Journal of Alzheimer's Disease - Volume 75, issue 4

Authors: Korczyn, Amos D.

Article Type: Editorial

DOI: 10.3233/JAD-200609

Citation: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1071-1072, 2020

Authors: Enengl, Joachim | Hamblin, Michael R. | Dungel, Peter

Article Type: Review Article

Abstract: One of the challenges in translating new therapeutic approaches to the patient bedside lies in bridging the gap between scientists who are conducting basic laboratory research and medical practitioners who are not exposed to highly specialized journals. This review covers the literature on photobiomodulation therapy as a novel approach to prevent and treat Alzheimer’s disease, aiming to bridge that gap by gathering together the terms and technical specifications into a single concise suggestion for a treatment protocol. In light of the predicted doubling in the number of people affected by dementia and Alzheimer’s disease within the next 30 years, a …treatment option which has already shown promising results in cell culture studies and animal models, and whose safety has already been proven in humans, must not be left in the dark. This review covers the mechanistic action of photobiomodulation therapy against Alzheimer’s disease at a cellular level. Safe and effective doses have been found in animal models, and the first human case studies have provided reasons to undertake large-scale clinical trials. A brief discussion of the minimally effective and maximum tolerated dose concludes this review, and provides the basis for a successful translation from bench to bedside. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, dementia, low-level light therapy, neuroimmunomodulation, photobiomodulation therapy

DOI: 10.3233/JAD-191210

Citation: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1073-1082, 2020

Authors: Rosa, Gianmarco | Giannotti, Chiara | Martella, Lucia | Massa, Federico | Serafini, Gianluca | Pardini, Matteo | Nobili, Flavio Mariano | Monacelli, Fiammetta | for the Disease Management Team on Dementia of the IRCCS Ospedale Policlinico San Martino (Genoa, I)

Article Type: Review Article

Abstract: Dementia is an age-related clinical condition, with higher incidence rates in older ages. However, there is some evidence that a reverse epidemiology is also observed. Namely, the cohort analysis of dementia incidence rates by birth in selected populations demonstrated a decreased incidence of dementia in late life across the last twenty years, possibly due to decreased incidence of cardiovascular disorders and increased education and cognitive reserve. In line with that, age is probably a proxy for other pathophysiological processes rather than a strictly causative factor for the onset of dementia, especially in oldest old persons. The present narrative review provides …an update on the clinical interplay between the spectrum of brain aging, cardiovascular morbidity, dementia pathologies, and their clinical expression in the oldest old patients. Available evidence suggests that vascular prevention in the perspective of dementia largely involve middle ages, with an apparent reverse epidemiology in oldest old. Similarly, the present findings underline how cognitive resilience and frailty may be key relevant mediators in the modulation of the clinical expression of brain mixed neuropathologies in persons over 85 years old, providing a new integrated conceptual framework. Show more

Keywords: Brain aging, brain resilience, cardiovascular comorbidity, frailty, hippocampal sclerosis, mixed dementia, oldest old

DOI: 10.3233/JAD-191075

Citation: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1083-1103, 2020

Authors: Robert, Claude | Wilson, Concepción S. | Lipton, Richard B. | Arreto, Charles-Daniel

Article Type: Review Article

Abstract: This study surveys the development of Alzheimer’s disease (AD) in the research literature, the scientific community, and the journals containing AD papers over a 35-year period. Research papers on AD published from 1983 to 2017 in journals indexed in the Web of Science were analyzed in seven five-year periods. The number of AD papers increased from 1,095 in 1983–1987 to 50,532 by 2013–2017 and in the same time period, the number of participating countries went from 27 to 152. The US was the most prolific country throughout, followed by several European countries, Canada, Australia, and Japan. Asian countries have emerged …and by 2013–2017, China surpassed all but the US in productivity. Countries in Latin America and Africa have also contributed to AD research. Additionally, several new non-governmental institutions (e.g., ADNI, ADI) have emerged and now play a key role in the fight against AD. Likewise the AD scientific publishing universe evolved in various aspects: an increase in number of journals containing AD papers (227 journals in 1983–1987 to 3,257 in 2013–2017); appearance of several AD-focused journals, e.g., Alzheimer ’s & Dementia , Journal of Alzheimer ’s Disease ; and the development of special issues dedicated to AD. Our paper complements the numerous extant papers on theoretical and clinical aspects of AD and provides a description of the research landscape of the countries and journals contributing papers related to AD. Show more

Keywords: AD institutions, Alzheimer’s disease, bibliometrics, country contribution, journal analysis, publication growth

DOI: 10.3233/JAD-191281

Citation: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1105-1134, 2020

Authors: Hajek, André | König, Hans-Helmut

Article Type: Short Communication

Abstract: The aim was to identify the determinants of fear of dementia in the general population. Data were taken from the innovation sample (n  = 1,498; year 2012) of a nationally representative, longitudinal study. Summarizing, 28.8% reported no fear of dementia, 34.3% reported a little fear of dementia, 21.2% reported some fear of dementia, and 15.7% reported severe fear of dementia. Regressions showed that increased fear of dementia was associated with increased age, being female, an increased perceived own risk for developing dementia, an increased agreement that a diagnosis of dementia would ruin one’s life, and a decreased perception that memory deterioration …is preventable. Addressing modifiable factors may assist in reducing fear of dementia. Show more

Keywords: Dementia, dementia worry, fear of dementia, German Socio-Economic Panel

DOI: 10.3233/JAD-200106

Citation: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1135-1140, 2020

Authors: Khandker, Rezaul K. | Ritchie, Craig W. | Black, Christopher M. | Wood, Robert | Jones, Eddie | Hu, Xiaohan | Ambegaonkar, Baishali M.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is one of the most disabling conditions worldwide and the disease burden increases with the aging global population. There are only a few prospective studies using real-world data to support effective healthcare resource utilization (HCRU) in AD. Objective: To confirm the association between HCRU and AD severity in a real-world population, including patients with all cognitive impairment (CI) severities. Methods: Data were drawn from a multi-national, cross-sectional survey of physicians and their consulted patients with all stages (very mild, mild, moderate, and severe) of CI including AD conducted in France, Germany, Italy, …Spain, UK, US, and Canada. Elements of HCRU including medical consultations, professional caregiver hours, hospitalization, and institutionalization were compared between CI severity subgroups, and by country and region. Results: 6,143 CI patients were included with very mild (n  = 659), mild (n  = 2,473), moderate (n  = 2,603), and severe (n  = 408) dementia. HCRU increased with increasing CI severity (p  < 0.001) for the majority of elements measured. Further analyses of overall and regional populations also confirmed significant increases in most HCRU elements with increasing disease severity. The general trend toward increased HCRU with increased CI severity was also seen in individual countries. Individual country data appeared to indicate that earlier intervention decreased hospitalizations and full-time institutionalization at the later (more severe) disease stages. Conclusion: Our findings confirmed that HCRU increases with increasing CI severity. Effective intervention in early disease could therefore reduce or delay incurring greater HCRU costs associated with more severe disease. Further studies are needed to confirm this hypothesis. Show more

Keywords: Alzheimer’s disease, cognitive impairment, disease specific program, healthcare resource utilization

DOI: 10.3233/JAD-190760

Citation: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1141-1152, 2020

Authors: Wang, Pan | Zhou, Bo | Yao, Hongxiang | Xie, Sangma | Feng, Feng | Zhang, Zengqiang | Guo, Yan’e | An, Ningyu | Zhou, Yuying | Zhang, Xi | Liu, Yong

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common cause of dementia in older individuals, and amnestic mild cognitive impairment (aMCI) is currently considered the prodromal stage of AD. The hippocampus and fornix interact functionally and structurally, with the fornix being the major efferent white matter tract from the hippocampus. Objective: The main aim of this study was to examine the impairments present in subjects with AD or aMCI and the relationship of these impairments with the microstructure of the fornix and the functional connectivity (FC) and gray matter volume of the hippocampus. Methods: Forty-four AD, 34 …aMCI, and 41 age- and gender-matched normal controls (NCs) underwent neuropsychological assessments and multimode MRI. We chose the bilateral hippocampi as the region of interest in which gray matter alterations and FC with the whole brain were assessed and the fornix body as the region of interest in which the microstructural integrity of the white matter was observed. We also evaluated the relationship among gray matter alterations, the abnormal FC of the hippocampus and the integrity of the fornix in AD/aMCI Results: Compared to the NC group, the AD and aMCI groups demonstrated decreased gray matter volume, reduced FC between the bilateral hippocampi and several brain regions in the default mode network and control network, and damaged integrity of the fornix body (decreased fractional anisotropy and increased diffusivity). We also found that left hippocampal FC with some regions, the integrity of the fornix body, and cognition ability were significantly correlated. Therefore, our findings suggest that damage to white matter integrity may partially explain the reduced resting-state FC of the hippocampus in AD and aMCI. Conclusion: AD and aMCI are diseases of disconnectivity including not only functional but also structural disconnectivity. Damage to white matter integrity may partially explain the reduced resting-state FC in AD and aMCI. These findings have significant implications for diagnostics and modeling and provide insights for understanding the disconnection syndrome in AD. Show more

Keywords: Alzheimer’s disease, fornix, functional connectivity, hippocampus, mild cognitive impairment, white matter integrity

DOI: 10.3233/JAD-200066

Citation: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1153-1168, 2020

Authors: Williams, Owen A. | An, Yang | Armstrong, Nicole M. | Kitner-Triolo, Melissa | Ferrucci, Luigi | Resnick, Susan M.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is now understood to have a long preclinical phase in which pathology starts to accumulate in the absence of clinical symptoms. Identifying the temporal stages of accelerated cognitive decline in this phase may help in developing more sensitive neuropsychological tools for early screening of preclinical cognitive decline. Change-point analyses are increasingly used to characterize the temporal stages of accelerated cognitive decline in the preclinical stages of AD. However, statistical comparisons of change-points between specific cognitive measures have not been reported. Objective: To characterize and compare the temporal stages of accelerated decline in performance on …multiple cognitive tests in a sample of participants from the Baltimore Longitudinal Study on Aging (BLSA) who later developed AD. Methods: 165 older adults (baseline age range: 61.1–91.2) from the BLSA developed AD during follow-up. Linear and non-linear mixed models were fit for 11 cognitive measures to determine change-points in rates of decline before AD diagnosis. Bootstrapping was used to compare the timing of change-points across cognitive measures. Results: Change-points followed by accelerated decline ranged from 15.5 years (Standard Error (S.E.) = 1.72) for Card Rotations to 1.9 years (S.E. = 0.68) for the Trail-Making Test Part A before AD diagnosis. Accelerated decline in Card Rotations occurred significantly earlier than all other measures, including learning and memory measures. Conclusion: Results suggest that visuospatial ability, as assessed by Card Rotations, may have the greatest utility as an early predictive tool in identifying preclinical AD. Show more

Keywords: Alzheimer’s disease, change-point analysis, cognitive decline, preclinical, prodromal, visuospatial ability

DOI: 10.3233/JAD-191268

Citation: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1169-1180, 2020

Authors: Zibrandtsen, Ivan C. | Agger, Mikkel | Kjaer, Troels W.

Article Type: Research Article

Abstract: Background: Studies on mice models of Alzheimer’s disease (AD) have suggested potential therapeutic benefits of intermittent photic stimulation at 40 Hz. Objective: We examined the physiological response of 40 Hz intermittent photic stimulation (IPS) on routine EEG in a large retrospective cohort to investigate the effects of age on induced gamma oscillations by intermittent photic stimulation. Since most AD patients are elderly, it is important for future research to know if age affects photic stimulation. Methods: Retrospective data from 1,464 subjects aged 0– 91. We performed frequency analysis and automatic peak detection and used regression analysis to investigate …the effects of age and sex on peak frequencies and amplitude changes. To investigate the spread of the induced gamma oscillations, we assessed averaged topographies of 40 Hz band power. Results: There was a statistically significant but very minor effect of age on amplitude change (– 0.002 normalized power per year, p  < 0.0001) but not for sex (p  = 0.728). Detection probability of induced peaks was significantly predicted by both age (OR = 0.988, CI 95 % [0.984, 0.993], p  < 0.00001) and sex (OR = 0.625, CI 95 % [0.496, 0.787>], p  < 0.0001). The induced 40 Hz gamma entrainment is spatially confined to the occipital area. Conclusion: There is a significant effect of age on induced gamma activity, but advanced age does not fundamentally change the behavior of the response in either magnitude or spatial distribution. This fact is important regarding future research into the possible therapeutic effects of photic stimulation in patients with AD. Show more

Keywords: 40 Hz, aging, Alzheimer’s disease, electroencephalography, frequency analysis, gamma rhythm, photic stimulation

DOI: 10.3233/JAD-200083

Citation: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1181-1190, 2020

Authors: Petrazzuoli, Ferdinando | Vestberg, Susanna | Midlöv, Patrik | Thulesius, Hans | Stomrud, Erik | Palmqvist, Sebastian

Article Type: Research Article

Abstract: Background: Differentiating mild cognitive impairment (MCI) from subjective cognitive decline (SCD) is important because of the higher progression rate to dementia for MCI and when considering future disease-modifying drugs that will have treatment indications at the MCI stage. Objective: We examined if the two most widely-used cognitive tests, the Mini-Mental State Examination (MMSE) and clock-drawing test (CDT), and a test of attention/executive function (AQT) accurately can differentiate MCI from SCD. Methods: We included 466 consecutively recruited non-demented patients with cognitive complaints from the BioFINDER study who had been referred to memory clinics, predominantly from primary care. …They were classified as MCI (n  = 258) or SCD (n  = 208) after thorough neuropsychological assessments. The accuracy of MMSE, CDT, and AQT for identifying MCI was examined both in training and validation samples and in the whole population. Results: As a single test, MMSE had the highest accuracy (sensitivity 73%, specificity 60%). The best combination of two tests was MMSE < 27 points or AQT > 91 seconds (sensitivity 56%, specificity 78%), but in logistic regression models, their AUC (0.76) was not significantly better than MMSE alone (AUC 0.75). CDT and AQT performed significantly worse (AUC 0.71; p  < 0.001–0.05); otherwise no differences were seen between any combination of two or three tests. Conclusion: Neither single nor combinations of tests could differentiate MCI from SCD with adequately high accuracy. There is a great need to further develop, validate, and implement accurate screening-tests for primary care to improve accurate identification of MCI among individuals that seek medical care due to cognitive symptoms. Show more

Keywords: AQT, clock drawing test, cognitive screening, diagnostic accuracy, mild cognitive impairment, Mini-Mental State Examination, subjective cognitive decline

DOI: 10.3233/JAD-191191

Citation: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1191-1201, 2020