Journal of Alzheimer's Disease - Volume 73, issue 1

Authors: Cechova, Katerina | Andel, Ross | Angelucci, Francesco | Chmatalova, Zuzana | Markova, Hana | Laczó, Jan | Vyhnalek, Martin | Matoska, Vaclav | Kaplan, Vojtech | Nedelska, Zuzana | Ward, David D. | Hort, Jakub

Article Type: Research Article

Abstract:  Apolipoprotein (APOE ) ɛ 4 is a well-known risk factor for late-onset Alzheimer’s disease (AD), but other AD-related gene polymorphisms might also be important, such as the polymorphism within the brain-derived neurotrophic factor (BDNF ) gene. Carriage of BDNF Val66Met has been associated with faster cognitive decline and greater hippocampal atrophy in cognitively normal elderly. Thus, we examined the effects of the concurrent presence of APOE and BDNF polymorphisms on cognitive functions and brain morphometry in amnestic mild cognitive impairment (aMCI) patients. 107 aMCI patients (mean age = 72.2) were recruited from the Czech Brain Aging Study and, based …on APOE and BDNF genes polymorphisms, were divided into four groups: ɛ 4– BDNF Val/Val (n  = 37), ɛ 4– BDNF Met (n  = 19), ɛ 4+ BDNF Val/Val (n  = 35), and ɛ 4+ BDNF Met (n  = 16). All patients underwent clinical examination, magnetic resonance imaging, and complex neuropsychological battery. The combination of APOE ɛ 4+ and BDNF Met was associated with significantly worse memory performance in immediate and delayed recall compared to other polymorphism groups. We did not observe increased atrophy in areas related to memory function in the ɛ 4+ BDNF Met group. Our findings suggest that carriage of ɛ 4+ BDNF Met is associated with more pronounced memory dysfunction, a typical feature of early AD, but not with structural brain changes in aMCI patients. These findings suggest that in APOE ɛ 4/BDNF Met carriers, synaptic dysfunction affecting memory may precede pronounced structural changes. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, Apolipoprotein E, brain-derived neurotrophic factor, cognition, gene polymorphism

DOI: 10.3233/JAD-190464

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 247-257, 2020

Authors: Jensen-Dahm, Christina | Christensen, Ane Nørgaard | Gasse, Christiane | Waldemar, Gunhild

Article Type: Research Article

Abstract: Background: Opioids are used with increasing frequency. Elderly with dementia are prescribed opioids more frequent than elderly without. One possible explanation is that opioids may be used not only to treat pain but also behavioral symptoms. Objective: To test the hypothesis that strong opioid use, especially transdermal formulations, had increased, especially in elderly with dementia, in parallel with a decrease in antipsychotic use. Methods: Population-based cross-sectional study conducted using nationwide Danish registers with data on Denmark’s entire elderly population age ≥65 (2000: n  = 802,106; 2015: n  = 1,056,476). The registers were used to identify elderly with and …without dementia and filled prescriptions for opioids and antipsychotics. Annual prevalence of opioid and antipsychotic use from 2000–2015 was calculated. Results: Prevalence of opioid use increased by 35% (24.2 to 32.5%) among elderly with dementia and by 13% among elderly without (14.9 to 16.8%) from 2000–2015. The disproportionate increase in opioid use among elderly with dementia was mainly driven by an increase in strong opioids (dementia: 11.7 to 23.1%; without dementia: 5.9 to 7.4%). Use of antipsychotics decreased during the same period (dementia: 31.3 to 19.3%; no dementia: 4.5 to 2.7%). Conclusion: From 2000–2015, use of opioids among the elderly increased with a disproportionately higher increase among elderly with dementia. The parallel decrease in the use of antipsychotics may suggest that opioids to some extent have replaced antipsychotics in managing behavioral symptoms, despite safety concerns and lack of evidence for effect of opioids. Future research should focus on potential risks associated with increased opioid use. Show more

Keywords: Antipsychotic, behavioral symptoms, dementia, drug use, opioid, pain

DOI: 10.3233/JAD-190787

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 259-267, 2020

Authors: Vergouw, Leonie J.M. | Bosman, Brechje | van de Beek, Marleen | Salomé, Mariet | Hoogers, Susanne E. | van Steenoven, Inger | Roks, Gerwin | Bonifati, Vincenzo | van Swieten, John C. | Lemstra, Afina W. | de Jong, Frank Jan

Article Type: Research Article

Abstract: It is currently unknown whether patients with dementia with Lewy bodies (DLB) with relatives with dementia or Parkinson’s disease (familial DLB patients) have a different phenotype than sporadic DLB patients. In this study, we aimed to examine disease onset, rate of cognitive decline, survival, and Alzheimer’s disease (AD) biomarkers in patients with familial DLB (n  = 154) and sporadic DLB (n  = 137), using linear mixed model analysis and Cox regression analysis, among others. Familial patients had a shorter survival (8.0 years) and more often elevated cerebrospinal fluid AD biomarkers (47%) than sporadic patients (9.0 years; p ≤0.001; 30%, p  = 0.037). Our …findings suggest that genetic factors are important in DLB and that the identification of new genetic factors will probably improve the prediction of prognosis. Show more

Keywords: Dementia with Lewy bodies, family history, phenotype, survival

DOI: 10.3233/JAD-190825

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 269-275, 2020

Authors: Chen, Haoyu | Liang, Lu | Xu, Hua | Xu, Jia | Yao, Leyi | Li, Yanling | Tan, Yufan | Li, Xiaofen | Huang, Qingtian | Yang, Zhenjun | Wu, Jiawen | Chen, Jinghong | Huang, Hongbiao | Wang, Xuejun | Zhang, Chang-E. | Liu, Jinbao

Article Type: Research Article

Abstract: Hyperbilirubinemia may increase the risk of Alzheimer’s disease (AD) but its mechanistic role in AD pathogenesis remains obscure. Here, we used animal models to investigate the short- and long-term effects of neonatal systemic exposure to bilirubin on brain histology and function as well as the acute effect of lateral ventricle injection of bilirubin in adult rats. We found that three days exposure to bilirubin in newborn rats could induce AD-like pathological changes in late life, including tau protein hyperphosphorylation at multiple sites, increased Aβ production in brain tissues, and spatial learning and memory injury. Bilirubin activated the activities of several …protein kinases (GSK-3β, CDK5, and JNK), which were positively correlated with hyperphosphorylated tau; simultaneously increased the expression of AβPP γ -secretase PS2 and decreased the expression of α -secretase ADAM17, which were positively correlated with Aβ production. The above results were well replicated in primary hippocampal cell cultures. These data demonstrate that bilirubin encephalopathy is an AD-like disease, suggesting a potent role of bilirubin in AD. Show more

Keywords: AβPP, α-secretase, Alzheimer’s disease, amyloid-β, bilirubin, γ-secretase, protein kinase, spatial learning and memory injury, tau hyperphosphorylation, tau protein

DOI: 10.3233/JAD-190945

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 277-295, 2020

Authors: Lee, Tsung-Lin | Liu, Chi-Hung | Chang, Yu-Ming | Lin, Tien-Yu | Chien, Chung-Yao | Chen, Chih-Hung | Tsai, Kuen-Jer | Lin, Sheng-Hsiang | Sung, Pi-Shan

Article Type: Research Article

Abstract: Background: Antiplatelet use on the risk of intracerebral hemorrhage (ICH) in patients with Alzheimer’s disease (AD) has not yet been completely elucidated. Objective: This large epidemiologic study aims to estimate the risk of ICH in AD patients treated with antiplatelet therapy (APT). Methods: Using data from Taiwan’s National Health Insurance Research Database, ICH risk in APT-treated AD patients with a validated diagnosis (N = 824) was determined. AD without APT and non-AD with and without APT comparison cohorts were selected. To adjust for confounders and competing risk of death, inverse probability of treatment weighting using propensity scores and …competing risks regression (CRR) were applied. Cox proportional hazards regression analysis estimated ICH risk in all cohorts comparing with non-AD without APT. Results: Among the 824 AD patients with APT, 79.6% were prescribed aspirin. ICH incidence rates in the AD (with/without APT) and non-AD (with/without APT) cohorts were 2.88/2.70 and 2.24/1.20 per 1,000 person-years, respectively. Overall, AD with (adjusted hazards ratio (aHR), 2.29; 95% CI, 1.19–4.38) and without (aHR, 1.97; 95% CI, 1.08–3.61) APT and non-AD with APT (aHR, 1.80; 95% CI, 1.34–2.42) were at a higher risk and had elevated subdistribution HR obtained from CRR than non-AD without APT controls. However, the risk was comparable between the AD cohorts with and without APT (HR, 1.16; 95% CI, 0.51–2.66). Conclusions: Our study indicated both the APT and non-APT users in AD population yielded higher ICH risks. However, whether APT use potentiate the risk of ICH in AD patients may warrant further evaluation. Show more

Keywords: Alzheimer’s disease, antiplatelet therapy, aspirin, intracranial hemorrhage, risk

DOI: 10.3233/JAD-190762

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 297-306, 2020

Authors: Yeh, Tian-Shin | Wang, Jung-Der | Ku, Li-Jung Elizabeth

Article Type: Research Article

Abstract: Background: People with early onset Alzheimer’s disease (EOAD) seem to suffer greater impact. But there is a lack of population-based studies on loss of life expectancy (LE) and lifetime healthcare costs. Objectives: We conducted this study to estimate LE, expected years of life lost (EYLL), and lifetime healthcare costs for Alzheimer’s disease (AD) in Taiwan stratified by onset age and gender, using a method which integrates the product of the survival function and the mean cost function over a lifetime horizon. Methods: We linked the National Health Insurance datasets with the National Mortality Registry and extrapolated …the survival to lifetime to estimate the mean cumulative costs since the date of the first AD diagnosis using medical claims between 2001 and 2012. Results: A total of 21,615 mild to moderate AD patients (including 20,358 late-onset (LOAD) and 1,257 EOAD) were recruited. The average onset age for EOAD was 61 years old, while that of LOAD was 78. Although the LE of EOAD was 4.8 years longer than that of LOAD due to younger age, the EYLL for the former was 8.7 years versus 1.7 years for the latter. EOAD also had higher lifetime healthcare costs than the LOAD group (USD$37,957±2,403 versus 33,809±786). Conclusions: Since EOAD patients had both higher EYLL and lifetime healthcare costs than LOAD, future studies should pay more attention to the needs of EOAD patients. Show more

Keywords: Early-onset Alzheimer’s disease, healthcare costs, late-onset Alzheimer’s disease, life expectancy

DOI: 10.3233/JAD-181060

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 307-315, 2020

Authors: Chosy, E. Julia | Gross, Noele | Meyer, Marnie | Liu, Catherine Y. | Edland, Steven D. | Launer, Lenore J. | White, Lon R.

Article Type: Research Article

Abstract: Background: Findings are inconsistent regarding the role of traumatic head injury in the subsequent development of neurologic outcomes. Objective: Examine the relationship between head injury and later cognitive impairment. Methods: A sample of 3,123 Japanese-American men was assessed for history of head injury and evaluated for cognitive impairment using the Cognitive Abilities Screening Instrument (CASI). For a subsample of 676 respondents, neuropathologic results from those with and without head injury were compared. Results: Although the crude model showed an association between history of head injury and later severe cognitive impairment, the relationship lost significance …in the adjusted model (OR = 1.320, CI: 0.90–1.93), regardless of time between injury and impairment. Similar to cognitive impairment, hippocampal sclerosis was observed significantly more in the brains of respondents with a history of head injury in the crude model, but the relationship weakened in the adjusted model (OR = 1.462, CI: 0.68–3.12). After adjustment, decedents with a head injury demonstrated marginally higher brain weight (OR = 1.003, CI: 1.00–1.01). Conclusion: We did not find a relationship between head injury and subsequent cognitive decline in this cohort. The neuropathology results also displayed no strong association between history of head injury and specific brain lesions and characteristics. These results support other findings in prospective cohorts. However, they could be influenced by the demographic make-up of the sample (male Japanese-Americans) or by the observation that the majority reported only a single head injury. Show more

Keywords: Alzheimer’s disease, brain lesions, cognitive dysfunction, dementia, Honolulu-Asia Aging Study, neuropathology, traumatic brain injury

DOI: 10.3233/JAD-190053

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 317-325, 2020

Authors: Agarwal, Puja | Brockman, John D. | Wang, Yamin | Schneider, Julie A. | Morris, Martha C.

Article Type: Research Article

Abstract: Background: Bromine is a naturally occurring element that is widely present in the human environment in various chemical forms primarily as flame retardants, pesticides, and water treatments. Objective: In this exploratory study, we investigated the association of brain bromine concentrations on Alzheimer’s disease (AD) neuropathology, cerebral infarcts, and Lewy bodies. Methods: The study was conducted in 215 deceased participants of the Memory and Aging Project, a clinical-pathologic cohort study. Brain bromine levels were measured using instrumental neutron activation analysis. Multiple brain regions were assessed for diffuse and neuritic plaques, neurofibrillary tangles, cerebral macro-and microinfarcts, and Lewy …bodies. Standardized measures of AD pathology (Braak, CERAD, NIA-Reagan, global AD pathology) were computed. Results: In linear regression models, the higher brain bromine levels were associated with more AD neuropathology (Braak (p trend = 0.01); CERAD (p trend = 0.02); NIA-Reagan (p trend = 0.02). Conclusion: Bromine accumulation in the brain is associated with higher level of AD neuropathology. The potential deleterious effects of this element on AD need further exploration. Show more

Keywords: Alzheimer’s disease, bromine, metals, neuropathology

DOI: 10.3233/JAD-190646

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 327-332, 2020

Authors: Arfanakis, Konstantinos | Evia, Arnold M. | Leurgans, Sue E. | Cardoso, Luis F.C. | Kulkarni, Arman | Alqam, Nabil | Lopes, Lucas F. | Vieira, Diego | Bennett, David A. | Schneider, Julie A.

Article Type: Research Article

Abstract: Background: The association of white matter hyperintensities (WMH) with age-related vascular and neurodegenerative pathologies remains incompletely understood. Objective: The objective of this work was to elucidate the neuropathologic correlates of WMH in a large community-based cohort of older adults. Methods: Cerebral hemispheres from 603 community-based older adults were imaged with MRI ex vivo . All participants underwent annual clinical evaluation, cognitive assessment, and neuropathologic examination. WMH burden was assessed using a modified Fazekas rating scale. Multiple ordinal logistic regression was used to test the association of WMH burden with an array of age-related neuropathologies, adjusting for …demographics. Mixed effects models of cognition controlling for neuropathologies and demographics were used to determine whether WMH burden contributes to cognitive decline beyond measured pathologies. Results: WMH burden in the whole group was associated with both vascular and Alzheimer’s disease (AD) pathologies: arteriolosclerosis (p  < 10–4 ), gross (p  < 10–4 ), and microscopic infarcts (p  = 0.04), and amyloid-β plaques (p  = 0.028). In non-demented participants (mild or no cognitive impairment) (N = 332), WMH burden was related to gross infarcts (p  = 10–4 ) and arteriolosclerosis (p  < 10–4 ), but not to AD pathology. Similarly, in those with no cognitive impairment (N = 178), WMH burden was related to gross infarcts (p  = 8×10–4 ) and arteriolosclerosis (p  = 0.014). WMH burden was associated with faster decline in perceptual speed in both the whole (p  = 0.038) and non-demented (p  = 0.006) groups. Conclusion: WMH burden has independent associations with vascular pathologies in older adults regardless of clinical status, and with AD pathology later in the progression of AD. Moreover, WMH burden may reflect additional tissue injury not captured with traditional neuropathologic indices. Show more

Keywords: Cognition, magnetic resonance imaging, pathology, white matter hyperintensities

DOI: 10.3233/JAD-190687

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 333-345, 2020

Authors: Reas, Emilie T. | Hagler Jr. , Donald J. | Kuperman, Joshua M. | Wierenga, Christina E. | Galasko, Douglas | White, Nathan S. | Dale, Anders M. | Banks, Sarah J. | McEvoy, Linda K. | Brewer, James B.

Article Type: Research Article

Abstract: Background: Although amyloid-β (Aβ) and microstructural brain changes are both effective biomarkers of Alzheimer’s disease, their independent or synergistic effects on cognitive decline are unclear. Objective: To examine associations of Aβ and brain microstructure with cognitive decline in amnestic mild cognitive impairment and dementia. Methods: Restriction spectrum imaging, cerebrospinal fluid Aβ, and longitudinal cognitive data were collected on 23 healthy controls and 13 individuals with mild cognitive impairment or mild to moderate Alzheimer’s disease. Neurite density (ND) and isotropic free water diffusion (IF) were computed in fiber tracts and cortical regions of interest. We examined associations …of Aβ with regional and whole-brain microstructure, and assessed whether microstructure mediates effects of Aβ on cognitive decline. Results: Lower ND in limbic and association fibers and higher medial temporal lobe IF predicted baseline impairment and longitudinal decline across multiple cognitive domains. ND and IF predicted cognitive outcomes after adjustment for Aβ or whole-brain microstructure. Correlations between microstructure and cognition were present for both amyloid-positive and amyloid-negative individuals. Aβ correlated with whole-brain, rather than regional, ND and IF. Conclusion: Aβ correlates with widespread microstructural brain changes, whereas regional microstructure correlates with cognitive decline. Microstructural abnormalities predict cognitive decline regardless of amyloid, and may inform about neural injury leading to cognitive decline beyond that attributable to amyloid. Show more

Keywords: Aging, Alzheimer’s disease, amyloid, cognitive decline, dementia, diffusion imaging, magnetic resonance imaging, memory, mild cognitive impairment

DOI: 10.3233/JAD-190871

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 347-357, 2020