Journal of Alzheimer's Disease - Volume 71, issue 3

Authors: Noguchi-Shinohara, Moeko | Hirako, Kohei | Fujiu, Makoto | Sagae, Masahiko | Samuta, Hikaru | Nakamura, Hiroyuki | Yamada, Masahito

Article Type: Research Article

Abstract: Background: Both cigarette smoking and diabetes mellitus are well-established risk factors for development of dementia. However, the interaction between smoking and diabetes is yet unknown. Objective: In this study, we clarify association between smoking, diabetes, and dementia risk in older adults. Methods: Participants in this study included community residents aged 65 years and older who had participated in a health checkup in 2006, followed for 10 years (n  = 9,403) and had long-term care insurance information data. Furthermore, the risk estimates of smoking status and diabetes diagnosis on dementia adjusted for the competing risk of death prior …to dementia were analyzed. Results: During follow-up, 2,647 participants developed dementia. The smoking status–diabetes interaction on development of dementia was statistically significant (p ≤0.001). Among those patients exposed to both factors, 17% of risk of development of dementia was attributable to the interaction of these factors. Current smokers with diabetes had significantly greater risks of development of dementia than never smokers without diabetes (reference): multivariable-adjusted risk of dementia in current smokers without diabetes (subdistribution hazard ratio [sHR], 1.25; 95% confidence interval [CI], 1.05–1.48); never smokers with diabetes (1.31, 1.16–1.47); and current smokers with diabetes (1.86, 1.39–2.48). However, no such association was noted for former smokers with and without diabetes. Conclusions: Current smoking, but not former smoking, was associated with increased risk of development of dementia in older adults with and without diabetes. Moreover, the synergistic effect of current smoking and diabetes on dementia was noted. Show more

Keywords: Cigarette smoking, dementia, diabetes mellitus, insurance, long-term care

DOI: 10.3233/JAD-190340

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 833-840, 2019

Authors: Mayelle, Amandine | El Haj, Mohamad | Antoine, Pascal

Article Type: Research Article

Abstract: Background: People with Alzheimer’s disease (PwAD) remain able to speak coherently about their daily life for a long time, and their level of awareness could be determined through their discourse. In a grounded-theory approach, awareness of self and awareness of disease are intertwined and can be observed through three domains: mechanisms, objects and modes of expression. Objective: Based on preliminary results, in this article, we present the ASDA (Awareness of Self and Disease Assessment), a new subjective measurement tool for awareness in PwAD. To consider its use in research and practice, we initially performed validation analyses, including internal …consistency, test-retest reliability and interrater reliability analyses. Methods: The new assessment tool consists of a semi-structured interview and ratings of 22 items divided into three categories. As part of our observational study, we assessed a sample of 28 PwAD who participated in four interviews (one every two weeks). Results: The ASDA shows good homogeneity within the domains of awareness and a certain degree of stability between two measurement times and between investigators. Missing values in the results provided information regarding awareness levels within and across the subjects. Conclusion: The results suggest that awareness could be assessed through subjective experience without reference to a comparison. Show more

Keywords: Alzheimer’s disease, anosognosia, awareness, self, self-assessment

DOI: 10.3233/JAD-190371

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 841-850, 2019

Authors: Javanshiri, Keivan | Haglund, Mattias | Englund, Elisabet

Article Type: Research Article

Abstract: Background: Research concerning the potential roles of cardiovascular disease (CaVD) and diabetes mellitus (DM) as risk factors for Lewy body disease (LBD) is limited. These disorders are, however, established risk factors for vascular dementia (VaD) and have been proposed as risk factors for Alzheimer’s disease (AD). Objective: The aim of this study was to investigate the prevalence of CaVD and DM in LBD and compare the results with previous findings in cases with AD, VaD, and mixed AD-VaD (MD). Methods: Autopsy reports at the Clinical Department of Pathology in Lund from 2001–2018 were analyzed. All cases …with a complete neuropathological diagnosis of LBD were selected, not distinguishing between subjects with clinical Parkinson disease dementia and dementia with Lewy bodies, on the condition of a clinical diagnosis of dementia. Clinical data were retrieved through the patients’ medical records and the Swedish National Diabetes Register (NDR) and compared with those of the AD, VaD, and MD cases. Results: In LBD, there was less CaVD, significantly less DM (p  = 0.002) and likewise significantly less hypertension (p  < 0.001) than in VaD. The results of the LBD group were consistent with the results of the AD group. Conclusion: Our findings of a low prevalence of CaVD and CaVD risk factors in LBD and in AD argue against the association between these risk factors and their contribution to the development of neurodegenerative diseases. Show more

Keywords: Alzheimer’s disease, autopsy, cardiovascular disease, dementia, diabetes mellitus, hypertension, Lewy body disease, risk factors, vascular

DOI: 10.3233/JAD-190485

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 851-859, 2019

Authors: Schlegel, Petr | Novotny, Michal | Klimova, Blanka | Valis, Martin

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is one of the most common forms of dementia, which cannot be cured at the moment. Therefore, researchers also look for the alternative approaches to its treatment. It is suggested that changes in human gut microbiome mediated by exercise could influence the development and progression of AD and a new term “muscle-gut-brain axis” is introduced. There is much evidence to support this assumption. The gut microbiology is closely related to a wide range of diseases of the nervous system and therefore any negative qualitative and quantitative changes in the composition of the gut microbiota can potentially contribute …to the pathophysiology of AD. Research shows that the treatment of intestinal dysbiosis with probiotics/synbiotics/eubiotics can prevent or alleviate the symptoms of these chronic neurological diseases. Studies also point to the positive effects of movement on the health of seniors. A positive correlation can be found between cognitive functions and physical stress, both in the elderly and in AD patients. Even short-term interventions with a relatively low frequency seem to produce positive results, while physical activities can be performed by using relatively simple and cost-effective means. In addition, physical activity can significantly modulate gut microbiome. Thus, it can be concluded that physical activity in humans seems to correlate with gut microbiome, which can prevent the incidence and development of AD. Show more

Keywords: Alzheimer’s disease, cognitive disorders, dementia, exercise, microbiome, physical activity, probiotics

DOI: 10.3233/JAD-190460

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 861-878, 2019

Authors: Krishtal, Jekaterina | Metsla, Kristel | Bragina, Olga | Tõugu, Vello | Palumaa, Peep

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a currently incurable neurodegenerative disorder being the major form of dementia worldwide. AD pathology is initiated by cerebral aggregation of amyloid-β (Aβ) peptides in the form of amyloid plaques; however, the mechanism how Aβ peptide aggregates participate in the disease progression and neurodegeneration is still under debate. Human neuroblastoma cell line SH-SY5Y is a convenient cellular model, which is widely used in biochemical and toxicological studies of neurodegenerative diseases. This model can be further improved by differentiation of the cells toward more neuron-like culture using different protocols. In the current study, dbcAMP, retinoic acid with TPA, …or BDNF were used for differentiation of SH-SY5Y cells, and the resulting cultures were tested for the toxicity toward the Aβ42 peptide. The toxicity of Aβ42 peptide depended on the type of differentiated cells: RA and TPA- differentiated cells were most resistant, whereas dbcAMP and RA/BDNF- differentiated cells were more sensitive to Aβ toxicity as compared with non-differentiated cells. The differentiated cultures provide more appropriate cellular models of human origin that can be used for studies of the mechanism of Aβ pathogenesis and for a screening of compounds antagonistic to the toxicity of Aβ peptides. Show more

Keywords: Alzheimer’s disease, amyloid-β, differentiation, SH-SY5Y, toxicity

DOI: 10.3233/JAD-190705

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 879-887, 2019

Authors: Bonfiglio, Viviana | Umegaki, Hiroyuki | Kuzuya, Masafumi

Article Type: Research Article

Abstract: Background: With multimorbidity increasing among older people, polypharmacy and the use of potentially inappropriate medications (PIMs) are assuming a prominent role in the life of the geriatric population. Objective: To investigate the association of polypharmacy and PIM use with a wide range of factors in older people with mild cognitive impairment (MCI) to mild dementia. Methods: The study population comprised 160 outpatients with a Clinical Dementia Rating of 0.5–1 and a Mini-Mental State Examination score of 20–30. Patients were classified as receiving polypharmacy when they took ≥5 different medications at the same time. PIMs were identified …using the STOPP-J criteria. Cognitive, neuropsychological, nutritional, and physical function tests were performed and body measurements taken. Quality of life (QOL) was assessed using both components of the EQ-5D scale, the index score and the visual analogue scale (QOL VAS). A comorbidity index was calculated for all participants. Results: PIM use was significantly associated with lower scores on the verbal fluency (initial letters) test and QOL index. Participants receiving polypharmacy showed an increased likelihood of worse frailty status and lower QOL VAS score. The number of medications was significantly associated with a worse frailty status. Conclusion: In a geriatric population with MCI to mild dementia, PIM use was associated with lower verbal fluency (initial letters) score and lower QOL, while the presence of polypharmacy was correlated with a worse frailty status and lower QOL. The number of medicines, instead, was correlated with a worse frailty status only. Show more

Keywords: Dementia, frailty, polypharmacy, potentially inappropriate medications, quality of life

DOI: 10.3233/JAD-190284

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 889-897, 2019

Authors: Pyun, Jung-Min | Kang, Min Ju | Youn, Young Chul | Park, Young Ho | Kim, SangYun

Article Type: Research Article

Abstract: Background: Although dementia with Lewy bodies (DLB) is a degenerative disease involving irreversible pathological changes and subsequent progressive cognitive decline, some patients have presented with improved cognitive function at follow-ups. Their clinical and neuropsychological characteristics and the factors influencing this improvement remain unclear. Objective: To investigate differences in clinical and neuropsychological characteristics between DLB patients with and without cognitive improvement at a one-year follow-up, and to identify predictive factors of cognitive improvement. Methods: This retrospective study included 60 DLB patients, 28 patients in the improved group, and 32 patients in the non-improved group. A multiple linear …regression model was used to compare changes in cognitive function test scores between groups over the course of one year. Binary logistic regression analysis was performed to determine the odds ratios (ORs) of depressive symptoms as a predictor for cognitive improvement. Results: The improved group showed significant increases in immediate and delayed verbal memory function in one year over the non-improved group. We also found that baseline depressive symptoms were associated with an increased probability of cognitive improvement (OR 1.234, CI 1.043– 1.460). Conclusion: Depressive symptoms at baseline were related to a higher probability of a cognitive improvement at one-year follow-up. In addition, immediate and delayed verbal memory function showed significant improvement during one year in improved patients compared to non-improved patients. Show more

Keywords: Cognitive improvement, dementia with Lewy bodies, depressive symptoms

DOI: 10.3233/JAD-190685

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 899-905, 2019

Authors: Guglielmotto, Michela | Repetto, Ivan Enrico | Monteleone, Debora | Vasciaveo, Valeria | Franchino, Claudio | Rinaldi, Sara | Tabaton, Massimo | Tamagno, Elena

Article Type: Research Article

Abstract:  Neuroinflammation is involved in the pathogenesis of Alzheimer’s disease, and the transcription factor NF-κ B is a player in this event. We found here that the ischemic damage alone or in association with Aβ1-42 activates the NF-κ B pathway, induces an increase of BACE1 and a parallel inhibition of Uch-L1 and TREM2, both in vitro and in vivo , in Tg 5XFAD and in human brains of sporadic AD. This mechanism creates a synergistic loop that fosters inflammation. We also demonstrated a significant protection exerted by the restoration of Uch-L1 activity. The rescue of the enzyme is able …to abolish the decrease of TREM2 and the parameters of neuroinflammation. Show more

Keywords: Alzheimer’s disease, neuroinflammation, NF-kB pathway, stroke, TREM2, Uch-L1

DOI: 10.3233/JAD-190494

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 907-920, 2019

Authors: Smith, Patrick J. | Mabe, Stephanie | Sherwood, Andrew | Babyak, Michael A. | Doraiswamy, P. Murali | Welsh-Bohmer, Kathleen A. | Kraus, William | Burke, James | Hinderliter, Alan | Blumenthal, James A.

Article Type: Research Article

Abstract: Background: Greater body weight has been associated impairments in neurocognition and greater dementia risk, although the mechanisms linking weight and neurocognition have yet to be adequately delineated. Objective: To examine metabolic mechanisms underlying the association between obesity and neurocognition. Methods: We conducted a secondary analysis of weight, neurocognition, and the potentially mediating role of metabolic and inflammatory biomarkers among 160 participants from the ENLIGHTEN trial of vascular cognitive impairment, no dementia (CIND). Neurocognition was assessed using a 45-minute assessment battery assessing Executive Function, Verbal and Visual Memory. We considered three metabolic biomarkers: insulin resistance (homeostatic model …assessment [HOMA-IR]), plasma leptin, and insulin-like growth factor (IGF-1). Inflammation was assessed using C-reactive protein. Multiple regression analyses were used. Results: Participants included 160 sedentary older adults with CIND. Participants tended to be overweight or obese (mean BMI = 32.5 [SD = 4.8]). Women exhibited higher BMI (p  = 0.043), CRP (p  < 0.001), and leptin (p  < 0.001) compared with men. Higher BMI levels were associated with worse performance on measures of Executive Function (β= –0.16, p  = 0.024) and Verbal Memory (β= –0.16, p  = 0.030), but not Visual Memory (β= 0.05, p  = 0.500). Worse metabolic biomarker profiles also were associated with lower Executive Function (β= –0.12, p  = 0.050). Mediation analyses suggested leptin was a plausible candidate as a mediator between BMI and Executive Function. Conclusions: In overweight and obese adults with vascular CIND, the association between greater weight and poorer executive function may be mediated by higher leptin resistance. Show more

Keywords: Cognitive function, executive function, inflammation, insulin sensitivity, leptin, metabolic function, obesity

DOI: 10.3233/JAD-190569

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 921-929, 2019

Authors: Bangen, Katherine J. | Armstrong, Nicole M. | Au, Rhoda | Gross, Alden L.

Article Type: Research Article

Abstract: Metabolic syndrome (MetS) has been linked to increased risk of developing cognitive impairment and dementia including Alzheimer’s disease. It remains unclear whether and at what stage in the adult lifespan MetS and its components begin to alter the trajectory of cognitive performance. In the present study, 2,892 Framingham Offspring participants completed health assessments every four years since 1971 and underwent repeat neuropsychological testing from 1999 to 2014. We estimated the associations of levels and changes in cognitive trajectories with hazard of MetS using a joint growth/survival model. All models were adjusted for baseline age, sex, education, and smoking status. Findings …showed that both mid-life and late-life MetS were associated with lower level of cognitive functioning but not cognitive trajectories. Associations were strongest among those who were nondemented and apolipoprotein (APOE ) ɛ 4 noncarriers. In addition, individuals with the most rapid cognitive decline were more likely to have MetS. The pattern of results showed that associations between MetS and cognition varied, depending upon whether the sample was stratified by genetic and cognitive status and whether we considered cognitive performance as a continuous variable or examined categorical groupings. Given that mid-life MetS was associated with poorer cognition at age 55, cognitive changes may occur early during the MetS process. Our findings suggest that those with MetS are at greater risk of dementia given their lower level of cognitive functioning and also suggest that MetS may be a risk factor for decline in the absence of known risk factors including the APOE ɛ 4 allele. Show more

Keywords: Aging, Alzheimer’s disease, apolipoprotein E, cognition, diabetes, metabolic syndrome, neuropsychology, vascular risk

DOI: 10.3233/JAD-190261

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 931-943, 2019

Authors: Yang, Alex J.T. | Frendo-Cumbo, Scott | MacPherson, Rebecca E.K.

Article Type: Research Article

Abstract: Background: Obesity, insulin resistance, and type 2 diabetes are established risk factors for the development of Alzheimer’s disease (AD). Given this connection, two drugs, metformin (MET) and resveratrol (RESV), are considered for the clearance of amyloid-β peptides through AMPK-mediated activation of autophagy. However, overactivation of AMPK observed in late-stage AD brains and relationships between AMPK and neurogenesis (through mTORC1 inhibition), questions treatment with these drugs. Objective: To examine if MET and/or RESV supplementation activates brain AMPK, regulates markers of autophagy, and affects markers of neuronal health/neurogenesis. Methods: 8-week-old male C57BL/6J mice were fed a low (N = 12; …10% kcal fat; LFD) or high fat diet (N = 40; 60% kcal fat; HFD) for 9 weeks to induce insulin resistance and obesity. HFD mice were then treated with/without MET (250 mg/kg/day), RESV (100 mg/kg/day), or COMBO (MET: 250 mg/kg/day, RESV: 100 mg/kg/day) for 5 weeks. Hippocampus and prefrontal cortex were extracted for western blotting analysis. Results: Cortex AMPK (T172) and raptor (S792, the regulatory subunit of mTORC1) phosphorylation were upregulated following RESV, COMBO treatments. mTOR (S2448) and ULK1 (S555) activation was seen following MET, COMBO and RESV, COMBO treatments, respectively, in the cortex and hippocampus. p62 content was decreased following RESV, COMBO, with LC3 content being increased following RESV treatment in the cortex. Brain derived neurotropic factor (BDNF) was significantly decreased following RESV, COMBO, and synaptophysin following all treatment in the cortex. Conclusion: These results demonstrate that while treatments upregulated markers of autophagy in the prefrontal cortex, reductions in neuronal health markers question the efficacy of AMPK as a therapy for AD. Show more

Keywords: Autophagy, BDNF, metformin, resveratrol, synaptophysin

DOI: 10.3233/JAD-190123

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 945-956, 2019

Authors: Kulshreshtha, Ambar | Goetz, Margarethe | Alonso, Alvaro | Shah, Amit J. | Bremner, J. Douglas | Goldberg, Jack | Vaccarino, Viola

Article Type: Research Article

Abstract: Background/Objective: The 2020 Strategic Impact Goal introduced by the American Heart Association (AHA) aims at improving cardiovascular health (CVH) of all Americans by 20%. AHA defined ideal CVH across seven established modifiable risk factors for cardiovascular diseases. Prior studies have indicated that ideal CVH also benefits brain health and cognitive aging, but it is possible that this association is explained by familial factors. Methods: We examined 272 male monozygotic and dizygotic twin pairs (total 544 subjects) free of overt cardiovascular disease and dementia from the Vietnam Era Twin Registry. Memory and learning were measured by Trail Making tests …and Wechsler Memory Scale (Immediate and Delayed Memory tests and Visual Reproductive Test). Each of the seven CVH components (smoking, body mass index, physical activity, diet, total cholesterol, blood pressure, and blood glucose) was scored per established criterion. Results: The mean age of the twins was 55 years, 96% were whites, and 61% monozygotic. When considering twins as individuals, for every unit increase in CVH score (indicating better cardiovascular health), twins demonstrated faster cognitive processing speed (Trail B: – 5.6 s, 95% CI – 10.3, – 0.9; p  = 0.03) and better story recall, both immediate (0.35, 95% CI 0.06, 0.62; p  = 0.02) and delayed (0.39, 95% CI 0.08, 0.70; p  = 0.01). Conclusions: Better CVH is associated with better cognitive health in several domains. As suggested by within-pair analysis, this association is largely explained by familial factors, implying that early life exposures are shared determinants of both brain health and cardiovascular health. Show more

Keywords: Epidemiology, prevention, risk factors

DOI: 10.3233/JAD-190217

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 957-968, 2019

Authors: Petersen, Maria Skaalum | Restorff, Marjun | Stórá, Tórmóður | Waldemar, Gunhild | Joensen, Sofus

Article Type: Research Article

Abstract: Background: Dementia has become an important public health, economic, and social issue. Knowledge about prevalence, incidence, and trends of dementia in a country is of crucial importance. However, no studies of incidence or prevalence of dementia have been undertaken in the Faroe Islands. Objectives: The aim was to estimate the overall and trend in incidence and prevalence of dementia among individuals ≥60 years in the Faroe Islands from 2010-2017. Methods: Population-based register study where all individuals ≥60 years with a dementia diagnosis from January 2010 to December 2017 were identified. The overall crude and age-and-sex-specific incidence …and prevalence was assessed. Results: The overall crude incidence among individuals ≥60 years from 2010 to 2017 was 5.1 per 1000 individuals and the prevalence 22.5 per 1000 individuals. The age-and sex-standardized annual incidence of dementia fluctuated between 4.8 and 6.7 per 1000, with no clear secular trend while the age-and sex-standardized prevalence increased steadily from 14.5 in 2010 to 30.8 per 1000 individuals in 2017. Conclusion: The age-standardized incidence or prevalence estimates in the Faroes seem to be lower than in other countries. The incidence was relatively stable in the period while the prevalence of dementia simultaneously increased. Show more

Keywords: Dementia, Faroe Islands, incidence study, nationwide study, prevalence study, trend in incidence and prevalence

DOI: 10.3233/JAD-190341

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 969-978, 2019

Authors: Huseby, Carol J. | Hoffman, Claire N. | Cooper, Grace L. | Cocuron, Jean-Christophe | Alonso, Ana P. | Thomas, Stefani N. | Yang, Austin J. | Kuret, Jeff

Article Type: Research Article

Abstract: Tau is a microtubule-associated protein that normally interacts in monomeric form with the neuronal cytoskeleton. In Alzheimer’s disease, however, it aggregates to form the structural component of neurofibrillary lesions. The transformation is controlled in part by age- and disease-associated post-translational modifications. Recently we reported that tau isolated from cognitively normal human brain was methylated on lysine residues, and that high-stoichiometry methylation depressed tau aggregation propensity in vitro . However, whether methylation stoichiometry reached levels needed to influence aggregation propensity in human brain was unknown. Here we address this problem using liquid chromatography–tandem mass spectrometry approaches and human-derived tau samples. Results …revealed that lysine methylation was present in soluble tau isolated from cognitively normal elderly cases at multiple sites that only partially overlapped with the distributions reported for cognitively normal middle aged and AD cohorts, and that the quality of methylation shifted from predominantly dimethyl-lysine to monomethyl-lysine with aging and disease. However, bulk mol methylation/mol tau stoichiometries never exceeded 1 mol methyl group/mol tau protein. We conclude that lysine methylation is a physiological post-translational modification of tau protein that changes qualitatively with aging and disease, and that pharmacological elevation of tau methylation may provide a means for protecting against pathological tau aggregation. Show more

Keywords: Aging, Alzheimer’s disease, mass spectrometry, methylation, phosphorylation, post-translational modification, tau protein

DOI: 10.3233/JAD-190604

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 979-991, 2019

Authors: Wiest, Isabella | Wiemers, Tim | Kraus, Max-Joseph | Neeb, Heiko | Strasser, Erwin F. | Hausner, Lucrezia | Frölich, Lutz | Bugert, Peter

Article Type: Research Article

Abstract: Background: Early diagnosis of Alzheimer’s disease (AD) is challenging, and easily accessible biomarkers are an unmet need. Blood platelets frequently serve as peripheral model for studying AD pathogenesis and might represent a reasonable biomarker source. Objective: In the present study, we investigated the potential to differentiate AD patients from healthy controls (HC) based on blood count, platelet morphology, and function as well as molecular markers at the time of first clinical diagnosis. Methods: Blood samples from 40 AD patients and 29 age-matched HC were included for determination of 78 parameter by blood counting, platelet morphometry, aggregometry, …flow cytometry (CD62P, CD63, activated fibrinogen receptor), protein quantification of nicotinic acetylcholine receptor α 7 (nAChRα 7) and caveolin-1 (CAV-1), and miRNA quantification (miR-26b, miR-199a, miR-335). Group comparison between patients and controls was performed in univariate and multivariate statistical analyses. Results: AD patients showed significantly lower aggregation response to ADP and arachidonic acid and significantly decreased CD62P and CD63 surface expression induced by ADP and U46619 compared to HC. Relative nAChRα 7 and CAV-1 expression was significantly higher AD platelets than in HC. Multivariate analysis of 63 parameter revealed significant differences between AD patients and healthy controls. The best performing feature model revealed a sensitivity of 96.6%, a specificity of 80.0%, and a positive predictive value of 89.3%. No grouping could be achieved by using single parameter groups. Conclusion: Significant differences between platelet characteristics from AD patients and HC at the time of first clinical diagnosis were observed. The best performing parameter can be used as a blood-based biomarker for AD diagnosis in a multivariate model in addition to the standardized mental tests. Show more

Keywords: Aggregometry, Alzheimer’s disease, blood-based biomarker, platelet morphology

DOI: 10.3233/JAD-190574

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 993-1004, 2019

Authors: Puthusseryppady, Vaisakh | Coughlan, Gillian | Patel, Martyn | Hornberger, Michael

Article Type: Research Article

Abstract: Background: Dementia-related missing incidents are highly prevalent but still poorly understood. This is particularly true for environmental/geospatial risk factors, which might contribute to these missing incidents. Objective: The study aimed to conduct a retrospective, observational analysis on a large sample of missing dementia patient case records provided by the police (n  = 210), covering dates from January 2014 to December 2017. In particular, we wanted to explore 1) whether there were any hotspot regions of missing incidents and 2) the relationship between outdoor landmark density and missing incidents. Methods: Global spatial autocorrelation (Moran’s I) was used to …identify the potential hotspot regions for missing incidents. Meanwhile, spatial buffer and regression modelling were used to determine the relationship between outdoor landmark density and missing incidents. Results: Our demographics measures replicated and extended previous studies of dementia-related missing incidents. Meanwhile, no hotspot regions for missing incidents were identified, while higher outdoor landmark density led to increased missing incidents. Conclusion: Our results highlight that missing incidents do not occur in isolated hotspots of regions but instead are endemic in patients regardless of location. Higher outdoor landmark density emerges as a significant geospatial factor for missing incidents in dementia, which crucially informs future safeguarding/intervention studies. Show more

Keywords: Dementia, risk factors, spatial navigation, spatial analysis

DOI: 10.3233/JAD-190244

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 1005-1013, 2019

Authors: Shaffer, Rachel M. | Sheppard, Lianne | Peskind, Elaine R. | Zhang, Jing | Adar, Sara D. | Li, Ge

Article Type: Research Article

Abstract: Background: Cerebrovascular diseases play an important role in dementia. Air pollution is associated with cardiovascular disease, with growing links to neurodegeneration. Prior studies demonstrate associations between fine particulate matter (PM2.5 ) and biomarkers of endothelial injury in the blood; however, no studies have evaluated these biomarkers in cerebrospinal fluid (CSF). Objective: We evaluate associations between short-term and long-term PM2.5 exposure with CSF vascular cell adhesion molecule-1 (VCAM-1) and e-selectin in cognitively normal and mild cognitive impairment (MCI)/Alzheimer’s disease (AD) individuals. Methods: We collected CSF from 133 community volunteers at VA Puget Sound between 2001–2012. …We assigned short-term PM2.5 from central monitors and long-term PM2.5 based on annual average exposure predictions linked to participant addresses. We performed analyses stratified by cognitive status and adjusted for key covariates with tiered models. Our primary exposure windows for the short-term and long-term analyses were 7-day and 1-year averages, respectively. Results: Among cognitively normal individuals, a 5 μg/m3 increase in 7-day and 1-year average PM2.5 was associated with elevated VCAM-1 (7-day: 35.4 (9.7, 61.1) ng/ml; 1-year: 51.8 (6.5, 97.1) ng/ml). A 5 μg/m3 increase in 1-year average PM2.5 , but not 7-day average, was associated with elevated e-selectin (53.3 (11.0, 95.5) pg/ml). We found no consistent associations among MCI/AD individuals. Conclusions: We report associations between short-term and long term PM2.5 and CSF biomarkers of vascular damage in cognitively normal adults. These results are aligned with prior research linking PM2.5 to vascular damage in other biofluids as well as emerging evidence of the role of PM2.5 in neurodegeneration. Show more

Keywords: Alzheimer’s disease, biomarkers, cellular adhesion molecules, cerebrospinal fluid, cerebrovascular disorders, dementia, particulate matter

DOI: 10.3233/JAD-190563

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 1015-1025, 2019

Authors: Ezzati, Ali | Zammit, Andrea R. | Harvey, Danielle J. | Habeck, Christian | Hall, Charles B. | Lipton, Richard B. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Predicting clinical course of cognitive decline can boost clinical trials’ power and improve our clinical decision-making. Machine learning (ML) algorithms are specifically designed for the purpose of prediction; however. identifying optimal features or algorithms is still a challenge. Objective: To investigate the accuracy of different ML methods and different features to classify cognitively normal (CN) individuals from Alzheimer’s disease (AD) and to predict longitudinal outcome in participants with mild cognitive impairment (MCI). Methods: A total of 1,329 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were included: 424 CN, 656 MCI, and 249 AD individuals. …Four feature-sets at baseline (hippocampal volume and volume of 47 cortical and subcortical regions with and without demographics and APOE4 ) and six machine learning methods (decision trees, support vector machines, K-nearest neighbor, ensemble linear discriminant, boosted trees, and random forests) were used to classify participants with normal cognition from participants with AD. Subsequently the model with best classification performance was used for predicting clinical outcome of MCI participants. Results: Ensemble linear discriminant models using demographics and all volumetric magnetic resonance imaging measures as feature-set showed the best performance in classification of CN versus AD participants (accuracy = 92.8%, sensitivity = 95.8%, and specificity = 88.3%). Prediction accuracy of future conversion from MCI to AD for this ensemble linear discriminant at 6, 12, 24, 36, and 48 months was 63.8% (sensitivity = 74.4, specificity = 63.1), 68.9% (sensitivity = 75.9, specificity = 67.8), 74.9% (sensitivity = 71.5, specificity = 76.3), 75.3%, (sensitivity = 65.2, specificity = 79.7), and 77.0% (sensitivity = 59.6, specificity = 86.1), respectively. Conclusions: Machine learning models trained for classification of CN versus AD can improve our prediction ability of MCI conversion to AD. Show more

Keywords: Alzheimer’s disease, classification, early diagnosis, machine learning, magnetic resonance imaging, mild cognitive impairment, predictive analytics

DOI: 10.3233/JAD-190262

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 1027-1036, 2019

Authors: Charil, Arnaud | Shcherbinin, Sergey | Southekal, Sudeepti | Devous, Michael D. | Mintun, Mark | Murray, Melissa E. | Miller, Bradley B. | Schwarz, Adam J.

Article Type: Research Article

Abstract: At autopsy, individuals with Alzheimer’s disease (AD) exhibit heterogeneity in the distribution of neurofibrillary tangles in neocortical and hippocampal regions. Subtypes of AD, defined using an algorithm based on the relative number of tangle counts in these regions, have been proposed—hippocampal sparing (relative sparing of the hippocampus but high cortical load), limbic predominant (high hippocampal load but lower load in association cortices), and typical (balanced neurofibrillary tangles counts in the hippocampus and association cortices) AD—and shown to be associated with distinct antemortem clinical phenotypes. The ability to distinguish these AD subtypes from the more typical tau signature in vivo …could have important implications for clinical research. Flortaucipir positron emission tomography (PET) images acquired from 45 amyloid-positive participants, defined clinically as mild cognitive impairment or AD, aged 50–92 years, 56% female, and estimated to be Braak V-VI based on their PET pattern of tau pathology, were studied. By translating the neuropathologic algorithm to flortaucipir PET scans, patterns of tau pathology consistent with autopsy findings, and with a similar prevalence, were identified in vivo . 6/45 (13%) participants were identified as hippocampal sparing and 6/45 (13%) as limbic predominant AD subtypes. Hippocampal sparing participants were significantly younger than those assigned to the other two subtypes. Worse performance on delayed recall was associated with increased hippocampal tau signal, and worse performance on the trail making test B-A was associated with lower values of the hippocampus to cortex ratio. Prospective studies can further validate the flortaucipir SUVR cut-points and the phenotype of the corresponding AD subtypes. Show more

Keywords: Hippocampal sparing, limbic predominant, subtype, tau

DOI: 10.3233/JAD-190264

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 1037-1048, 2019

Authors: Aguirre, Naiara | Costumero, Víctor | Marin-Marin, Lidón | Escudero, Joaquín | Belloch, Vicente | Parcet, María Antonia | Ávila, César

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) has been associated with memory impairment due to alterations in the medial temporal lobe (MTL) and the precuneus. Therefore, the goal of this study was to investigate the effects of AD on the brain networks associated with the hippocampus and precuneus during an encoding memory task. 68 mild cognitive impairment patients (MCI), 21 AD patients, and 20 healthy controls (HC) were included. Participants were instructed to memorize landscapes while undergoing fMRI scanning, followed by a recognition test. MCI were followed up clinically for 18 months to track conversion status. Independent component analysis (ICA) was performed to investigate …AD effects on precuneus and MTL networks during memory encoding. Behavioral analyses indicate that HC had a better performance than MCI converters (MCIc) and AD. ICA showed that MCIc had significantly higher activation in the MTL-associated network than MCI non converters (MCIn) and AD, including bilateral hippocampus, parahippocampus, and fusiform gyrus. Furthermore, the precuneus-associated network fitted the default mode network, showing a negative correlation with behavioral performance. These findings indicate that the hyperactivation of the hippocampal network displayed by MCIc has potential discrimination capacity to distinguish them of MCIn, and could be interpreted as a compensatory mechanism. Show more

Keywords: Alzheimer’s disease, hippocampus, independent component analysis, memory, precuneus

DOI: 10.3233/JAD-190421

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 1049-1061, 2019

Authors: Tadokoro, Koh | Morihara, Ryuta | Ohta, Yasuyuki | Hishikawa, Nozomi | Kawano, Satoko | Sasaki, Ryo | Matsumoto, Namiko | Nomura, Emi | Nakano, Yumiko | Takahashi, Yoshiaki | Takemoto, Mami | Yamashita, Toru | Ueno, Setsuko | Wakutani, Yosuke | Takao, Yoshiki | Morimoto, Nobutoshi | Kutoku, Yumiko | Sunada, Yoshihide | Taomoto, Katsushi | Manabe, Yasuhiro | Deguchi, Kentaro | Higashi, Yasuto | Inufusa, Haruhiko | You, Fukka | Yoshikawa, Toshikazu | von Greiffenclau, Markus Matuschka | Abe, Koji

Article Type: Research Article

Abstract: Oxidative stress is part of the entire pathological process that underlies the development of Alzheimer’s disease (AD), including the mild cognitive impairment (MCI) stage. Twendee X (TwX) is a supplement containing a strong antioxidative mix of eight antioxidants, which has been shown to have a clinical and therapeutic benefit in AD model mice. Here, we conducted a multicenter, randomized, double-blind, and placebo-controlled prospective interventional study to evaluate the efficacy of TwX in mitigating MCI. The primary outcomes were differences in Mini-Mental State Examination (MMSE) and Hasegawa Dementia Scale-revised (HDS-R) scores between baseline and six months for placebo and TwX groups. …Seventy-eight subjects with MCI were randomized into placebo (n  = 37) and TwX (n  = 41) groups. MMSE scores at six months differed significantly between the TwX and placebo groups (p  = 0.018), and HDS-R scores for the TwX group exhibited a significant improvement at six months relative to baseline (p  = 0.025). The TwX group did not show any change in affective or activities of daily living scores at six months. The present study indicates that strong antioxidative supplement TwX is clinical beneficial for cognitive function in subjects with MCI. Show more

Keywords: Dementia, dietary supplement, mild cognitive impairment, oxidative stress, randomized controlled trial

DOI: 10.3233/JAD-190644

Citation: Journal of Alzheimer's Disease, vol. 71, no. 3, pp. 1063-1069, 2019