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

Authors: Defrancesco, Michaela | Marksteiner, Josef | Kemmler, Georg | Dal-Bianco, Peter | Ransmayr, Gerhard | Benke, Thomas | Mosbacher, Jochen | Höller, Yvonne | Schmidt, Reinhold

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms (NPS) occur frequently in the course of Alzheimer’s disease (AD) and are suspected to be associated with a faster dementia progression. Numerous reports have defined specific subsyndromes, summarized in clusters of items of the Neuropsychiatric Inventory (NPI). Objective: This study investigated the influence of specific NPI subsyndromes and clinical patient characteristics on dementia progression. Methods: Data of the prospective registry on dementia in Austria (PRODEM) were retrospectively analyzed. Cognitive functioning was determined at baseline and 2 yearly follow-up visits using the Mini-Mental State Examination (MMSE) and the Consortium to Establish a Registry for …Alzheimer’s dementia neuropsychological test battery (CERAD). To assess NPS, the NPI was used: NPI items were classified in three subsyndromes (psychotic cluster, behavioral cluster, emotional cluster). Results: Out of the 662 included patients (mean age 76.4±8.4 years), 43% completed follow-up visits for two years. Significant correlation between higher scores in all three subsyndromes and worse cognitive performance were found for MMSE score, naming, and verbal fluency. Results of linear mixed model analysis revealed lower age and higher scores in the psychotic cluster as significant predictors of changes in MMSE with time. Conclusion: In this study, we report the influence of psychotic subsyndromes and lower age on faster MMSE decline in early AD. These results emphasize the importance of not only assessing but also differentiating neuropsychiatric symptoms in subsyndromes in the early stages of AD as a possible predictor of disease progression. Show more

Keywords: Alzheimer’s disease, disease progression, Neuropsychiatric Inventory, neuropsychiatric symptoms

DOI: 10.3233/JAD-190662

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 125-133, 2020

Authors: Babić Leko, Mirjana | Nikolac Perković, Matea | Klepac, Nataša | Švob Štrac, Dubravka | Borovečki, Fran | Pivac, Nela | Hof, Patrick R. | Šimić, Goran

Article Type: Research Article

Abstract: The noradrenergic and dopaminergic systems are affected in Alzheimer’s disease (AD). Polymorphisms in genes encoding enzymes and proteins that are components of these systems can affect products of transcription and translation and lead to altered enzymatic activity and alterations in overall dopamine and noradrenaline levels. Catechol-O -methyltransferase (COMT) and monoamine oxidase B (MAOB) are the enzymes that regulate degradation of dopamine, while dopamine β-hydroxylase (DBH) is involved in synthesis of noradrenaline. COMT Val158Met (rs4680), DBH rs1611115 (also called –1021C/T or –970C/T), and MAOB rs1799836 (also called A644G) polymorphisms have been previously associated with AD. We assessed whether …these polymorphisms are associated with cerebrospinal fluid (CSF) AD biomarkers including total tau (t-tau), phosphorylated tau proteins (p-tau181 , p-tau199 , and p-tau231 ), amyloid-β42 (Aβ42 ), and visinin-like protein 1 (VILIP-1) to test possible relationships of specific genotypes and pathological levels of CSF AD biomarkers. The study included 233 subjects: 115 AD, 53 mild cognitive impairment, 54 subjects with other primary causes of dementia, and 11 healthy controls. Significant decrease in Aβ42 levels was found in patients with GG compared to AG COMT Val158Met genotype, while t -tau and p -tau181 levels were increased in patients with AA compared to AG COMT Val158Met genotype. Aβ42 levels were also decreased in carriers of A allele in MAO-B rs1799836 polymorphism, while p -tau181 levels were increased in carriers of T allele in DBH rs1611115 polymorphism. These results indicate that COMT Val158Met, DBH rs1611115, and MAOB rs1799836 polymorphisms deserve further investigation as genetic markers of AD. Show more

Keywords: Alzheimer’s disease, biomarkers, COMT, DBH, dopamine, MAOB, noradrenaline, polymorphisms

DOI: 10.3233/JAD-190991

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 135-145, 2020

Authors: Davidowitz, Eliot J. | Krishnamurthy, Pavan K. | Lopez, Patricia | Jimenez, Heidy | Adrien, Leslie | Davies, Peter | Moe, James G.

Article Type: Research Article

Abstract: Tau oligomers have been shown to transmit tau pathology from diseased neurons to healthy neurons through seeding, tau misfolding, and aggregation that is thought to play an influential role in the progression of Alzheimer’s disease (AD) and related tauopathies. To develop a small molecule therapeutic for AD and related tauopathies, we have developed in vitro and cellular assays to select molecules inhibiting the first step in tau aggregation, the self-association of tau into oligomers. In vivo validation studies of an optimized lead compound were independently performed in the htau mouse model of tauopathy that expresses the human isoforms …of tau without inherited tauopathy mutations that are irrelevant to AD. Treated mice did not show any adverse events related to the compound. The lead compound significantly reduced the level of self-associated tau and total and phosphorylated insoluble tau aggregates. The dose response was linear with respect to levels of compound in the brain. A confirmatory study was performed with male htau mice that gave consistent results. The results validated our screening approach by showing that targeting tau self-association can inhibit the entire tau aggregation pathway by using the selected and optimized lead compound whose activity translated from in vitro and cellular assays to an in vivo model of tau aggregation. Show more

Keywords: Alzheimer’s disease, drug therapy, pathological, protein aggregation, tau protein

DOI: 10.3233/JAD-190465

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 147-161, 2020

Authors: Elias, Alby | Cummins, Tia | Lamb, Fiona | Tyrrell, Regan | Dore, Vincent | Williams, Rob | Rosenfeld, Jeffrey V. | Hopwood, Malcolm | Villemagne, Victor L. | Rowe, Christopher C.

Article Type: Research Article

Abstract: Background: Epidemiological studies suggest a relationship between posttraumatic stress disorder (PTSD) and dementia. Objective: This study assessed whether Alzheimer’s disease (AD) imaging biomarkers were elevated in Vietnam veterans with PTSD. Methods: The study compared cognition, amyloid-β, tau, regional brain metabolism and volumes, and the effect of APOE in 83 veterans with and without PTSD defined by the Clinician-Administered PTSD Scale. Results: The PTSD group had significantly lower education, predicted premorbid IQ, total intracranial volume, and Montreal Cognitive Assessment score compared with the controls. There was no difference between the two groups in the …imaging or genetic biomarkers for AD. Conclusion: Our findings do not support an association between AD pathology and PTSD of up to 50 years duration. Measures to assess cognitive reserve, a factor that may delay the onset of dementia, were lower in the PTSD group compared with the controls and this may account for the previously observed higher incidence of dementia with PTSD. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, dementia, positron emission tomography, posttraumatic stress disorder, tau

DOI: 10.3233/JAD-190913

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 163-173, 2020

Authors: Nerius, Michael | Haenisch, Britta | Gomm, Willy | Doblhammer, Gabriele | Schneider, Anja

Article Type: Research Article

Abstract: Background: Recent evidence indicates an important role for neuroinflammation in the pathological cascade of Alzheimer’s disease (AD), and neuroinflammation is increasingly being recognized as a potential therapeutic target. Objective: To assess the impact of glucocorticoids on the risk of developing dementia. Methods: We used health insurance data of the largest German health insurer from 2004–2013 with a baseline sample of 176,485 persons aged 50 years and older to study the association of glucocorticoid treatment and incidence of dementia. Cox proportional-hazard models were calculated adjusting for sex, age, and comorbidities known to be major risk factors for …dementia and were given as hazard ratios (HR) with 95% confidence intervals (CI). We further stratified glucocorticoid treatment by route of application and treatment duration. Results: Of the 176,485 dementia-free persons, 19,938 were diagnosed with dementia by the end of 2013. The risk of suffering from dementia was significantly lower for glucocorticoid users compared to non-users (HR = 0.81, CI = 0.78–0.84). The lowest risk was found among users of inhaled glucocorticoid (HR = 0.65, CI = 0.57–0.75), followed by nasal (HR = 0.76, CI = 0.66–0.87), other (HR = 0.84, CI = 0.80–0.88), and oral users (HR = 0.83, CI = 0.78–0.88). We found no difference in risk reduction between long- and short-term-users. Conclusion: Longitudinal German health insurance data indicate that the use of glucocorticoids is associated with a lower risk of dementia. Prospective clinical trials will be necessary to determine whether glucocorticoids can have a positive impact on neuroinflammation and thus protect persons against dementia. Show more

Keywords: Administrative claims, cohort studies, dementia, epidemiology, glucocorticoids, inflammation

DOI: 10.3233/JAD-190444

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 175-183, 2020

Authors: Briceño, Emily M. | Mehdipanah, Roshanak | Gonzales, Xavier | Heeringa, Steven | Levine, Deborah A. | Langa, Kenneth M. | Garcia, Nelda | Longoria, Ruth | Morgenstern, Lewis B.

Article Type: Research Article

Abstract: Background: As the Mexican American (MA) population grows and ages, there is an urgent need to estimate the prevalence of cognitive impairment or dementia (CID), cognitive trajectories, and identify community resource needs. The Brain Attack Surveillance in Corpus Christi (BASIC)-Cognitive project is a population-based study to address these issues among older MAs and non-Hispanic whites (NHW) and their informal care providers. Objective: Present the methodology and initial recruitment findings for the BASIC-Cognitive project. Method: Random, door-to-door case ascertainment is used in Nueces County, Texas, to recruit community-dwelling and nursing home residents ≥65 and informal care providers. …Households are identified from a two-stage area probability sample, using Census data to aim for equal balance of MAs and NHWs. Individuals with cognitive screens indicative of possible CID complete neuropsychological assessment (Harmonized Cognitive Assessment Protocol from the Health and Retirement Study). Informal care providers complete comprehensive interview and needs assessment. Study pairs repeat procedures at 2-year follow-up. Asset and concept mapping are performed to identify community resources and study care providers’ perceptions of needs for individuals with CID. Results: 1,030 age-eligible households were identified, or 27% of households for whom age could be determined. 1,320 individuals were age-eligible, corresponding to 1.3 adults per eligible household. Initial recruitment yielded robust participation in the MA eligible population (60% of 689 individuals that completed cognitive screening). Conclusion: The BASIC-Cognitive study will provide critical information regarding the prevalence of CID in MAs, the impact of caregiving, and allocation of community resources to meet the needs of this population. Show more

Keywords: Caregivers, dementia, epidemiology, health resources, mild cognitive impairment, Mexican American

DOI: 10.3233/JAD-190761

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 185-196, 2020

Authors: Imai, Masamichi | Tanaka, Mika | Sakata, Muneyuki | Wagatsuma, Kei | Tago, Tetsuro | Toyohara, Jun | Sengoku, Renpei | Nishina, Yuji | Kanemaru, Kazutomi | Ishibashi, Kenji | Murayama, Shigeo | Ishii, Kenji

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) are often misdiagnosed with each other because of similar symptoms including progressive memory loss. The metabolic network topology that describes inter-regional metabolic connections can be generated using fluorodeoxyglucose positron emission tomography (FDG-PET) data with the graph-theoretical method. We hypothesized that different metabolic connectivity underlies the symptoms of AD patients, DLB patients, and cognitively normal (CN) individuals. Objective: This study aimed to generate metabolic connectivity using FDG-PET data and assess the network topology to differentiate AD patients, DLB patients, and CN individuals. Methods: This study included 45 …AD patients, 18 DLB patients, and 142 CN controls. We analyzed FDG-PET data using the graph-theoretical method and generated the network topology in AD patients, DLB patients, and CN individuals. We statistically assessed the topology with global and nodal parameters. Results: The whole metabolic network was preserved in CN; however, diffusely decreased connection was found in AD and partially but more deeply decreased connection was observed in DLB. The metabolic topology revealed that the right posterior cingulate and the left transverse temporal gyrus were significantly different between AD and DLB. Conclusion: The present findings indicate that metabolic connectivity decreased in both AD and DLB, compared with CN. DLB was characterized restricted but deeper stereotyped network disruption compared with AD. The right posterior cingulate and the left transverse temporal gyrus are significant regions in the metabolic connectivity for differentiating AD from DLB. Show more

Keywords: Alzheimer’s disease, dementia with Lewy bodies, fluorodeoxyglucose, graph theory, network analysis, neuroimaging biomarkers, positron emission tomography

DOI: 10.3233/JAD-190843

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 197-207, 2020

Authors: Tsunoda, Keiichiro | Yamashita, Toru | Osakada, Yosuke | Sasaki, Ryo | Tadokoro, Koh | Matsumoto, Namiko | Nomura, Emi | Morihara, Ryuta | Nakano, Yumiko | Takahashi, Yoshiaki | Hatanaka, Noriko | Shang, Jingwei | Sato, Kota | Takemoto, Mami | Hishikawa, Nozomi | Ohta, Yasuyuki | Abe, Koji

Article Type: Research Article

Abstract: The world is rapidly aging and facing an increase in the number of dementia patients, so it is important to detect the preclinical stage of dementia in such countries. We examined both cognitive and affective functions among cognitively normal control (n  = 218), mild cognitive impairment (MCI, n  = 146), and Alzheimer’s disease (AD, n  = 305) subjects using two evaluation tools for behavioral and psychological symptoms of dementia (BPSD) [Abe’s BPSD score (ABS) and mild behavioral impairment (MBI)]. BPSD were present in 12.4% (ABS) and 9.6% (MBI) of cognitively normal people, 34.9% and 32.2% in MCI subjects, and 66.2% and 51.1% in …AD patients. Both ABS (§ p <0.05) and MBI (§§ p  < 0.01) score showed worse score with cognitive decline of the Mini-Mental State Examination in the AD group in BPSD-positive participants. Similar correlations were found in all participants in AD group (|||| p  < 0.01 versus ABS and MBI). Among the subscales in BPSD-positive participants, an apathy/indifference score of ABS and a decreased motivation of MBI showed significant differences in AD patients compared to the control and MCI subjects (**p <0.01). In addition, subscale analyses further showed a downward trend from the control to MCI and AD subjects in four ABS subscales and three MBI subscales. The present study showed the preclinical presence of BPSD in cognitively normal people, more so in MCI subjects, and ABS detected BPSD more sensitively than MBI in all three groups. Show more

Keywords: Affective symptoms, behavioral symptoms, cognitive dysfunction, dementia

DOI: 10.3233/JAD-190669

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 209-215, 2020

Authors: Abe, Koji | Shang, Jingwei | Shi, Xiaowen | Yamashita, Toru | Hishikawa, Nozomi | Takemoto, Mami | Morihara, Ryuta | Nakano, Yumiko | Ohta, Yasuyuki | Deguchi, Kentaro | Ikeda, Masaki | Ikeda, Yoshio | Okamoto, Koichi | Shoji, Mikio | Takatama, Masamitsu | Kojo, Motohisa | Kuroda, Takeshi | Ono, Kenjiro | Kimura, Noriyuki | Matsubara, Etsuro | Osakada, Yosuke | Wakutani, Yosuke | Takao, Yoshiki | Higashi, Yasuto | Asada, Kyoichi | Senga, Takehito | Lee, Lyang-Ja | Tanaka, Kenji

Article Type: Research Article

Abstract: Background: Because dementia is an emerging problem in the world, biochemical markers of cerebrospinal fluid (CSF) and radio-isotopic analyses are helpful for diagnosing Alzheimer’s disease (AD). Although blood sample is more feasible and plausible than CSF or radiological biomarkers for screening potential AD, measurements of serum amyloid- β (Aβ), plasma tau, and serum antibodies for Aβ1 - 42 are not yet well established. Objective: We aimed to identify a new serum biomarker to detect mild cognitive impairment (MCI) and AD in comparison to cognitively healthy control by a new peptidome technology. Methods: With only 1.5μ l of …serum, we examined a new target plate “BLOTCHIP® ” plus a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS) to discriminate control (n  = 100), MCI (n  = 60), and AD (n  = 99). In some subjects, cognitive Mini-Mental State Examination (MMSE) were compared to positron emission tomography (PET) with Pittsburgh compound B (PiB) and the serum probability of dementia (SPD). The mother proteins of candidate serum peptides were examined in autopsied AD brains. Results: Apart from Aβ or tau, the present study discovered a new diagnostic 4-peptides-set biomarker for discriminating control, MCI, and AD with 87% of sensitivity and 65% of specificity between control and AD (*** p  < 0.001). MMSE score was well correlated to brain Aβ deposition and to SPD of AD. The mother proteins of the four peptides were upregulated for coagulation, complement, and plasticity (three proteins), and was downregulated for anti-inflammation (one protein) in AD brains. Conclusion: The present serum biomarker set provides a new, rapid, non-invasive, highly quantitative and low-cost clinical application for dementia screening, and also suggests an alternative pathomechanism of AD for neuroinflammation and neurovascular unit damage. Show more

Keywords: Alzheimer’s disease, biomarker, coagulation, complement, MALDI-TOF, mild cognitive impairment, neuroinflammation, peptidome, plasticity

DOI: 10.3233/JAD-191016

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 217-227, 2020

Authors: Brewer, Gregory J. | Herrera, Robert A. | Philipp, Stephan | Sosna, Justyna | Reyes-Ruiz, Jorge Mauricio | Glabe, Charles G.

Article Type: Research Article

Abstract:  This work provides new insight into the age-related basis of Alzheimer’s disease (AD), the composition of intraneuronal amyloid (iAβ), and the mechanism of an age-related increase in iAβ in adult AD-model mouse neurons. A new end-specific antibody for Aβ45 and another for aggregated forms of Aβ provide new insight into the composition of iAβ and the mechanism of accumulation in old adult neurons from the 3xTg-AD model mouse. iAβ levels containing aggregates of Aβ45 increased 30-50-fold in neurons from young to old age and were further stimulated upon glutamate treatment. iAβ was 8 times more abundant in 3xTg-AD …than non-transgenic neurons with imaged particle sizes following the same log-log distribution, suggesting a similar snow-ball mechanism of intracellular biogenesis. Pathologically misfolded and mislocalized Alz50 tau colocalized with iAβ and rapidly increased following a brief metabolic stress with glutamate. AβPP-CTF, Aβ45 , and aggregated Aβ colocalized most strongly with mitochondria and endosomes and less with lysosomes and autophagosomes. Differences in iAβ by sex were minor. These results suggest that incomplete carboxyl-terminal trimming of long Aβs by gamma-secretase produced large intracellular deposits which limited completion of autophagy in aged neurons. Understanding the mechanism of age-related changes in iAβ processing may lead to application of countermeasures to prolong dementia-free health span. Show more

Keywords: Aging, Alzheimer’s disease, amyloid, autophagosomes, endosomes, lysosomes, mitochondria

DOI: 10.3233/JAD-190835

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 229-246, 2020

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

Authors: Francis, Nikita | Robison, Lisa S. | Popescu, Dominique L. | Michaelos, Michalis | Hatfield, Joshua | Xu, Feng | Zhu, Xiaoyue | Davis, Judianne | Anderson, Maria E. | Anderson, Brenda J. | Van Nostrand, William E. | Robinson, John K.

Article Type: Research Article

Abstract: Exercise has been shown to be protective against the risk of dementias, including Alzheimer’s disease (AD). Intervention studies have demonstrated its ability to mitigate cognitive and behavioral impairments and reduce disease in both humans and animals. However, information is lacking in regard to the volume and intensity, as well as timing of exercise onset with respect to disease stage, which produces optimal benefits. Here, utilizing the Tg2576 mouse, a model of AD-like parenchymal amyloid pathology and cognitive impairment, we sought to understand the effects of different lengths of daily access to a running wheel on advanced stage disease. This study …is the first to determine the benefits of long-term exercise (4 months of voluntary running) and different periods of daily access to a running wheel (0 h, 1 h, 3 h, and 12 h running wheel access) beginning in 14-month-old Tg2576 mice, an age with significant amyloid pathology. We found that exercising Tg2576 animals showed lower levels of some aspects of AD pathology and reduced behavioral dysfunction compared to sedentary Tg2576 animals. High intensity exercise, rather than high volume exercise, was generally most beneficial in reducing amyloid pathology. Our results suggest that engaging in vigorous exercise programs, even after living a sedentary life, may lead to a measurable reduction in AD pathology and preservation of some cognitive abilities. Show more

Keywords: Amyloid, behavior, dementia, exercise, transgenic

DOI: 10.3233/JAD-190810

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 359-374, 2020

Authors: Song, Shasha | Chen, Jingjiong | Xiao, Pinpin | Duan, Hao | Zhou, Yajun | Wang, Feng | Wang, Hongmei | Zhao, Yuwu | Geng, Zhi

Article Type: Research Article

Abstract: Continuous epileptic seizures hallmark status epilepticus, leading to preferential neuronal cell loss in the hippocampus that can progress into Alzheimer’s disease. Previous studies have shown that status epilepticus prompts an overproduction of nitric oxide (NO) by upregulation of NO synthase II (NOS II) to induce apoptosis of neuronal cells in the hippocampus, in a nuclear factor-kappaB (NF-κ B) signaling dependent manner. Here, in an experimental rat model for status epilepticus, elicitation of sustained seizure activity was achieved by microinjection of kainic acid (KA) into the hippocampal CA3 subfield. We found that KA induced features of status epilepticus, which could be …attenuated by blocking NF-κ B signaling through a specific inhibitor. Interestingly, infiltration of macrophages of primarily pro-inflammatory subtype was detected in the hippocampal CA3 region immediately after KA injection. Experimental elimination of macrophages by an anti-CD115 antibody significantly attenuated the features of status epilepticus, likely through suppressing activation of NF-κ B signaling. Together, these data suggest that macrophages play a critical role in NF-κ B signaling-mediated status epilepticus that predisposes to Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, kainic acid, macrophages, NF-κB, status epilepticus

DOI: 10.3233/JAD-190994

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 375-382, 2020

Authors: Wada-Isoe, Kenji | Kikuchi, Takashi | Umeda-Kameyama, Yumi | Mori, Takahiro | Akishita, Masahiro | Nakamura, Yu | on behalf of the ABC Dementia Scale Research Group

Article Type: Research Article

Abstract: The course of Alzheimer’s disease (AD) varies between individuals, and the relationship between cognitive and functional decline and the deterioration of behavioral and psychological symptoms of dementia (BPSD) is still poorly understood. Until recently, it was challenging to monitor subsequent changes in these symptoms because there was no single composite scale available that could simultaneously evaluate activities of daily living (ADL), BPSD, and cognitive function (CF) states. The present authors developed a new, brief assessment scale, the “ABC Dementia Scale” (ABC-DS), which is based on item response theory and facilitates concurrent measurement of ADL, BPSD, and CF states. We previously …presented the reliability, construct validity, concurrent validity, and responsiveness of the ABC-DS. We obtained the evidence through three clinical trials featuring 1,400 subjects in total. In the present study, we performed a secondary analysis of the data obtained in the previous study. We conducted hierarchical cluster analyses that allowed us to classify 197 AD patients in terms of similarities regarding ADL, BPSD, and CF domain scores, as measured by the ABC-DS. Consequently, the scale identified subgroups of patients with global clinical dementia ratings of 1, 2, and 3. Considering our results in conjunction with the clinical experiences of the AD expert among the present authors regarding longitudinal changes in ADL, BPSD, and CF, we were able to propose potential progression pathways of AD in the form of a hypothetical roadmap. Show more

Keywords: ABC dementia scale, activities of daily living, Alzheimer’s disease, cognitive function, cluster analysis, psychological symptoms of dementia

DOI: 10.3233/JAD-190767

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 383-392, 2020

Authors: Bastrup, Joakim | Kastaniegaard, Kenneth | Asuni, Ayodeji A. | Volbracht, Christiane | Stensballe, Allan

Article Type: Research Article

Abstract: Amyloid plaques are one of the hallmarks of Alzheimer’s disease (AD). The main constituent of amyloid plaques is amyloid-β peptides, but a complex interplay of other infiltrating proteins also co-localizes. We hypothesized that proteomic analysis could reveal differences between amyloid plaques and adjacent control tissue in the transgenic mouse model of AD (APPPS1-21) and in similar regions from non-transgenic littermates. Our microproteomic strategy included isolation of regions of interest by laser capture microdissection and analysis by liquid chromatography mass spectrometry-based label-free relative quantification. We consistently identified 183, 224, and 307 proteins from amyloid plaques, adjacent control and non-tg samples, respectively. …Pathway analysis revealed 27 proteins that were significantly regulated when comparing amyloid plaques and corresponding adjacent control regions. We further elucidated that co-localized proteins were subjected to post-translational modifications and are the first to report 193 and 117 unique modifications associated to amyloid plaques and adjacent control extracts, respectively. The three most common modifications detected in proteins from the amyloid plaques were oxidation, deamidation, and pyroglutamylation. Together, our data provide novel information about the biological processes occurring within and around amyloid plaques in the APPPS1-21 mouse model of AD. Show more

Keywords: Alzheimer’s disease, amyloid plaque, mass spectrometry, microdissection, pyroglutamate

DOI: 10.3233/JAD-190652

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 393-411, 2020

Authors: Kuroda, Eriko | Takata, Kazuyuki | Nishimura, Kaneyasu | Oka, Hikaru | Sueyoshi, Mari | Aitani, Mayu | Kouda, Atsushi | Satake, Shiho | Shima, Chiaki | Toda, Yuki | Nakata, Susumu | Kitamura, Yoshihisa | Ashihara, Eishi

Article Type: Research Article

Abstract: Amyloid-β (Aβ) accumulation in the brain triggers the onset of Alzheimer’s disease (AD), and its prevention and elimination are high priorities for anti-AD therapeutic strategies. Microglia, the resident immune cells in the brain, promote Aβ clearance by phagocytosis. Previously, we demonstrated that injection of primary cultured rat microglia and mouse bone marrow-derived microglia-like cells into the brain decreases the level of Aβ and that intrahippocampal injection of these cells ameliorates cognitive impairment in a mouse model of AD. To advance this cell therapeutic strategy to the clinical stage, less invasive ways of preparing autologous microglia-like cells from elderly patients are …required. In this study, we demonstrated that hematopoietic stem cells mobilized from the bone marrow to peripheral blood by administering granulocyte colony-stimulating factor and a CXCR4 antagonist to mice differentiated into microglia-like cells upon stimulation with colony-stimulating factor 1 and interleukin-34. The peripheral blood-derived microglia-like (PBDML) cells expressed microglial markers and engaged in Aβ phagocytosis. Although PBDML cells were in an anti-inflammatory state under nonstimulated conditions, they expressed mRNAs encoding proinflammatory cytokines following lipopolysaccharide treatment. PBDML cells injected into the hippocampi of a mouse AD model survived for at least 36 days while phagocytosing Aβ, contributed to a reduction in brain Aβ burden, and ameliorated cognitive impairment in the mice. These results strongly suggest that PBDML cells are a promising source for the development of a novel cell therapy against AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , cell therapy, cognitive impairment, intrahippocampal injection, microglia, Morris water maze, novel object recognition test, peripheral blood, stereology

DOI: 10.3233/JAD-190974

Citation: Journal of Alzheimer's Disease, vol. 73, no. 1, pp. 413-429, 2020