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

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

Article Type: Research Article

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

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

DOI: 10.3233/JAD-201576

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

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

Article Type: Research Article

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

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

DOI: 10.3233/JAD-210074

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

Authors: Jaul, Efraim | Meiron, Oded

Article Type: Review Article

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

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

DOI: 10.3233/JAD-201563

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

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

Article Type: Research Article

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

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

DOI: 10.3233/JAD-210144

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

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

Article Type: Research Article

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

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

DOI: 10.3233/JAD-201540

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

Authors: Norins, Leslie C.

Article Type: Research Article

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

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

DOI: 10.3233/JAD-210080

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

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

Article Type: Research Article

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

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

DOI: 10.3233/JAD-210052

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

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

Article Type: Research Article

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

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

DOI: 10.3233/JAD-210049

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

Authors: Feldman, Robin

Article Type: Research Article

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

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

DOI: 10.3233/JAD-210294

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

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

Article Type: Research Article

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

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

DOI: 10.3233/JAD-201054

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