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

Authors: Jin, Nanxiang | Babiloni, Claudio | Drinkenburg, Wilhelmus H. | Hajós, Mihály | Nygaard, Haakon B. | Tanila, Heikki

Article Type: Research Article

Abstract: Recent evidence suggests that about 30%of patients with mild to moderate Alzheimer’s disease (AD) without a known diagnosis of epilepsy may display epileptiform spikes during electroencephalographic (EEG) recordings. These abnormal discharges occur predominantly during sleep and may be associated with accelerated disease progression. Subclinical spikes may represent a relevant target for clinical drug interventions, and there is a clear unmet need for preclinical testing of novel disease modifying agents in suitable animal models. Transgenic rodent models of AD pathology exhibit various forms of epileptiform EEG activity related to the abnormal levels of amyloid species in the brain. Among them, large-amplitude …cortical and hippocampal EEG spikes in mouse and rat AD models may be reminiscent of the subclinical epileptiform EEG spikes recorded in some AD patients. This article reports the recommendations of a multidisciplinary panel of experts on optimal EEG markers and experimental designs to measure and report epileptiform activities and their response to symptomatic and disease-modifying drugs in transgenic AD model rodents. These recommendations may harmonize future preclinical EEG studies in the drug discovery research and may increase the comparability of experimental outcomes and their translational clinical value. Show more

Keywords: Drug, EEG, epilepsy, epileptiform, mouse, rat, transgenic

DOI: 10.3233/JAD-210209

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

Authors: Makino, Taeko | Umegaki, Hiroyuki | Ando, Masahiko | Cheng, Xian Wu | Ishida, Koji | Akima, Hiroshi | Oshida, Yoshiharu | Yoshida, Yasuko | Uemura, Kazuki | Shimada, Hiroyuki | Kuzuya, Masafumi

Article Type: Research Article

Abstract: Background: Physical exercise is suggested to be effective for preventing cognitive decline in older adults, but the relative efficacy of different types of exercise have yet to be clarified. Objective: This single-blinded randomized controlled trial was designed to investigate the differential effects of aerobic exercise training (AT), resistance exercise training (RT), and combined exercise training (CT) on cognition in older adults with subjective memory complaints (SMC). Methods: Community-dwelling older adults with SMC (n  = 415; mean age = 72.3 years old) were randomly assigned to one of the four groups: AT, RT, CT, or control group. The study consisted …of two phases: a 26-week intervention and a 26-week follow-up. The participants were evaluated at baseline, 26 weeks (postintervention), and 52 weeks (follow-up). The primary outcome of this study was memory function, which was assessed using the Logical Memory II subtest of the Wechsler Memory Scale-Revised (WMS-R) score. The secondary outcomes included global cognitive function, verbal fluency, working memory, processing speed, and executive functions. Results: Intention-to-treat analysis by a mixed-effect model repeated measure showed that the AT group had significantly improved performance on the WMS-R Logical Memory II test (2.74 [1.82–3.66] points) than the control group (1.36 [0.44–2.28] points) at the postintervention assessment (p  = 0.037). The effect was more pronounced in those without amnesia than those with amnesia. No significant improvement was observed in the RT and CT groups. Conclusion: This study suggests that AT intervention can improve delayed memory in community-dwelling older adults, particularly in individuals without objective memory decline. Show more

Keywords: Amnesia, cognition, cognitive dysfunction, executive function, exercise, memory, physical activity, randomized controlled trial, resistance training, wechsler memory scale

DOI: 10.3233/JAD-210047

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

Authors: Delazer, Margarete | Zamarian, Laura | Djamshidian, Atbin

Article Type: Research Article

Abstract: Background: Agraphia is a typical feature in the clinical course of Alzheimer’s disease (AD). Objective: Assess the differences between AD and normal aging as regards kinematographic features of handwriting and elucidate writing deficits in AD. Methods: The study included 23 patients with AD (78.09 years/SD = 7.12; MMSE 21.39/SD = 3.61) and 34 healthy controls (75.56 years/SD = 5.85; MMSE 29.06/SD = 0.78). Both groups performed alphabetical and non-alphabetical writing tasks. The kinematographic assessment included the average number of inversions per stroke (NIV; number of peaks in the velocity profile in a single up or down stroke), percentage of automated segments, frequency (average number …of strokes per second), writing pressure, and writing velocity on paper. Results: A total of 14 patients showed overt writing difficulties reflected by omissions or substitutions of letters. AD patients showed less automated movements (as measured by NIV), lower writing velocity, and lower frequency of up-and-down strokes in non-alphabetical as well as in alphabetical writing. In the patient group, Spearman correlation analysis between overt writing performance and NIV was significant. That means patients who had less errors in writing a sentence showed a higher automaticity in handwriting. The correctness of alphabetical writing and some kinematographic measures in writing non-alphabetical material reached excellent diagnostic values in ROC analyses. There was no difference in the application of pressure on the pen between patients and controls. Conclusion: Writing disorders are multi-componential in AD and not strictly limited to one processing level. The slow and poorly automated execution of motor programs is not bound to alphabetical material. Show more

Keywords: Agraphia, dementia, inversions, kinematographic analysis, writing velocity

DOI: 10.3233/JAD-210279

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

Authors: Karanth, Shama D. | Schmitt, Frederick A. | Nelson, Peter T. | Katsumata, Yuriko | Kryscio, Richard J. | Fardo, David W. | Harp, Jordan P. | Abner, Erin L.

Article Type: Research Article

Abstract: Background: Late-life cognitive function is heterogeneous, ranging from no decline to severe dementia. Prior studies of cognitive trajectories have tended to focus on a single measure of global cognition or individual tests scores, rather than considering longitudinal performance on multiple tests simultaneously. Objective: The current study aimed to examine cognitive trajectories from two independent datasets to assess whether similar patterns might describe longitudinal cognition in the decade preceding death, as well as what participant characteristics were associated with trajectory membership. Methods: Data were drawn from autopsied longitudinally followed participants of two cohorts (total N  = 1,346), community-based …cohort at the University of Kentucky Alzheimer’s Disease Research Center (n  = 365) and National Alzheimer’s Coordinating Center (n  = 981). We used group-based multi-trajectory models (GBMTM) to identify cognitive trajectories over the decade before death using Mini-Mental State Exam, Logical Memory-Immediate, and Animal Naming performance. Multinomial logistic and Random Forest analyses assessed characteristics associated with trajectory groups. Results: GBMTM identified four similar cognitive trajectories in each dataset. In multinomial models, death age, Braak neurofibrillary tangles (NFT) stage, TDP-43, and α-synuclein were associated with declining trajectories. Random Forest results suggested the most important trajectory predictors were Braak NFT stage, cerebral atrophy, death age, and brain weight. Multiple pathologies were most common in trajectories with moderate or accelerated decline. Conclusion: Cognitive trajectories associated strongly with neuropathology, particularly Braak NFT stage. High frequency of multiple pathologies in trajectories with cognitive decline suggests dementia treatment and prevention efforts must consider multiple diseases simultaneously. Show more

Keywords: Cognitive decline, dementia, neurodegenerative disorders, neuropsychological tests, trajectories

DOI: 10.3233/JAD-210293

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

Authors: Sun, Xiaoyan | Dong, Chuanhui | Levin, Bonnie | Caunca, Michelle | Zeki Al Hazzouri, Adina | DeRosa, Janet T. | Stern, Yaakov | Cheung, Ying Kuen | Elkind, Mitchell S.V. | Rundek, Tatjana | Wright, Clinton B. | Sacco, Ralph L.

Article Type: Research Article

Abstract: Background: Increasing evidence suggests that hypertension is a risk factor for cognitive impairment and dementia. The relationship between blood pressure and cognition in a racially and ethnically diverse population remains unclear. Objective: To study association of blood pressure with cognition cross-sectionally and longitudinally in the elderly. Methods: Participants are stroke-free individuals from the racially and ethnically diverse Northern Manhattan Study (NOMAS) (n  = 1215). General linear models are constructed to examine blood pressure in relation to cognition cross-sectionally and longitudinally at a five-year follow-up. Results: We found a cross-sectional association of systolic blood pressure (SBP) …with word fluency/semantic memory, executive function, and processing speed/visual motor integration (VMI) function. This association was independent of demographics, vascular risk factors, white matter hyperintensity volume (WMHV), and carotid intima-media thickness (cIMT). The cross-sectional association of SBP with processing speed/VMI and executive function was attenuated after adjusting anti-hypertension medications in the models. Baseline SBP was associated with the change of processing speed/VMI function after adjusting vascular risk factors, WMHV, and cIMT at a 5-year follow-up. This longitudinal association was not found after adjusting anti-hypertension medications in the models. Further analyses revealed that individuals with category SBP from <  120 mmHg to≥140 mmHg had a linear decline in processing speed/VMI function at a 5-year follow-up. Conclusion: We show that SBP is negatively associated with cognition cross-sectionally and longitudinally in the elderly. Anti-hypertension treatment eliminates the negative association of SBP with processing speed/VMI function longitudinally. Our findings support the treatment of stage 1 systolic hypertension in the elderly. Show more

Keywords: Cognition, northern manhattan study (NOMAS), race/ethnicity, systolic blood pressure

DOI: 10.3233/JAD-210252

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

Authors: Xiao, Tian | Wijnant, Sara R.A. | Licher, Silvan | Terzikhan, Natalie | Lahousse, Lies | Ikram, M. Kamran | Brusselle, Guy G. | Ikram, M. Arfan

Article Type: Research Article

Abstract: Background: The etiology of dementia may partly be underpinned by impaired lung function via systemic inflammation and hypoxia. Objective: To prospectively examine the association between chronic obstructive pulmonary disease (COPD) and subclinical impairments in lung function and the risk of dementia. Methods: In the Rotterdam Study, we assessed the risk of incident dementia in participants with Preserved Ratio Impaired Spirometry (PRISm; FEV1 /FVC≥0.7, FEV1  < 80% predicted) and in participants with COPD (FEV1 /FVC < 0.7) compared to those with normal spirometry (controls; FEV1 /FVC≥0.7, FEV1 ≥80% predicted). Hazard ratios (HRs) with 95% confidence intervals (CI) for dementia were …adjusted for age, sex, education attainment, smoking status, systolic blood pressure, body mass index, triglycerides, comorbidities and Apolipoprotein E (APOE) genotype. Results: Of 4,765 participants, 110 (2.3%) developed dementia after 3.3 years. Compared to controls, participants with PRISm, but not COPD, had an increased risk for all-type dementia (adjusted HRPRISm 2.70; 95% CI, 1.53–4.75; adjusted HRCOPD 1.03; 95% CI, 0.61–1.74). These findings were primarily driven by men and smokers. Similarly, participants with FVC% predicted values in the lowest quartile compared to those in the highest quartile were at increased risk of all-type dementia (adjusted HR 2.28; 95% CI, 1.31–3.98), as well as Alzheimer’s disease (AD; adjusted HR 2.13; 95% CI, 1.13–4.02). Conclusion: Participants with PRISm or a low FVC% predicted lung function were at increased risk of dementia, compared to those with normal spirometry or a higher FVC% predicted, respectively. Further research is needed to elucidate whether this association is causal and how PRISm might contribute to dementia pathogenesis. Show more

Keywords: Alzheimer’s disease, chronic obstructive pulmonary disease, dementia, forced vital capacity (FVC), preserved ratio impaired spirometry

DOI: 10.3233/JAD-210162

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

Authors: Rasu, Rafia S. | Shrestha, Nistha | Karpes Matusevich, Aliza R. | Zalmai, Rana | Large, Stephanie | Johnson, Leigh | O’Bryant, Sid E.

Article Type: Research Article

Abstract: Background: Polypharmacy (using≥5 medications) is associated with poor health outcomes. Mixed results from past studies surrounding chronic medication use, control of chronic conditions, and their effects on cognitive performance warrant further attention. Objective: Investigate a link between polypharmacy and cognition function in rural-dwelling adults in Texas, USA. Methods: Project FRONTIER (Facing Rural Obstacles to Healthcare Now Through Intervention, Education & Research) is a cross-sectional epidemiological study using community-based participatory research in three counties of Texas. Residents age >  40 were eligible for inclusion. The primary outcome is cognitive impairment, and exposures of interest are polypharmacy; comorbidities; and …diabetes, hypertension, and depression medication. Logistic regression was used to assess association. Results: Six hundred eighty-nine individuals participated; the mean age was 61, and the majority were female (68.7%).The median number of medications taken by participants was 3.3 (IQR: 0–5); the rate of polypharmacy was 29.6%. Anti-hypertensive agents were the most common medications (15%) used. Polypharmacy users were 2.84 times more likely to have cognitive impairment [OR: 2.84, 95%CI (1.32–6.09)] than those using <  5 medications. Participants on hypertensive medications had 1.85 times higher odds [OR: 1.85, 95%CI (1.14–3.01)] of having cognitive impairment than those who did not have cognitive impairment. Conclusion: Polypharmacy increases the odds of cognitive impairment. The odds of presenting with cognitive impairment increased as the number of medications increased. Additionally, we identified a large, concerning number of participants with pharmacotherapy and poor chronic disease management. A larger study should examine medication adherence among rural elders to manage chronic disease and any healthcare barriers to adherence. Show more

Keywords: Antidepressants, antidiabetics, antihypertensive, cognitive impairment, cognition performance, dementia, medications, polypharmacy

DOI: 10.3233/JAD-200951

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

Authors: Wei, Wei | Liu, Yinghua | Dai, Chunling | Baazaoui, Narjes | Tung, Yunn-Chyn | Liu, Fei | Iqbal, Khalid

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by impairments in synaptic plasticity and cognitive performance. Cognitive dysfunction and loss of neuronal plasticity are known to begin decades before the clinical diagnosis of the disease. The important influence of congenital genetic mutations on the early development of AD provides a novel opportunity to initiate treatment during early development to prevent the Alzheimer-like behavior and synaptic dysfunction. Objective: To explore strategies for early intervention to prevent Alzheimer’s disease. Methods: In the present study, we investigated the effect of treatment during early development with a ciliary …neurotrophic factor (CNTF) derived peptidergic compound, P021 (Ac-DGGLA G-NH2) on cognitive function and synaptic plasticity in 3xTg-AD transgenic mouse model of AD. 3xTg-AD and genetic background-matched wild type female mice were treated from birth to postnatal day 120 with P021 in diet or as a control with vehicle diet, and cognitive function and molecular markers of neuroplasticity were evaluated. Results: P021 treatment during early development prevented cognitive impairment and increased expressions of pCREB and BDNF that activated downstream various signaling cascades such as PLC/PKC, MEK/ERK and PI3K/Akt, and ameliorated synaptic protein deficit in 4-month-old 3xTg-AD mice. Conclusion: These findings indicate that treatment with the neurotrophic peptide mimetic such as P021 during early development can be an effective therapeutic strategy to rescue synaptic deficit and cognitive impairment in familial AD and related tauopathies. Show more

Keywords: Alzheimer’s disease, brain-derived neurotrophic factor, ciliary neurotrophic factor, cognition, neurotrophin, synaptic plasticity

DOI: 10.3233/JAD-201599

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

Authors: Jeong, Wonjeong | Joo, Jae Hong | Kim, Hyunkyu | Kim, Yun Kyung | Park, Eun-Cheol | Jang, Sung-In

Article Type: Research Article

Abstract: Background: Hypnotics, including benzodiazepines, are extensively and inappropriately prescribed for older people to treat anxiety and sleep disorders, despite the adverse health outcomes associated with their use. Objective: This study aimed to examine the association of the use of long- and short-acting hypnotics with the risk of Alzheimer’s disease. Methods: Data from 234,634 participants, derived from the Korean National Health Insurance Service National Sample Cohort from 2002 to 2013, were examined. Individuals over the age of 50 years were included in the study. The dependent variable was the risk of Alzheimer’s disease. Hypnotics were categorized by …the period of the prescription of benzodiazepines, i.e., either till the participants were diagnosed with Alzheimer’s disease or the end of the study period (December 31, 2013). Cox regression model was built to analyze the association between variables. Results: Individuals who used long-acting hypnotics were found to have a higher risk of Alzheimer’s disease than non-users. Moreover, among individuals with sleep disorders, those who used hypnotics had a higher risk of Alzheimer’s disease than those who did not. Conclusion: This study identified an association between the use of hypnotics and the risk of Alzheimer’s disease among South Korean middle-aged and older people. Show more

Keywords: Alzheimer’s disease, benzodiazepines, dementia, hypnotics

DOI: 10.3233/JAD-201319

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

Authors: Babić Leko, Mirjana | Jurasović, Jasna | Nikolac Perković, Matea | Španić, Ena | Sekovanić, Ankica | Orct, Tatjana | Lukinović Škudar, Vesna | Bačić Baronica, Koraljka | Kiđemet-Piskač, Spomenka | Vogrinc, Željka | Pivac, Nela | Borovečki, Fran | Hof, Patrick R. | Šimić, Goran

Article Type: Research Article

Abstract: Background: The major confirmed genetic risk factor for late-onset, sporadic Alzheimer’s disease (AD) is variant ɛ4 of apolipoprotein E gene (APOE ). It is proposed that ApoE, a protein involved in transport of cholesterol to neurons can cause neurodegeneration in AD through interaction with metals. Previous studies mostly associated copper, iron, zinc, and calcium with ApoE4-mediated toxicity. Objective: To test the association of essential metals with APOE genotype. Methods: We compared plasma and cerebrospinal fluid (CSF) levels of copper, zinc, iron, sodium, magnesium, calcium, cobalt, molybdenum, manganese, boron, and chromium, and CSF ferritin levels among …AD, mild cognitive impairment (MCI) patients, and healthy controls (HC) with different APOE genotype. Results: Sodium, copper, and magnesium levels were increased in carriers of ɛ4 allele. Additionally, the increase in sodium, calcium and cobalt plasma levels was observed in carriers of ɛ4/ɛx genotype. The decrease in boron plasma levels was observed in carriers of ɛ4 allele and ɛ4/ɛ4 genotype. Additionally, CSF zinc levels as well as plasma sodium levels were increased in AD patients compared to HC. Conclusion: These results indicate that the molecular underpinnings of association of essential metals and metalloids with APOE should be further tested and clarified in vivo and in vitro . Show more

Keywords: Alzheimer’s disease, apolipoprotein E, copper, metals, mild cognitive impairment, zinc

DOI: 10.3233/JAD-210158

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