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

Authors: Gottesman, Reena T. | Kociolek, Anton | Fernandez, Kayri | Cosentino, Stephanie | Devanand, D.P. | Stern, Yaakov | Gu, Yian

Article Type: Research Article

Abstract: Background: Psychotic symptoms are an important and increasingly recognized aspect of Alzheimer’s disease (AD). They have been shown to contribute to faster disease progression in clinic-based, demographically homogenous samples with high educational attainment. Objective: We studied the association between baseline psychotic symptoms and disease progression among individuals with incident AD or ‘at risk’ of developing AD, from a demographically heterogenous, community-based cohort with minimal educational attainment. Methods: 212 participants received the Columbia University Scale of Psychopathology in Alzheimer’s Disease scale. Participants had psychotic symptoms with any of: visual illusions, delusions, hallucinations, or agitation/aggression. Disease progression was …measured yearly and defined by meeting cognitive (≤10 on the Folstein MMSE) or functional endpoints (≥10 on the Blessed Dementia Rating Scale or ≥4 on the Dependence Scale). Results: The mean age was 85 years old. The cohort was 78.3% female, 75.9% Hispanic, and had a mean 6.96 years of education. Within the follow-up period (mean: 3.69 years), 24 met the cognitive endpoint, 59 met the functional endpoint, and 132 met the cutoff for dependence. The presence of at least one psychotic symptom was initially associated with an increased risk of reaching the functional endpoint (HR 3.12, 95% CI 1.67–5.86, p  < 0.001) and the endpoint of dependence (HR = 1.498, 95% CI 1.05–2.13, p  = 0.03). However, these associations were attenuated and non-significant when adjusted for baseline functional status. Psychotic symptoms were not associated with the cognitive endpoint. Conclusion: Psychotic symptoms may predict functional decline in patients of non-Caucasian ethnicity and with lower educational attainment. Show more

Keywords: Alzheimer’s disease, ethnic groups, neurobehavioral manifestations, prognosis

DOI: 10.3233/JAD-200729

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

Authors: Szegeczki, Vince | Perényi, Helga | Horváth, Gabriella | Hinnah, Barbara | Tamás, Andrea | Radák, Zsolt | Ábrahám, Dóra | Zákány, Róza | Reglodi, Dora | Juhász, Tamás

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative illness, with several peripheral pathological signs such as accumulation of amyloid-β (Aβ) plaques in the kidney. Alterations of transforming growth factor β (TGFβ) signaling in the kidney can induce fibrosis, thus disturbing the elimination of Aβ. Objective: A protective role of increased physical activity has been proven in AD and in kidney fibrosis, but it is not clear whether TGFβ signalization is involved in this effect. Methods: The effects of long-term training on fibrosis were investigated in the kidneys of mice representing a model of AD (B6C3-Tg(APPswe,PSEN1dE9)85Dbo/J) by comparing …wild type and AD organs. Alterations of canonical and non-canonical TGFβ signaling pathways were followed with PCR, western blot, and immunohistochemistry. Results: Accumulation of collagen type I and interstitial fibrosis were reduced in kidneys of AD mice after long-term training. AD induced the activation of canonical and non-canonical TGFβ pathways in non-trained mice, while expression levels of signal molecules of both TGFβ pathways became normalized in trained AD mice. Decreased amounts of phosphoproteins with molecular weight corresponding to that of tau and the cleaved C-terminal of AβPP were detected upon exercising, along with a significant increase of PP2A catalytic subunit expression. Conclusion: Our data suggest that physical training has beneficial effects on fibrosis formation in kidneys of AD mice and TGFβ signaling plays a role in this phenomenon. Show more

Keywords: Alzheimer’s disease, fibrosis, physical activity, Smad, TGFβ

DOI: 10.3233/JAD-201206

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

Authors: Hayat, Shabina A | Luben, Robert | Khaw, Kay-Tee | Brayne, Carol

Article Type: Research Article

Abstract: Background: Exploring the domains of cognitive function which are most strongly associated with future dementia may help with understanding risk factors for, and the natural history of dementia. Objective: To examine the association of performance on a range of cognitive tests (both global and domain specific) with subsequent diagnosis of dementia through health services in a population of relatively healthy men and women and risk of future dementia. Methods: We examined the association between performance on different cognitive tests as well as a global score and future dementia risk ascertained through health record linkage in a …cohort of 8,581 individuals (aged 48–92 years) between 2004–2019 with almost 15 years follow-up (average of 10 years) before and after adjustment for socio-demographic, lifestyle, and health characteristics. Results: Those with poor performance for global cognition (bottom 10%) were almost four times as likely to receive a dementia diagnosis from health services over the next 15 years than those who performed well HR = 3.51 (95% CI 2.61, 4.71 p  <  0.001) after adjustment for socioeconomic, lifestyle, and biological factors and also prevalent disease. Poor cognition performance in multiple tests was associated with 10-fold increased risk compared to those not performing poorly in any test HR = 10.82 (95% CI 6.85, 17.10 p  <  0.001). Conclusion: Deficits across multiple cognitive domains substantially increase risk of future dementia over and above neuropsychological test scores ten years prior to a clinical diagnosis. These findings may help further understanding of the natural history of dementia and how such measures could contribute to strengthening future models of dementia. Show more

Keywords: Cognition, dementia, epidemiology, risk

DOI: 10.3233/JAD-210030

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

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: 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

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: 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: 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: Suh, Seung Wan | Kim, You Joung | Kwak, Kyung Phil | Kim, Kiwon | Kim, Moon-Doo | Kim, Byung-Soo | Kim, Bong Jo | Kim, Shin Gyeom | 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: 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: 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: 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: 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: 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