalence and sociodemographic disparities. Chronic pain is linked to lower cognition and accelerated biological aging. Objective: The purpose of this study is to seek understanding of potential cognitive and temporal lobe structural brain AD vulnerabilities based on chronic pain stage and ethnicity/race. Methods: Participants included 147 community dwelling NHB and NHW adults without …dementia between 45–85 years old who had or were at risk of knee osteoarthritis. All participants received an MRI (3T Philips), the Montreal Cognitive Assessment (MoCA), and assessment of clinical knee pain stage. Results: There were ethnic/race group differences in MoCA scores but no relationships with chronic knee pain stage. Ethnicity/race moderated the relationship between AD-related temporal lobe thickness and chronic pain stage with quadratic patterns suggesting thinner cortex in high chronic pain stage NHB adults. Conclusion: There appear to be complex relationships between chronic knee pain stage, temporal lobe cortex, and sociodemographic variables. Specifically, NHB participants without dementia but with high chronic knee pain stage appeared to have thinner temporal cortex in areas associated with AD. Understanding the effects of sociocultural and socioeconomic factors on health outcomes is the first step to challenging the disparities in healthcare that now appear to link disease conditions to neurodegenerative processes. Show more

Keywords: Alzheimer’s disease, chronic pain, ethnic groups, magnetic resonance imaging, race factors, risk factors, socioeconomic factors, temporal lobe

DOI: 10.3233/JAD-201345

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: van Zutphen, Elisabeth Maria | Rijnhart, Judith Johanna Maria | Rhebergen, Didericke | Muller, Majon | Huisman, Martijn | Beekman, Aartjan | Kok, Almar | Appelman, Yolande

Article Type: Research Article

Abstract: Background: Sex differences in cognitive functioning in old age are known to exist yet are still poorly understood. Objective: This study examines to what extent differences in cardiovascular risk factors and cardiovascular disease between men and women explain sex differences in cognitive functioning. Methods: Data from 2,724 older adults from the Longitudinal Aging Study Amsterdam were used. Information processing speed and episodic memory, measured three times during six years of follow-up, served as outcomes. The mediating role of cardiovascular risk factors and cardiovascular disease was examined in single and multiple mediator models. Determinant-mediator effects were estimated …using linear or logistic regression, and determinant-outcome and mediator-outcome effects were estimated using linear mixed models. Indirect effects were estimated using the product-of-coefficients estimator. Results: Women scored 1.58 points higher on information processing speed and 1.53 points higher on episodic memory. Several cardiovascular risk factors had small mediating effects. The sex difference in information processing speed was mediated by smoking, depressive symptoms, obesity, and systolic blood pressure. The sex difference in episodic memory was mediated by smoking, physical activity, and depressive symptoms. Effects of smoking, LDL cholesterol, and diabetes mellitus on information processing speed differed between men and women. Conclusion: Differences in cardiovascular risk factors between women and men partially explained why women had better cognitive functioning. A healthy cardiovascular lifestyle seems beneficial for cognition and sex-specific strategies may be important to preserve cognitive functioning at older age. Show more

Keywords: Aged, behavior, cardiovascular diseases, cognition, epidemiology, episodic memory, sex

DOI: 10.3233/JAD-201173

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Ten Brinke, Lisanne F. | Hsu, Chun Liang | Erickson, Kirk I. | Handy, Todd C. | Liu-Ambrose, Teresa

Article Type: Research Article

Abstract: Background: Evidence suggests that computerized cognitive training (CCT) can improve cognitive function in older adults, particularly executive functions. However, the underlying mechanisms by which CCT may improve executive functions are not well established. Objective: To determine: 1) inter-network functional connectivity correlates of changes in executive functions; and 2) the effect of CCT on these functional connectivity correlates. Methods: This secondary analysis included a subset of 124 adults aged 65–85 years enrolled in an 8-week randomized controlled trial of CCT. Participants were randomized to either: 1) group-based CCT 3x/week for 1 hour plus 3x/week home-based training; 2) …group-based CCT preceded by brisk walking (Ex-CCT) 3x/week for 1 hour plus 3x/week home-based training (exercise+CCT); or 3) group-based balanced and toned (BAT) classes 3x/week for 1 hour (control). At baseline and trial completion, 65 of the 124 participants completed resting-state functional magnetic resonance imaging and neuropsychological tests of executive functions, specifically the Stroop Colour-Word Test and Flanker Test. Results: Improved performance on the Stroop Colour-Word Test and Flanker Test were associated with decreased correlation between the default mode network (DMN) and the fronto-parietal network (FPN) (p  <  0.05). Compared with BAT, CCT alone significantly decreased correlation between the left dorsolateral prefrontal cortex and both the left and right medial temporal gyrus (–0.143, 95%CI [–0.256,–0.030], p  = 0.014, and –0.123, 95%CI [–0.242,–0.004], p  = 0.043, respectively). Conclusion: Decreased correlation between DMN and FPN, indicating less connection between these networks, may be an underlying mechanism by which CCT improves executive functions. Future studies are needed to replicate this finding. Show more

Keywords: Clinical trial, cognitive aging, executive function, magnetic resonance imaging

DOI: 10.3233/JAD-200844

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: El Said, Salma M.S. | Adly, Nermien N. | Abdul-Rahman, Samia A.

Article Type: Research Article

Abstract: Background: The ongoing scientific debate regarding the association between physical function and cognitive impairment has focused mainly on global cognitive performance rather than specific cognitive functions tests and the importance of recognition of its associations and any factors that could play a role later in the prevention of such decline. Objective: This study examined the association between physical function, using handgrip strength (HGS) and Timed Up-and-Go test (TUGT), and executive function (EF), using Clock Drawing Test (CDT), among community-dwelling Egyptian elderly. Methods: A cross-sectional study was conducted in 5 social clubs in Cairo, Egypt and included …a sample of 136 elderly males and females aged≥55 years old. All participants had their physical function assessed using TUGT, and measurement of HGS using a pneumatic hand-held dynamometer. Assessment of EF using CDT was also done. Results: Higher CDT scores were significantly associated with both better HGS, and lower TUGT (OR = 3.77, and 0.65 respectively). This persisted even after adjustment for age and gender (OR = 2.56, and 0.71 respectively) and after further adjustment for weight, systolic blood pressure, education, smoking, hyperlipidemia, hypothyroidism, and physical activity (O.R. = 4.79, and 0.76 respectively). Adjustment for both male and female genders showed an association between physical (HGS and TUGT) and EF was stronger among men. Conclusion: A strong association between CDT score and both of HGS and TUGT was found among the studied sample. Higher HGS and lower TUGT was significantly associated with better performance in the CDT. This association is stronger in males than in females for both HGS and TUGT. Show more

Keywords: Clock Drawing Test, elderly, executive function, handgrip strength, Timed Up-and-Go test

DOI: 10.3233/JAD-201423

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2021

Authors: Taslima, Ferdous | Jung, Cha-Gyun | Zhou, Chunyu | Abdelhamid, Mona | Abdullah, Mohammad | Goto, Tetsuya | Saito, Takashi | Saido, Takaomi C. | Michikawa, Makoto

Article Type: Research Article

Abstract: Background: Epidemiological studies have shown that tooth loss is associated with Alzheimer’s disease (AD) and dementia. However, the molecular and cellular mechanisms by which tooth loss causes AD remain unclear. Objective: We investigated the effects of tooth loss on memory impairment and AD pathogenesis in App NL  - G  - F mice. Methods: Maxillary molar teeth on both sides were extracted from 2-month-old AppNL  - G  - F mice, and the mice were reared for 2 months. The short- and long-term memory functions were evaluated using a novel object recognition test and a …passive avoidance test. Amyloid plaques, amyloid-β (Aβ) levels, glial activity, and neuronal activity were evaluated by immunohistochemistry, Aβ ELISA, immunofluorescence staining, and western blotting. The mRNA expression levels of neuroinflammatory cytokines were determined by qRT-PCR analysis. Results: Tooth loss induced memory impairment via an amyloid-cascade-independent pathway, and decreased the neuronal activity, presynaptic and postsynaptic protein levels in both the cortex and hippocampus. Interestingly, we found that tooth loss induced glial activation, which in turn leads to the upregulation of the mRNA expression levels of the neuroinflammation cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β in the hippocampus. We also found that tooth loss activated a stress-activated protein kinase, c-Jun N-terminal kinase (JNK), and increased heat shock protein 90 (HSP90) levels in the hippocampus, which may lead to a glial activation. Conclusion: Our findings suggest that taking care of teeth is very important to preserve a healthy oral environment, which may reduce the risk of cognitive dysfunction. Show more

Keywords: Alzheimer’s disease, AppNL - G - Fknock-in mice, chronic stress, glial activation, memory impairment, synapses, tooth loss

DOI: 10.3233/JAD-201055

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2021

Authors: Lukkarinen, Heikki | Tesseur, Ina | Pemberton, Darrel | Van Der Ark, Peter | Timmers, Maarten | Slemmon, Randy | Janssens, Luc | Streffer, Johannes | Van Nueten, Luc | Bottelbergs, Astrid | Rauramaa, Tuomas | Koivisto, Anne M. | Herukka, Sanna-Kaisa | Korhonen, Ville E. | Junkkari, Antti | Hiltunen, Mikko | Engelborghs, Sebastiaan | Blennow, Kaj | Zetterberg, Henrik | Kolb, Hartmuth C. | Leinonen, Ville

Article Type: Research Article

Abstract: Background: Longitudinal changes in cerebrospinal fluid (CSF) biomarkers are seldom studied. Furthermore, data on biomarker gradient between lumbar (L-) and ventricular (V-) compartments seems to be discordant. Objective: To examine alteration of CSF biomarkers reflecting Alzheimer’s disease (AD)-related amyloid-β (Aβ) aggregation, tau pathology, neurodegeneration, and early synaptic degeneration by CSF shunt surgery in idiopathic normal pressure hydrocephalus (iNPH) in relation to AD-related changes in brain biopsy. In addition, biomarker levels in L- and V-CSF were compared. Methods: L-CSF was collected prior to shunt placement and, together with V-CSF, 3–73 months after surgery. Thereafter, additional CSF sampling …took place at 3, 6, and 18 months after the baseline sample from 26 iNPH patients with confirmed Aβ plaques in frontal cortical brain biopsy and 13 iNPH patients without Aβ pathology. CSF Amyloid-β42 (Aβ42 ), total tau (T-tau), phosphorylated tau (P-tau181 ), neurofilament light (NFL), and neurogranin (NRGN) were analyzed with customized ELISAs. Results: All biomarkers but Aβ42 increased notably by 140–810% in L-CSF after CSF diversion and then stabilized. Aβ42 instead showed divergent longitudinal decrease between Aβ-positive and -negative patients in L-CSF, and thereafter increase in Aβ-negative iNPH patients in both L- and V-CSF. All five biomarkers correlated highly between V-CSF and L-CSF (Aβ42 R = 0.87, T-tau R = 0.83, P-tau R = 0.92, NFL R = 0.94, NRGN R = 0.9; all p  <  0.0001) but were systematically lower in V-CSF (Aβ42 14 %, T-tau 22%, P-tau 20%, NFL 32%, NRGN 19%). With APOE genotype-grouping, only Aβ42 showed higher concentration in non-carriers of allele ɛ 4. Conclusion: Longitudinal follow up shows that after an initial post-surgery increase, T-tau, P-tau, and NRGN are stable in iNPH patients regardless of brain biopsy Aβ pathology, while NFL normalized toward its pre-shunt levels. Aβ42 as biomarker seems to be the least affected by the surgical procedure or shunt and may be the best predictor of AD risk in iNPH patients. All biomarker concentrations were lower in V- than L-CSF yet showing strong correlations. Show more

Keywords: Aβ42 , biomarkers, idiopathic normal pressure hydrocephalus, neurofilament light, neurogranin, P-tau, T-tau

DOI: 10.3233/JAD-201361

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Luca, Antonina | Nicoletti, Alessandra | Donzuso, Giulia | Terravecchia, Claudio | Cicero, Calogero Edoardo | D’Agate, Concetta | Rascuná, Cristina | Manna, Roberta | Mostile, Giovanni | Zappia, Mario

Article Type: Research Article

Abstract: Background: The neuropsychological profile of progressive supranuclear palsy (PSP) patients is mainly characterized by executive dysfunction, but the relationship between the latter and midbrain atrophy is still unclear. Objective: The aims of the study were to investigate which test evaluating executive functioning is more frequently impaired in PSP patients and to evaluate the relationship between midbrain-based MRI morphometric measures and executive dysfunction. Methods: PSP patients who had undergone a neuropsychological battery assessing executive functioning with the Frontal Assessment Battery (FAB), the phonemic verbal fluency F-A-S, the Raven’s Progressive Colored Matrix, and the Stroop word colors test …(time and errors) were enrolled in the study. A group of Parkinson’s disease (PD) patients matched by age, sex, education, and global cognitive status was selected. All the enrolled patients also underwent a volumetric T1-3D brain MRI. Results: Thirty-five PSP patients and 35 PD patients were enrolled. Patients with PSP as compared to patients with PD showed a significant greater impairment in verbal fluency (16.0±7.9 and 23.4±8.7 words/180 s; p  <  0.001) and a significant lower score at the FAB total score (11.5±3.8 and 13.7±3.4; p  = 0.013). Midbrain area was significantly smaller in PSP patients than in PD patients (83.9±20.1 and 134.5±19.9 mm2 ; p  <  0.001). In PSP patients, a significant positive correlation between verbal fluency and the midbrain area (r  = 0.421; p  = 0.028) was observed. Conclusion: Our findings suggest that the phonemic verbal fluency is among the most frequently impaired executive functions in PSP patients and is strongly correlated to midbrain atrophy. Show more

Keywords: Executive functions, midbrain atrophy, progressive supranuclear palsy, verbal fluency

DOI: 10.3233/JAD-210023

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2021

Authors: Gupta, Harsh V. | Beach, Thomas G. | Mehta, Shyamal H. | Shill, Holly A. | Driver-Dunckley, Erika | Sabbagh, Marwan N. | Belden, Christine M. | Liebsack, Carolyn | Dugger, Brittany N. | Serrano, Geidy E. | Sue, Lucia I. | Siderowf, Andrew | Pontecorvo, Michael J. | Mintun, Mark A. | Joshi, Abhinay D. | Adler, Charles H.

Article Type: Research Article

Abstract: Background: Imaging biomarkers have the potential to distinguish between different brain pathologies based on the type of ligand used with PET. AV-45 PET (florbetapir, Amyvid) is selective for the neuritic plaque amyloid of Alzheimer’s disease (AD), while AV-133 PET (florbenazine) is selective for VMAT2, which is a dopaminergic marker. Objective: To report the clinical, AV-133 PET, AV-45 PET, and neuropathological findings of three clinically diagnosed dementia patients who were part of the Avid Radiopharmaceuticals AV133-B03 study as well as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Methods: Three subjects who had PET imaging with …both AV-133 and AV-45 as well as a standardized neuropathological assessment were included. The final clinical, PET scan, and neuropathological diagnoses were compared. Results: The clinical and neuropathological diagnoses were made blinded to PET scan results. The first subject had a clinical diagnosis of dementia with Lewy bodies (DLB); AV-133 PET showed bilateral striatal dopaminergic degeneration, and AV-45 PET was positive for amyloid. The final clinicopathological diagnosis was DLB and AD. The second subject was diagnosed clinically with probable AD; AV-45 PET was positive for amyloid, while striatal AV-133 PET was normal. The final clinicopathological diagnosis was DLB and AD. The third subject had a clinical diagnosis of DLB. Her AV-45 PET was positive for amyloid and striatal AV-133 showed dopaminergic degeneration. The final clinicopathological diagnosis was multiple system atrophy and AD. Conclusion: PET imaging using AV-133 for the assessment of striatal VMAT2 density may help distinguish between AD and DLB. However, some cases of DLB with less-pronounced nigrostriatal dopaminergic neuronal loss may be missed. Show more

Keywords: Alzheimer’s disease, amyloid, AV-133, dementia with Lewy bodies, synucleinopathy, VMAT2

DOI: 10.3233/JAD-200323

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Beishon, Lucy C. | Panerai, Ronney B. | Budgeon, Charley | Subramaniam, Hari | Mukaetova-Ladinska, Elizabeta | Robinson, Thompson G. | Haunton, Victoria J.

Article Type: Research Article

Abstract: Background: Cognitive training (CT) has demonstrated benefits for healthy older adults (HG) and mild cognitive impairment (MCI), but the effects on vascular function are unknown. Objective: This is a feasibility trial investigating the effects of CT on cerebral blood flow velocity (CBFv). Methods: Twenty HG, 24 with Alzheimer’s disease (AD), and 12 with MCI were randomized to 12 weeks of multi-domain CT or control. Outcomes included: cognition (Addenbrooke’s Cognitive Examination III), mood, quality of life (QoL), physical, and neurovascular function (transcranial Doppler ultrasonography measured task activation of CBFv responses). Data are presented as mean difference (MD) …and 95% confidence interval (CI). Results: 47 participants completed the trial. There were three dropouts from the training arm in the AD group, and one in the HG group. The intervention was acceptable and feasible to the majority of participants with a high completion rate (89%). The dropout rate was higher among participants with dementia. Few changes were identified on secondary analyses, but QoL was significantly improved in HG post-training (MD: 4.83 [95% CI: 1.13, 8.54]). CBFv response rate was not significantly different in HG (MD: 1.84 [95% CI: –4.81, 1.12]), but a significant increase was seen in the patient group (MD: 1.79 [95% CI: 0.005, 3.58]), requiring sample sizes of 56 and 84 participants respectively for a fully-powered trial. Conclusion: A 12-week CT program was acceptable and feasible in HG, AD, and MCI. CT may be associated with alterations in vascular physiology which require further investigation in an appropriately powered randomized controlled trial. Show more

Keywords: Cerebral blood flow, cerebral hemodynamics, cognition, cognitive impairment, dementia

DOI: 10.3233/JAD-201444

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2021

Authors: Chen, Yongjie | Du, Yue | Sun, Zhuoyu | Liu, Qian | Sun, Changqing | Lin, Hongyan | Jin, Mengdi | Fu, Jingzhu | Ma, Fei | Li, Wen | Liu, Huan | Zhang, Xumei | Wang, Guangshun | Huang, Guowei

Article Type: Research Article

Abstract: Background: Handgrip strength (HGS) and serum folate and homocysteine (Hcy) levels were associated with cognitive function. However, little was known whether there were interactions between HGS and serum folate and Hcy levels on cognitive function. Objective: To examine the interactions between HGS and serum folate and Hcy levels on cognitive function. Methods: This study analyzed the baseline data of the Tianjin Elderly Nutrition and Cognition Cohort study. All participants aged ≥60 years were potential eligible. HGS was measured using a grip strength dynamometer. Serum folate and Hcy levels were assayed using standard laboratory protocol. A Mini-Mental …State Examination was used to assess cognitive function. Linear regressions were employed to examine the interactions between HGS and serum folate and Hcy levels on cognitive function. Results: 4,484 participants were included in this study. There were interactions between HGS and serum folate and Hcy levels on cognitive function. Furthermore, subjects with strong HGS and sufficient folate level had the best cognitive function (β= 2.018), sequentially followed by those with strong HGS and insufficient folate level (β= 1.698) and with poor HGS and sufficient folate level (β= 0.873). Similarly, cognitive function was ranked in the descending order of subjects with strong HGS and normal Hcy level (β= 1.971), strong HGS and high Hcy level (β= 1.467), and poor HGS and normal Hcy level (β= 0.657). Conclusion: There were interactions between HGS and serum folate and Hcy levels on cognitive function. However, the temporal associations cannot be examined in a cross-sectional study. Further cohort study should be conducted to confirm these associations in the future. Show more

Keywords: Alzheimer’s disease, cognitive function, handgrip strength, serum folate, serum homocysteine

DOI: 10.3233/JAD-201537

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021