Journal of Alzheimer's Disease - Volume 93, issue 3

Authors: Press, Daniel Zvi | Musaeus, Christian Sandøe | Zhao, Li | Breton, Jocelyn M. | Shafi, Mouhsin M. | Dai, Weiying | Alsop, David C.

Article Type: Research Article

Abstract: Background: Patients with Alzheimer’s disease (AD) have an increased risk of developing epileptiform discharges, which is associated with a more rapid rate of progression. This suggests that suppression of epileptiform activity could have clinical benefit in patients with AD. Objective: In the current study, we tested whether acute, intravenous administration of levetiracetam led to changes in brain perfusion as measured with arterial spin labeling MRI (ASL-MRI) in AD. Methods: We conducted a double-blind, within-subject crossover design study in which participants with mild AD (n  = 9) received placebo, 2.5 mg/kg, and 7.5 mg/kg of LEV intravenously in a random …order in three sessions. Afterwards, the participants underwent ASL-MRI. Results: Analysis of relative cerebral blood flow (rCBF) between 2.5 mg of levetiracetam and placebo showed significant decreases in a cluster that included the posterior cingulate cortex, the precuneus, and the posterior part of the cingulate gyrus, while increased cerebral blood flow was found in both temporal lobes involving the hippocampus. Conclusion: Administration of 2.5 mg/kg of LEV in patients without any history of epilepsy leads to changes in rCBF in areas known to be affected in the early stages of AD. These areas may be the focus of the epileptiform activity. Larger studies are needed to confirm the current findings. Show more

Keywords: Alzheimer’s disease, arterial spin labeling MRI, epilepsy, epileptiform activity, levetiracetam, randomized controlled trial

DOI: 10.3233/JAD-220614

Citation: Journal of Alzheimer's Disease, vol. 93, no. 3, pp. 939-948, 2023

Authors: Gibbons, Laura E. | Power, Melinda C. | Walker, Rod L. | Kumar, Raj G. | Murphy, Alia | Latimer, Caitlin S. | Nolan, Amber L. | Melief, Erica J. | Beller, Allison | Bogdani, Marika | Keene, C. Dirk | Larson, Eric B. | Crane, Paul K. | Dams-O’Connor, Kristen

Article Type: Research Article

Abstract: Background: Prior studies into the association of head trauma with neuropathology have been limited by incomplete lifetime neurotrauma exposure characterization. Objective: To investigate the neuropathological sequelae of traumatic brain injury (TBI) in an autopsy sample using three sources of TBI ascertainment, weighting findings to reflect associations in the larger, community-based cohort. Methods: Self-reported head trauma with loss of consciousness (LOC) exposure was collected in biennial clinic visits from 780 older adults from the Adult Changes in Thought study who later died and donated their brain for research. Self-report data were supplemented with medical record abstraction, and, …for 244 people, structured interviews on lifetime head trauma. Neuropathology outcomes included Braak stage, CERAD neuritic plaque density, Lewy body distribution, vascular pathology, hippocampal sclerosis, and cerebral/cortical atrophy. Exposures were TBI with or without LOC. Modified Poisson regressions adjusting for age, sex, education, and APOE ɛ4 genotype were weighted back to the full cohort of 5,546 participants. Results: TBI with LOC was associated with the presence of cerebral cortical atrophy (Relative Risk 1.22, 95% CI 1.02, 1.42). None of the other outcomes was associated with TBI with or without LOC. Conclusion: TBI with LOC was associated with increased risk of cerebral cortical atrophy. Despite our enhanced TBI ascertainment, we found no association with the Alzheimer’s disease-related neuropathologic outcomes among people who survived to at least age 65 without dementia. This suggests the pathophysiological processes underlying post-traumatic neurodegeneration are distinct from the hallmark pathologies of Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, atrophy, dementia, neuropathology, traumatic brain injury

DOI: 10.3233/JAD-221224

Citation: Journal of Alzheimer's Disease, vol. 93, no. 3, pp. 949-961, 2023

Authors: White, Lon R.

Article Type: Article Commentary

Abstract: While we know that brain injuries related to sport and military activities sometimes lead to cognitive impairment or early onset dementia, it is unclear if and how they might influence the development of Alzheimer’s Disease and Related Dementias (ADRD). Published analytic conclusions have been mixed. Two reports in the Journal of Alzheimer ’s Disease reach the same answer: a history of brain injury appears to be a risk factor for generalized brain atrophy, which would likely increase vulnerability to the subsequent development of any variety of ADRD, or to dementia directly attributable to reduced brain mass.

Keywords: ADRD, Alzheimer’s disease, atrophy, brain trauma, dementia, neuropathology, risk factor

DOI: 10.3233/JAD-230332

Citation: Journal of Alzheimer's Disease, vol. 93, no. 3, pp. 963-965, 2023

Authors: Malhotra, Chetna | Balasubramanian, Ishwarya

Article Type: Research Article

Abstract: Background: Family caregivers make end-of-life (EOL) decisions for persons with severe dementia (PWSDs). It is not known whether the family caregivers’ goals change over time. Objective: Assess caregivers’ EOL care goal for PWSDs and change in these goals over time. Methods: Using a prospective cohort of 215 caregivers of PWSDs, we assessed the proportion of caregivers whose EOL care goal for PWSDs changed between two consecutive time points. Mixed effects multinomial regression models assessed factors associated with caregivers’ EOL care goals for PWSD (maximal, moderate, minimal life extension); and change in EOL care goal from previous …time point. Results: At baseline, 20% of the caregivers had a goal of maximal life extension for their PWSD, and 59% changed their EOL care goal at least once over a period of 16 months. Caregivers of PWSDs with lower quality of life (RR: 1.15, CI: 1.06, 1.24), who expected shorter life expectancy for PWSDs (RR: 10.34, CI: 2.14, 49.99) and who had an advance care planning discussion (RR: 3.52, CI: 1.11, 11.18) were more likely to have a goal of minimal life extension for PWSD. Caregivers with higher anticipatory grief (RR: 0.96, CI: 0.93,1) were more likely to have a goal of maximal life extension. Change in PWSDs’ quality of life and change in caregivers’ anticipatory grief were associated with change in caregivers’ EOL care goals. Conclusion: Caregivers’ EOL care goals for PWSDs change over time with change in PWSD and caregiver related factors. Findings have implications regarding how health care providers can engage with caregivers. Show more

Keywords: Anticipatory grief, caregivers, decision-making, dementia, end-of-life care goals, quality of life, Singapore

DOI: 10.3233/JAD-221161

Citation: Journal of Alzheimer's Disease, vol. 93, no. 3, pp. 967-975, 2023

Authors: Zhang, Rui-Qi | Ou, Ya-Nan | Huang, Shu-Yi | Li, Yu-Zhu | Huang, Yu-Yuan | Zhang, Ya-Ru | Chen, Shi-Dong | Dong, Qiang | Feng, Jian-Feng | Cheng, Wei | Yu, Jin-Tai

Article Type: Research Article

Abstract: Background: The association between poor oral health and the risk of incident dementia remains unclear. Objective: To investigate the associations of poor oral health with incident dementia, cognitive decline, and brain structure in a large population-based cohort study. Methods: A total of 425,183 participants free of dementia at baseline were included from the UK Biobank study. The associations between oral health problems (mouth ulcers, painful gums, bleeding gums, loose teeth, toothaches, and dentures) and incident dementia were examined using Cox proportional hazards models. Mixed linear models were used to investigate whether oral health problems were associated …with prospective cognitive decline. We examined the associations between oral health problems and regional cortical surface area using linear regression models. We further explored the potential mediating effects underlying the relationships between oral health problems and dementia. Results: Painful gums (HR = 1.47, 95% CI [1.317–1.647], p  < 0.001), toothaches (HR = 1.38, 95% CI [1.244–1.538], p  < 0.001), and dentures (HR = 1.28, 95% CI [1.223–1.349], p  < 0.001) were associated with increased risk of incident dementia. Dentures were associated with a faster decline in cognitive functions, including longer reaction time, worse numeric memory, and worse prospective memory. Participants with dentures had smaller surface areas of the inferior temporal cortex, inferior parietal cortex, and middle temporal cortex. Brain structural changes, smoking, alcohol drinking, and diabetes may mediate the associations between oral health problems and incident dementia. Conclusion: Poor oral health is associated with a higher risk of incident dementia. Dentures may predict accelerated cognitive decline and are associated with regional cortical surface area changes. Improvement of oral health care could be beneficial for the prevention of dementia. Show more

Keywords: Brain structure, cognition, dementia, oral health

DOI: 10.3233/JAD-221176

Citation: Journal of Alzheimer's Disease, vol. 93, no. 3, pp. 977-990, 2023

Authors: Noble, James M. | Papapanou, Panos N.

Article Type: Article Commentary

Abstract: Periodontitis is a chronic inflammatory, bacterially-driven disease of the tooth-supporting tissues that shares several risk factors and elements of host response with Alzheimer’s disease and related dementias (ADRD). Epidemiological studies have identified relatively consistent associations between adverse oral health conditions and ADRD. In this issue of the journal, a large study from the UK Biobank further explores these relationships along with MRI cognitive biomarkers. Despite its strength due to the large sample size, challenges in the study of periodontitis and neuroepidemiology markers include potential sampling bias, appropriate assessment of exposures, and the possibility of reverse causality.

Keywords: Alzheimer’s disease, neuroepidemiology, neuroinflammation, periodontitis

DOI: 10.3233/JAD-230346

Citation: Journal of Alzheimer's Disease, vol. 93, no. 3, pp. 991-994, 2023

Authors: Smith, Patrick J. | Sherwood, Andrew | Avorgbedor, Forgive | Ingle, Krista K. | Kraus, William E. | Hinderliter, Alan E. | Blumenthal, James A.

Article Type: Research Article

Abstract: Background: Resistant hypertension (RH) is a major risk factor for stroke, cognitive decline, and dementia. Sleep quality is increasingly suggested to play an important role linking RH to cognitive outcomes, although the mechanisms linking sleep quality to poor cognitive function have yet to be fully delineated. Objective: To delineate biobehavioral mechanisms linking sleep quality, metabolic function, and cognitive function among 140 overweight/obese adults with RH in the TRIUMPH clinical trial. Methods: Sleep quality was indexed using actigraphy measures of sleep quality and sleep fragmentation, as well as self-reported sleep quality from the Pittsburgh Sleep Quality Index …(PSQI). Cognitive function was assessed using a 45-minute battery assessing executive function, processing speed, and memory. Participants were randomized to a cardiac rehabilitation-based lifestyle program (C-LIFE) or a standardized education and physician advice condition (SEPA) for 4 months. Results: Better sleep quality at baseline was associated with better executive function (B  = 0.18 p  = 0.027), as well as greater fitness (B  = 0.27, p  = 0.007) and lower HBA1c (B  = –0.25, p  = 0.010). Cross-sectional analyses revealed that the sleep quality executive function association was mediated by HBA1c (B  = 0.71 [0.05, 2.05]). C-LIFE improved sleep quality (–1.1 [–1.5, –0.6] versus+–0.1 [–0.8, 0.7]) and actigraphy steps (+922 [529, 1316] versus+56 [–548, 661]), with actigraphy mediating improvements in executive function (B  = 0.40 [0.02, 1.07]). Conclusion: Better metabolic function and improved physical activity patterns levels play important roles linking sleep quality and executive function in RH. Show more

Keywords: Cognitive function, metabolic function, physical activity, resistant hypertension, sleep quality

DOI: 10.3233/JAD-230029

Citation: Journal of Alzheimer's Disease, vol. 93, no. 3, pp. 995-1006, 2023

Authors: Topping, Michael | Kim, Jinho | Fletcher, Jason

Article Type: Research Article

Abstract: Background: Growing evidence suggests that critical periods in early life may contribute to one’s risk of Alzheimer’s disease and related dementias (ADRD) in later life. In this paper we explore the role that exposure to infant mortality plays in later life ADRD. Objective: To determine if exposure to early life infant mortality is associated with later mortality from ADRD. Also, we explore how these associations differ by sex and age group, along with the role of state of birth and competing risks of death. Methods: We use a sample of over 400,000 individuals aged 50 and …above with the NIH-AARP Diet and Health Study with mortality follow-up, allowing us to examine how early life infant mortality rates along with other risk factors play in one’s individual mortality risk. Results: We show that infant mortality rates are associated with death from ADRD among those under 65 years of age, but not those over 65 at baseline interview. Moreover, when factoring in competing risks of death, the associations are relatively unchanged. Conclusion: These results suggest that those exposed to worse adverse conditions during critical periods increase their likelihood of death from ADRD earlier than average, due to that exposure increasing their susceptibility to develop illness later on in life. Show more

Keywords: Alzheimer’s disease, early life, infant mortality, mortality, place of birth

DOI: 10.3233/JAD-230086

Citation: Journal of Alzheimer's Disease, vol. 93, no. 3, pp. 1007-1016, 2023

Authors: Defrancesco, Michaela | Deisenhammer, Eberhard A. | Schurr, Timo A. | Ortner, Markus

Article Type: Research Article

Abstract: Background: The COVID-19 pandemic was associated with high mortality and negative consequences for patients with Alzheimer’s disease or dementia and their caregivers. Memory clinics play an important role in enabling early dementia diagnosis and providing support for patients and their caregivers. Objective: This study investigates the impact of the COVID-19 pandemic and its restrictions on patients of a memory clinic and their caregivers between March 2020 and March 2021. Methods: We conducted a prospective, single-center, questionnaire-based, observational study to assess consequences and perception of the COVID-19 pandemic on emotion, cognitive function, social living, areas of care, …and information retrieval. Results: Results of 255 participants’ (mean age 76.78, SD 8.9; 12% cognitively intact, 33% mild cognitive impairment, 55% dementia) and 203 caregivers’ COVID-19 questionnaires (valid response rate 71%) could be included in the study. Participants reported a prevalence of psychological symptoms associated with the pandemic between 3-20%. Caregivers living outside compared to those living with the participant reported higher rates of new onset or worsening of neuropsychiatric symptoms in participants since pandemic onset. Patients with dementia showed the lowest use of digital communication before (15.7%) and after (17.1%) pandemic onset in the diagnostic groups. Conclusion: The COVID-19 pandemic frequently led to social isolation and reduced cognitive stimulation due to restrictions in elderly persons with cognitive deficits resulting in negative effects on emotional and social levels. We hypothesize that the implementation and sensitization with digital communication in clinical routine could provide a useful tool to counteract these negative effects. Show more

Keywords: Alzheimer’s disease, caregiver, COVID-19, dementia, neuropsychiatric symptoms, pandemic

DOI: 10.3233/JAD-220887

Citation: Journal of Alzheimer's Disease, vol. 93, no. 3, pp. 1017-1031, 2023

Authors: Gollop, Celina | Zingel, Rebecca | Jacob, Louis | Smith, Lee | Koyanagi, Ai | Kostev, Karel

Article Type: Research Article

Abstract: Background: There is emerging evidence that coronavirus disease 2019 (COVID-19) is giving rise to seemingly unrelated clinical conditions long after the infection has resolved. Objective: The aim of this study is to examine whether COVID-19 is associated with an increased risk of dementia including Alzheimer’s disease. Methods: This retrospective cohort study is based on longitudinal data from the IQVIATM Disease Analyzer database and included patients aged≥65 with an initial diagnosis of COVID-19 or acute upper respiratory infection (AURI) from 1,293 general practitioner practices between January 2020 and November 2021. AURI patients were matched 1 : 1 with …COVID-19 patients using propensity scores based on sex, age, index quarter, health insurance type, the number of doctor visits, and comorbidities associated with dementia risk. Incidence rates of newly-diagnosed dementia were calculated using the person-years method. Poisson regression models were used to compute the incidence rate ratios (IRR). Results: The present study included 8,129 matched pairs (mean age 75.1 years, 58.9% females). After 12 months of follow-up, 1.84% of the COVID-19 patients and 1.78% of the AURI patients had been diagnosed with dementia. The Poisson regression model resulted in an IRR of 1.05 (95% CI: 0.85–1.29). Conclusion: This study did not find any association between COVID-19 infection and one-year dementia incidence after controlling for all common risk factors for dementia. Because dementia is a progressive disease, which can be difficult to diagnose, a longer follow-up period might offer a better insight into a possible association between COVID-19 infection and an increased incidence of dementia cases in the future. Show more

Keywords: Acute upper respiratory infection, Alzheimer’s disease, COVID-19, dementia

DOI: 10.3233/JAD-221271

Citation: Journal of Alzheimer's Disease, vol. 93, no. 3, pp. 1033-1040, 2023