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