Journal of Alzheimer's Disease - Volume 68, issue 3

Authors: Kumar, Dhiraj | Kumar, Pravir

Article Type: Research Article

Abstract: Intracellular accumulation of aggregated amyloid-β, misfolded and non-functional proteinopathy, is the hallmark feature in Alzheimer’s disease (AD). There are several mechanisms to clear the amyloid burden in a cell, including transcytosis across the blood-brain barrier, immune mediated, lysosomal pathway associated autophagy, enzymatic degradation by insulin degrading enzyme/neprilysin, and the proteasomal pathway. Among them, the ubiquitin proteasome system (UPS) is playing a critical role to prevent the intracellular amyloid-β deposition and to clear off the cellular burden in association with ubiquitin E3 ligase enzymes in AD. For ubiquitination, lysine moiety in a protein acts like a docking site for the attachment …of ubiquitin molecule and different lysine residues act differently in this reaction. Therefore, it is pertinent to understand and link the role of various lysine residues along with their effector molecules, for instance, E3 ligases PARK2 and STUB1 in the ubiquitination cascade. Herein, we 1) modeled the structure of AβPP and determined its topologies and studied the impact of lysine residues in AβPP stability, 2) reported K351 as the most promising target for AβPP ubiquitination, 3) investigated the plausible role of lysine residues in non-covalent interactions mediated ubiquitin positioning in the ubiquitination, 4) detected conserved amino acids that is crucial for AβPP ubiquitination, and 5) identified the key ubiquitination enzymes and their interaction network playing major role in the ubiquitination of AβPP. Show more

Keywords: Amyloid-β, amyloid-β protein precursor, lysine, neurodegeneration, therapeutics, ubiquitination

DOI: 10.3233/JAD-181219

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1125-1150, 2019

Authors: Somers, Charisse | Lewczuk, Piotr | Sieben, Anne | Van Broeckhoven, Christine | De Deyn, Peter Paul | Kornhuber, Johannes | Martin, Jean-Jacques | Bjerke, Maria | Engelborghs, Sebastiaan

Article Type: Research Article

Abstract: Background: Despite decades of research on the optimization of the diagnosis of Alzheimer’s disease (AD), its biomarker-based diagnosis is being hampered by the lack of comparability of raw biomarker data. In order to overcome this limitation, the Erlangen Score (ES), among other approaches, was set up as a diagnostic-relevant interpretation algorithm. Objective: To validate the ES algorithm in a cohort of neuropathologically confirmed cases with AD (n  = 106) and non-AD dementia (n  = 57). Methods: Cerebrospinal fluid (CSF) biomarker concentrations of Aβ1-42 , T-tau, and P-tau181 were measured with commercially available single analyte ELISA kits. Based …on these biomarkers, ES was calculated as previously reported. Results: This algorithm proved to categorize AD in different degrees of likelihood, ranging from neurochemically “normal”, “improbably having AD”, “possibly having AD”, to “probably having AD”, with a diagnostic accuracy of 74% using the neuropathology as a reference. Conclusion: The ability of the ES to overcome the high variability of raw CSF biomarker data may provide a useful diagnostic tool for comparing neurochemical diagnoses between different labs or methods used. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, cerebrospinal fluid, dementia, harmonization, standardization, tau

DOI: 10.3233/JAD-180563

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1151-1159, 2019

Authors: Yang, Hyun-Sik | Chhatwal, Jasmeer P. | Xu, Jishu | White, Charles C. | Hanseeuw, Bernard | Rabin, Jennifer S. | Papp, Kathryn V. | Buckley, Rachel F. | Schultz, Aaron P. | Properzi, Michael J. | Gatchel, Jennifer R. | Amariglio, Rebecca E. | Donovan, Nancy J. | Mormino, Elizabeth C. | Hedden, Trey | Marshall, Gad A. | Rentz, Dorene M. | Johnson, Keith A. | De Jager, Philip L. | Sperling, Reisa A.

Article Type: Research Article

Abstract: Background: The UNC5C rs3846455G allele has been linked to poor cognitive resilience against age-related neuropathologies, but this association remains to be replicated, and the allele’s effect on hippocampal neurodegeneration needs to be examined. Objective: To further validate the association between rs3846455G and faster cognitive decline, especially among cognitively normal older adults, and to assess whether rs3846455G predicts accelerated hippocampal volume loss in older adults. Methods: We assessed participants in the Harvard Aging Brain Study (HABS), a longitudinal cohort study of older adults who were clinically normal at baseline. To avoid bias from …population admixture, analyses were limited to participants of European descent with longitudinal neuroimaging data (n  = 174). Linear mixed effect models were used to examine the effect of rs3846455G on longitudinal change of the Preclinical Alzheimer Cognitive Composite (PACC) and MRI-measured bilateral hippocampal volume, adjusting for baseline amyloid-β (Aβ) measured by the cortical Pittsburgh Compound B PET distributed volume ratio. We also tested whether hippocampal atrophy mediates the association between rs3846455G and greater PACC decline through a mediation analysis. Results: rs3846455G was associated with greater PACC decline (β= –0.087/year, 95% CI –0.169 to –0.005, p  = 0.039) after controlling for baseline Aβ. Further, rs3846455G predicted accelerated hippocampal atrophy after controlling for baseline Aβ (β= –57.3 mm3 /year, 95% CI –102.8 to –11.9, p  = 0.014). The association between rs3846455G and greater PACC decline was partially mediated by accelerated hippocampal atrophy (mediated effect (relative scale) = –0.014, 95% CI –0.032 to –6.0×10–4 , p  = 0.039). Conclusion: UNC5C rs3846455G predicts greater cognitive decline and accelerated hippocampal atrophy in clinically normal older adults. Show more

Keywords: Alzheimer’s disease, amyloid plaques, cognitive reserve, genetics, hippocampus, neuroimaging

DOI: 10.3233/JAD-180788

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1161-1170, 2019

Authors: Zhou, Sheng-Lan | Tan, Chen-Chen | Hou, Xiao-He | Cao, Xi-Peng | Tan, Lan | Yu, Jin-Tai

Article Type: Research Article

Abstract: TREM2 (triggering receptor expressed on myeloid cells 2) gene variants were reported to increase the risk of Alzheimer’s disease (AD) and even other neurodegenerative diseases (frontotemporal dementia (FTD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS)), but so far, no definite conclusion has been drawn. The aim of our systematic review and meta-analysis was to investigate the role of TREM2 variants in neurodegenerative diseases. A total of 39 papers (including 26 case-control studies and 13 case reports) were retrieved from PubMed, MEDLINE, EMBASE, and the Cochrane library in this study. A fixed effect model was used to pool …results in the analysis. Three variants in TREM2 (rs75932628 (R47H), rs2234255 (H157Y), and rs143332484 (R62H)) were significantly associated with AD risk, but the similar associations between rs104894002 (Q33X), rs2234253 (T96K), rs142232675 (D87N), rs2234256 (L211P), and AD were not proven. Rs75932628 also increased risk of PD in North Americans and FTD, but not PD in Europeans or ALS. In the systematic review, 12 biallelic TREM2 mutations (e.g., rs104894002, rs201258663 (T66M), and rs386834144, etc.) have been described to cause Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy (PLOSL) in 14 families. And homozygous mutations also have been reported to cause FTD without typical bone phenotypes in 7 families. This study demonstrates that multiple variants in TREM2 have association with the onset of AD, FTD, and PD in North Americans and also play a key role in the phenotypes of the rare familial genetic disorder. Show more

Keywords: Meta-analysis, neurodegenerative diseases, PLOSL, TREM2 , variant

DOI: 10.3233/JAD-181038

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1171-1184, 2019

Authors: Klimova, Blanka | Kuca, Kamil | Valis, Martin | Hort, Jakub

Article Type: Research Article

Abstract:  Currently, there is an increase in the number of older people worldwide. Unfortunately, this demographic trend causes a rise in aging diseases, one of which is dementia. Recent research studies have indicated that mild cognitive impairment (MCI) may serve as a predictor of dementia in many patients. At present, there is no pharmacological treatment against MCI. Therefore, there is constant search for novel alternative non-pharmacological approaches to improve MCI. One of the effective complementary emerging approaches seems to be Traditional Chinese Medicine (TCM), which is nowadays becoming quite popular in the treatment of different disorders. The purpose of this study …is to explore the efficacy of TCM as an effective complementary non-pharmacological tool for the improvement and treatment of MCI in older adults. The methods used for this review study included a literature search in the world’s databases: Web of Science, Scopus, PubMed, and Springer. Afterwards, methods of comparison and evaluation of the findings from the selected studies were applied. The results of this review study indicate that TCM might be a beneficial complementary non-pharmacological approach to the improvement and treatment of MCI in older individuals. Nevertheless, more rigorously designed quality randomized clinical trials should be conducted in order to conclusively prove efficacy of TCM on the improvement of MCI among older population groups. In addition, there is an urgent call for a functional collaboration between western and eastern medicinal approaches, which could contribute to the enhancement of the overall quality of life of these aging population groups. Show more

Keywords: Benefits, collaboration, intervention, limitations, mild cognitive impairment, older people, Traditional Chinese Medicine

DOI: 10.3233/JAD-181281

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1185-1192, 2019

Authors: Hascup, Kevin N. | Britz, Jesse | Findley, Caleigh A. | Tischkau, Shelley | Hascup, Erin R.

Article Type: Research Article

Abstract: Chronically elevated basal glutamate levels are hypothesized to attenuate detection of physiological signals thereby inhibiting memory formation and retrieval, while inducing excitotoxicity-mediated neurodegeneration observed in Alzheimer’s disease (AD). However, current medication targeting the glutamatergic system, such as memantine, shows limited efficacy and is unable to decelerate disease progression, possibly because it modulates postsynaptic N-methyl-D-aspartate receptors rather than glutamate release or clearance. To determine if decreasing presynaptic glutamate release leads to long-term procognitive effects, we treated AβPP/PS1 mice with LY379268 (3.0 mg/kg; i.p.), a metabotropic glutamate receptor (mGluR)2/3 agonist from 2–6 months of age when elevated glutamate levels are first observed …but cognition is unaffected. C57BL/6J genetic background control mice and another cohort of AβPP/PS1 mice received normal saline (i.p.) as vehicle controls. After 6 months off treatment, mice receiving LY379268 did not show long-term improvement as assessed by the Morris water maze (MWM) spatial learning and memory paradigm. Following MWM, mice were isoflurane anesthetized and a glutamate selective microelectrode was used to measure in vivo basal and stimulus-evoked glutamate release and clearance independently from the dentate, CA3, and CA1 hippocampal subregions. Immunohistochemistry was used to measure hippocampal astrogliosis and plaque pathology. Similar to previous studies, we observed elevated basal glutamate, stimulus evoked glutamate release, and astrogliosis in AβPP/PS1 vehicle mice versus C57BL/6J mice. Treatment with LY379268 did not attenuate these responses nor diminish plaque pathology. The current study builds upon previous research demonstrating hyperglutamatergic hippocampal signaling in AβPP/PS1 mice; however, long-term therapeutic efficacy of LY379268 in AβPP/PS1 was not observed. Show more

Keywords: Alzheimer’s disease, amyloid-β , cognition, early intervention, glial fibrillary acidic protein, metabotropic glutamate receptor

DOI: 10.3233/JAD-181231

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1193-1209, 2019

Authors: Lim, Yen Ying | Yassi, Nawaf | Bransby, Lisa | Properzi, Michael | Buckley, Rachel

Article Type: Research Article

Abstract: Background: Characterizing the earliest demonstrable cognitive decline in middle-aged adults at risk of Alzheimer’s disease (AD) will allow for the better understanding of the early disease trajectory, and the provision of therapies prior to clinical symptom onset. We developed an online platform— healthybrainproject.org.au (Healthy Brain Project; HBP)— to recruit, assess, and monitor at-risk middle-aged adults. Objective: Describe the HBP methodology and report baseline characteristics and adherence indices of participants. Methods: Between February 2017 and August 2018, 4,000 community-based middle-aged Australian adults with a first or second-degree family history of dementia enrolled at our website (healthybrainproject.org.au). Participants …were directed to complete five modules: “Basics”, “Health History”, “How You Feel”, “How You Live”, and “How You Think”. Of these, 1,816 participants have received a saliva sampling kit for genetic analysis. Results: Participants had a mean (SD) age of 55.5 (6.8) years, 11.8 (3.4) years of education, and annual personal income of AUD$68,830 ($35,044). Participants took 26.4 (49.7) days after enrolment to complete questionnaires and cognitive tests. Most participants were from Victoria (63%), followed by New South Wales (14%). Most participants (74%) were female and 76% identified as Caucasian. Approximately 36% of participants completed all modules (n  = 1,450), and 56% (n  = 2,221) completed 4 out of 5 modules. Most saliva kits (89%) had been returned. Conclusion: The HBP joins a handful of online registries worldwide that assess and monitor a large cohort of individuals at risk of AD. Our study extends on these efforts by focusing on midlife, where the earliest signs of cognitive and pathological changes will manifest. Show more

Keywords: Alzheimer’s disease, neuropsychological test, neuropsychology, neuroscience, online systems, psychological test

DOI: 10.3233/JAD-181139

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1211-1228, 2019

Authors: Zhutovsky, Paul | Vijverberg, Everard G.B. | Bruin, Willem B. | Thomas, Rajat M. | Wattjes, Mike P. | Pijnenburg, Yolande A.L. | van Wingen, Guido A. | Dols, Annemiek

Article Type: Research Article

Abstract: Background: Patients with behavioral variant of frontotemporal dementia (bvFTD) initially may only show behavioral and/or cognitive symptoms that overlap with other neurological and psychiatric disorders. The diagnostic accuracy is dependent on progressive symptoms worsening and frontotemporal abnormalities on neuroimaging findings. Predictive biomarkers could facilitate the early detection of bvFTD. Objective: To determine the prognostic accuracy of clinical and structural MRI data using a support vector machine (SVM) classification to predict the 2-year clinical follow-up diagnosis in a group of patients presenting late-onset behavioral changes. Methods: Data from 73 patients were included and divided into probable /definite …bvFTD (n  = 18), neurological (n  = 28), and psychiatric (n  = 27) groups based on 2-year follow-up diagnosis. Grey-matter volumes were extracted from baseline structural MRI scans. SVM classifiers were used to perform three binary classifications: bvFTD versus neurological and psychiatric, bvFTD versus neurological, and bvFTD versus psychiatric group(s), and one multi-class classification. Classification performance was determined for clinical and neuroimaging data separately and their combination using 5-fold cross-validation. Results: Accuracy of the binary classification tasks ranged from 72–82% (p  < 0.001) with adequate sensitivity (67–79%), specificity (77–88%), and area-under-the-receiver-operator-curve (0.80–0.9). Multi-class accuracy ranged between 55–59% (p  < 0.001). The combination of clinical and voxel-wise whole brain data showed the best performance overall. Conclusion: These results show the potential for automated early confirmation of diagnosis for bvFTD using machine learning analysis of clinical and neuroimaging data in a diverse and clinically relevant sample of patients. Show more

Keywords: behavioral variant frontotemporal dementia, classification, magnetic resonance imaging, prognosis, support vector machine

DOI: 10.3233/JAD-181004

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1229-1241, 2019

Authors: Boscher, Emmanuelle | Husson, Thomas | Quenez, Olivier | Laquerrière, Annie | Marguet, Florent | Cassinari, Kevin | Wallon, David | Martinaud, Olivier | Charbonnier, Camille | Nicolas, Gaël | Deleuze, Jean-François | Boland, Anne | Lathrop, Mark | Frébourg, Thierry | FREX Consortium | Campion, Dominique | Hébert, Sébastien S. | Rovelet-Lecrux, Anne

Article Type: Research Article

Abstract: Early-onset Alzheimer’s disease (EOAD) accounts for 5-10% of all AD cases, with a heritability ranging between 92% to 100%. With the exception of rare mutations in APP , PSEN1, and PSEN2 genes causing autosomal dominant EOAD, little is known about the genetic factors underlying most of the EOAD cases. In this study, we hypothesized that copy number variations (CNVs) in microRNA (miR) genes could contribute to risk for EOAD. miRs are short non-coding RNAs previously implicated in the regulation of AD-related genes and phenotypes. Using whole exome sequencing, we screened a series of 546 EOAD patients negative for …autosomal dominant EOAD mutations and 597 controls. We identified 86 CNVs in miR genes of which 31 were exclusive to EOAD cases, including a duplication of the MIR138-2 locus. In functional studies in human cultured cells, we could demonstrate that miR-138 overexpression leads to higher Aβ production as well as tau phosphorylation, both implicated in AD pathophysiology. These changes were mediated in part by GSK-3β and FERMT2, a potential risk factor for AD. Additional disease-related genes were also prone to miR-138 regulation including APP and BACE1 . This study suggests that increased gene dosage of MIR138-2 could contribute to risk for EOAD by regulating different biological pathways implicated in amyloid and tau metabolism. Additional studies are now required to better understand the role of miR-CNVs in EOAD. Show more

Keywords: Copy number variants, early-onset Alzheimer’s disease, microRNA, miR-138

DOI: 10.3233/JAD-180940

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1243-1255, 2019

Authors: Wang, Desheng

Article Type: Research Article

Abstract:  Previous studies have shown tumor necrosis factor-alpha (TNF-α ) may impact neurodegeneration in Alzheimer’s disease (AD) by regulating amyloid-β and tau pathogenesis. However, it is unclear whether TNF-α has a role in a cholesterol-fed rabbit model of AD or TNF-α affects the electrophysiological properties of rabbit hippocampus. This study was designed to investigate whether long-term feeding of cholesterol diet known to induce AD pathology regulates TNF-α expression in the hippocampus and whether TNF-α would modulate electrophysiological properties of rabbit hippocampal CA1 neurons. TNF-α ELISA showed dietary cholesterol increased hippocampal TNF-α expression in a dose-dependent …manner. Whole-cell recordings revealed TNF-α altered the membrane properties of rabbit hippocampal CA1 neurons, which was characterized by a decrease in after-hyperpolarization amplitudes; Field potential recordings showed TNF-α inhibited long-term potentiation but did not influence presynaptic function. Interestingly, TNF-α did not significantly affect the after-hyperpolarization amplitudes of hippocampal CA1 neurons from cholesterol fed rabbits compared to normal chow fed rabbits. In conclusion, dietary cholesterol generated an in vivo model of chronic TNF-α elevation and TNF-α may underlie the learning and memory changes previously seen in the rabbit model of AD by acting as a bridge between dietary cholesterol and brain function and directly modulating the electrophysiological properties of hippocampal CA1 neurons. Show more

Keywords: Cholesterol, hippocampus, membrane properties, synaptic plasticity, tumor necrosis factor-alpha

DOI: 10.3233/JAD-190043

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1257-1271, 2019

Authors: Boomsma, Jooske M.F. | Exalto, Lieza G. | Barkhof, Frederik | van den Berg, Esther | de Bresser, Jeroen | Heinen, Rutger | Leeuwis, Anna E. | Prins, Niels D. | Scheltens, Philip | Weinstein, Henry C. | van der Flier, Wiesje M. | Biessels, Geert Jan | behalf of the TRACE-VCI study group

Article Type: Research Article

Abstract: Background: Memory clinic patients frequently present with different forms of vascular brain injury due to different etiologies, often co-occurring with Alzheimer’s disease (AD) pathology. Objective: We studied how cognition was affected by different forms of vascular brain injury, possibly in interplay with AD pathology. Methods: We included 860 memory clinic patients with vascular brain injury on magnetic resonance imaging (MRI), receiving a standardized evaluation including cerebrospinal fluid (CSF) biomarker analyses (n  = 541). The cognitive profile of patients with different forms of vascular brain injury on MRI (moderate/severe white matter hyperintensities (WMH) (n  = 398), microbleeds (n  = 368), …lacunar (n  = 188) and non-lacunar (n  = 96) infarct(s), macrobleeds (n  = 16)) was assessed by: 1) comparison of all these different forms of vascular brain injury with a reference group (patients with only mild WMH (n  = 205) without other forms of vascular brain injury), using linear regression analyses also stratified for CSF biomarker AD profile and 2) multivariate linear regression analysis. Results: The cognitive profile was remarkably similar across groups. Compared to the reference group effect sizes on all domains were <0.2 with narrow 95% confidence intervals, except for non-lacunar infarcts on information processing speed (age, sex, and education adjusted mean difference from reference group (β: – 0.26, p  = 0.05). Results were similar in the presence (n  = 300) or absence (n  = 241) of biomarker co-occurring AD pathology. In multivariate linear regression analysis, higher WMH burden was related to a slightly worse performance on attention and executive functioning (β: – 0.08, p  = 0.02) and working memory (β: – 0.08, p  = 0.04). Conclusion: Although different forms of vascular brain injury have different etiologies and different patterns of cerebral damage, they show a largely similar cognitive profile in memory clinic patients regardless of co-occurring AD pathology. Show more

Keywords: Cerebral small vessel diseases, cerebrovascular disorders, cognitive disorders, neuropsychological test

DOI: 10.3233/JAD-180696

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1273-1286, 2019

Authors: Andrés-Benito, Pol | Gelpi, Ellen | Povedano, Mónica | Ausín, Karina | Fernández-Irigoyen, Joaquín | Santamaría, Enrique | Ferrer, Isidro

Article Type: Research Article

Abstract: Background: Frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions (FTLD-TDP) may appear as sporadic (sFTLD-TDP) or linked to mutations in various genes including expansions of the non-coding region of C9ORF72 (c9FTLD). Objective: Analysis of differential mRNA and protein expression in the frontal cortex in c9FLTD and evaluation with previous observations in frontal cortex in sFTLD-TDP and amyotrophic lateral sclerosis with TDP-43 inclusions. Methods: Microarray hybridization and mass spectrometry-based quantitative proteomics followed by RT-qPCR, gel electrophoresis, and western blotting in frontal cortex area 8 in 19 c9FTLD cases and 14 age- and gender-matched controls. Results: …Microarray hybridization distinguish altered gene transcription related to DNA recombination, RNA splicing regulation, RNA polymerase transcription, myelin synthesis, calcium regulation, and ubiquitin-proteasome system in c9FTLD; proteomics performed in the same tissue samples pinpoints abnormal protein expression involving apoptosis, inflammation, metabolism of amino acids, metabolism of carbohydrates, metabolism of membrane lipid derivatives, microtubule dynamics, morphology of mitochondria, neuritogenesis, neurotransmission, phagocytosis, receptor-mediated endocytosis, synthesis of reactive oxygen species, and calcium signaling in c9FTLD. Conclusion: Transcriptomics and proteomics, as well as bioinformatics processing of derived data, reveal similarly altered pathways in the frontal cortex in c9FTLD, but different RNAs and proteins are identified by these methods. Combined non-targeted ‘-omics’ is a valuable approach to deciphering altered molecular pathways in FTLD provided that observations are approached with caution when assessing human postmortem brain samples. Show more

Keywords: C9ORF72, frontotemporal lobar degeneration, FTLD-TDP, gene expression, proteomics

DOI: 10.3233/JAD-181123

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1287-1307, 2019

Article Type: Correction

DOI: 10.3233/JAD-199001

Citation: Journal of Alzheimer's Disease, vol. 68, no. 3, pp. 1309-1309, 2019