Journal of Alzheimer's Disease - Volume 76, issue 3

Authors: Thomas, Jason A. | Burkhardt, Hannah A. | Chaudhry, Safina | Ngo, Anthony D. | Sharma, Saransh | Zhang, Larry | Au, Rhoda | Hosseini Ghomi, Reza

Article Type: Research Article

Abstract: Background: There is a need for fast, accessible, low-cost, and accurate diagnostic methods for early detection of cognitive decline. Dementia diagnoses are usually made years after symptom onset, missing a window of opportunity for early intervention. Objective: To evaluate the use of recorded voice features as proxies for cognitive function by using neuropsychological test measures and existing dementia diagnoses. Methods: This study analyzed 170 audio recordings, transcripts, and paired neuropsychological test results from 135 participants selected from the Framingham Heart Study (FHS), which includes 97 recordings of cognitively normal participants and 73 recordings of cognitively impaired …participants. Acoustic and linguistic features of the voice samples were correlated with cognitive performance measures to verify their association. Results: Language and voice features, when combined with demographic variables, performed with an AUC of 0.942 (95% CI 0.929–0.983) in predicting cognitive status. Features with good predictive power included the acoustic features mean spectral slope in the 500–1500 Hz band, variation in the F2 bandwidth, and variation in the Mel-Frequency Cepstral Coefficient (MFCC) 1; the demographic features employment, education, and age; and the text features of number of words, number of compound words, number of unique nouns, and number of proper names. Conclusion: Several linguistic and acoustic biomarkers show correlations and predictive power with regard to neuropsychological testing results and cognitive impairment diagnoses, including dementia. This initial study paves the way for a follow-up comprehensive study incorporating the entire FHS cohort. Show more

Keywords: Alzheimer’s disease, artificial intelligence, biomarkers, cognitive dysfunction, data collection, dementia, early diagnosis, language, neuropsychological tests, voice

DOI: 10.3233/JAD-190783

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 905-922, 2020

Authors: Angehrn, Zuzanna | Sostar, Jelena | Nordon, Clementine | Turner, Andrew | Gove, Dianne | Karcher, Helene | Keenan, Alexander | Mittelstadt, Brent | de Reydet-de Vulpillieres, Frederic

Article Type: Research Article

Abstract: Background: The therapeutic paradigm in Alzheimer’s disease (AD) is shifting from symptoms management toward prevention goals. Secondary prevention requires the identification of individuals without clinical symptoms, yet “at-risk” of developing AD dementia in the future, and thus, the use of predictive modeling. Objective: The objective of this study was to review the ethical concerns and social implications generated by this new approach. Methods: We conducted a systematic literature review in Medline, Embase, PsycInfo, and Scopus, and complemented it with a gray literature search between March and July 2018. Then we analyzed data qualitatively using a thematic …analysis technique. Results: We identified thirty-one ethical issues and social concerns corresponding to eight ethical principles: (i) respect for autonomy, (ii) beneficence, (iii) non-maleficence, (iv) equality, justice, and diversity, (v) identity and stigma, (vi) privacy, (vii) accountability, transparency, and professionalism, and (viii) uncertainty avoidance. Much of the literature sees the discovery of disease-modifying treatment as a necessary and sufficient condition to justify AD risk assessment, overlooking future challenges in providing equitable access to it, establishing long-term treatment outcomes and social consequences of this approach, e.g., medicalization. The ethical/social issues associated specifically with predictive models, such as the adequate predictive power and reliability, infrastructural requirements, data privacy, potential for personalized medicine in AD, and limiting access to future AD treatment based on risk stratification, were covered scarcely. Conclusion: The ethical discussion needs to advance to reflect recent scientific developments and guide clinical practice now and in the future, so that necessary safeguards are implemented for large-scale AD secondary prevention. Show more

Keywords: Biomedical ethics, dementia, early diagnosis, early intervention, prodromal symptoms, qualitative research, secondary prevention

DOI: 10.3233/JAD-191159

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 923-940, 2020

Authors: Thordardottir, Steinunn | Almkvist, Ove | Johansson, Charlotte | Zetterberg, Henrik | Blennow, Kaj | Graff, Caroline

Article Type: Research Article

Abstract: Background: YKL-40 and neurogranin are promising additional cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease (AD) which reflect different underlying disease mechanisms. Objective: To compare the levels of CSF YKL-40 and neurogranin between asymptomatic carriers of familial AD (FAD) mutations (MC) and non-carriers (NC) from the same families. Another objective was to assess changes in YKL-40 and neurogranin, from the presymptomatic to clinical phase of FAD. Methods: YKL-40 and neurogranin, as well as Aβ 42 , total tau-protein, and phospho-tau, were measured in the CSF of 14 individuals carrying one of three FAD mutations, APPswe (p.KM670/671NL), …APParc (p.E693G), and PSEN1 (p.H163Y), as well as in 17 NC from the same families. Five of the MC developed mild cognitive impairment (MCI) during follow-up. Results: In this pilot study, there was no difference in either CSF YKL-40 or neurogranin when comparing the presymptomatic MC to the NC. YKL-40 correlated positively with expected years to symptom onset and to age in both the MC and the NC, while neurogranin had no correlation to either variable in either of the groups. A subgroup of the participants underwent more than one CSF sampling in which half of the MC developed MCI during follow-up. The longitudinal data showed an increase in YKL-40 levels in the MC as the expected symptom onset approached. Neurogranin remained stable over time in both the MC and the NC. Conclusion: These findings support a positive correlation between progression from presymptomatic to symptomatic AD and levels of CSF YKL-40, but not neurogranin. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, chitinases, genetics, mutation, neurogranin

DOI: 10.3233/JAD-191261

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 941-953, 2020

Authors: Luukkainen, Laura | Huttula, Samuli | Väyrynen, Henri | Helisalmi, Seppo | Kytövuori, Laura | Haapasalo, Annakaisa | Hiltunen, Mikko | Remes, Anne M. | Krüger, Johanna

Article Type: Research Article

Abstract: Background: Alzheimer’s disease, frontotemporal lobar degeneration, dementia with Lewy bodies, and Parkinson’s disease (PD) overlap in clinical characteristics, neuropathology, and genetics. Objective: The aim of this study was to evaluate the role of pathogenic mutations and rare variants in genes associated with PD among early-onset dementia (EOD) patients. Methods: Rare non-synonymous variants (MAF < 0.01) in ten genes (SNCA, PARK2, PARK7, LRRK2, PINK1 , ATP13A2, UCHL1, HTRA2, GBA , and SNCAIP) and low-frequency (MAF < 0.05) GBA variants were screened using a targeted next-generation sequencing panel in a strictly defined cohort of 37 early-onset (age at onset (AAO) …<65 years) dementia patients presenting with atypical features (e.g., myoclonia or spasticity), rapidly progressive course of the disease or with a family history of dementia. The identified variations were further screened in a larger cohort of EOD (n  = 279, mean AAO 57, range 36–65) patients. Results: No pathogenic mutations were found, but we identified seven possible risk variants for neurodegeneration (LRRK2 p.Arg793Met, PARK2 p.Ala82Glu, SNCAIP p.Arg240Gln, SNCAIP p.Phe369Leu, GBA p.Asn409Ser, GBA p.Glu365Lys, GBA p.Thr408Met). Discussion: Altogether, the frequency of these variants was two times higher in the first selected cohort compared to the whole cohort. This suggests that specific rare variants in the genes associated with PD might play a role also especially in familial EOD. Show more

Keywords: Alzheimer’s disease, dementia, dementia with Lewy bodies, frontotemporal dementia, frontotemporal lobar degeneration, gene, mutation, neurodegenerative disease, Parkinson’s disease, single nucleotide polymorphism

DOI: 10.3233/JAD-200069

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 955-965, 2020

Authors: Guthrie, Heather | Honig, Lawrence S. | Lin, Helen | Sink, Kaycee M. | Blondeau, Kathleen | Quartino, Angelica | Dolton, Michael | Carrasco-Triguero, Montserrat | Lian, Qinshu | Bittner, Tobias | Clayton, David | Smith, Jillian | Ostrowitzki, Susanne

Article Type: Research Article

Abstract: Background: Crenezumab is a fully humanized, monoclonal anti-amyloid-β immunoglobulin G4 antibody. Objective: This Phase Ib study (NCT02353598) evaluated the safety, tolerability, and pharmacokinetics of crenezumabat doses of ≤120 mg/kg administered intravenously every 4 weeks (q4w). Immunogenicity and exploratory biomarkers were also evaluated. Methods: In this multicenter, double-blind study, participants (aged 50–90 years) with mild-to-moderate Alzheimer’s disease (AD) and amyloid-positive positron emission tomography (PET) scan were randomized to receive crenezumab 30 or 45 mg/kg (Cohort 1, n  = 21), 60 mg/kg (Cohort 2, n  = 21), or 120 mg/kg (Cohort 3, n  = 19) or corresponding placebo (n  = 14) intravenously q4w for 13 weeks. …Seventy-one participants were subsequently enrolled in an optional open-label extension (OLE) and received crenezumab at the originally assigned dose level, except for Cohort 3 (crenezumab 60 mg/kg during OLE). Participants received regular brain MRIs to assess amyloid-related imaging abnormalities (ARIA). Results up to Week 133 are reported. Results: Approximately 94% of participants experienced ≥1 adverse event (AE). Most AEs were mild or moderate; 15.5% experienced a Grade ≥3 AE. No ARIA-edema/effusion (ARIA-E) events were observed. New ARIA-micro hemorrhages and hemosiderosis (ARIA-H) were reported in 4.9% (double-blind treatment period) and 9.9% (combined double-blind treatment and OLE periods) of participants. Steady-state trough concentrations of crenezumab were dose-proportional and maintained for each dose level. Conclusion: Crenezumab doses of ≤120 mg/kg intravenously q4w were well tolerated. The observed safety profile for ≤133 weeks of treatment in a mild-to-moderate AD population was similar to that seen in previous trials. Show more

Keywords: Alzheimer’s disease, amyloid positron emission tomography, amyloid-β peptide, crenezumab, humanized monoclonal antibody, infusion site adverse event, magnetic resonance imaging, safety

DOI: 10.3233/JAD-200134

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 967-979, 2020

Authors: Wan, Xinkun | Ma, Bin | Wang, Xiaoxuan | Guo, Chenjia | Sun, Jing | Cui, Jing | Li, Liang

Article Type: Research Article

Abstract: Background: Glutathione (GSH) is an important endogenous antioxidant protecting cells from oxidative injury. Cysteine (Cys), the substrate limiting the production of GSH, is mainly generated from the trans-sulfuration pathway. S-adenosylmethionine (SAM) is a critical molecule produced in the methionine cycle and can be utilized by the trans-sulfuration pathway. Reductions in GSH and SAM as well as dysfunction in the trans-sulfuration pathway have been documented in the brains of Alzheimer’s disease (AD) patients. Our previous in vivo study revealed that SAM administration attenuated oxidative stress induced by amyloid-β (Aβ) through the enhancement of GSH. Objective: To investigate the …effect of Aβ-induced oxidative stress on the trans-sulfuration pathway in astrocytes and neurons, respectively, and the protective effect of SAM on neurons. Methods: APP/PS1 transgenic mice and the primary cultured astrocytes, neurons, and HT22 cells were used in the current study. Results: SAM could rescue the low trans-sulfuration pathway activity induced by Aβ only in astrocytes, accompanying with increasing levels of Cys and GSH. The decrease of cellular viability of neurons caused by Aβ was greatly reversed when co-cultured with astrocytes with SAM intervention. Meanwhile, SAM improved cognitive performance in APP/PS1 mice. Conclusion: In terms of astrocyte protection from oxidative stress, SAM might be a potent antioxidant in the therapy of AD patients. Show more

Keywords: Amyloid-β , astrocytes, glutathione, S-adenosylmethionine, trans-sulfuration pathway

DOI: 10.3233/JAD-200103

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 981-995, 2020

Authors: Narukawa, Masataka | Takahashi, Suzuka | Saito, Takashi | Saido, Takaomi C. | Misaka, Takumi

Article Type: Research Article

Abstract: Background: Some studies have reported a decline in taste sensitivities in patients with Alzheimer’s disease. However, the detail remains unknown. Objective: We investigated the effect of cognitive impairment on taste sensitivity using an App knock-in mouse model of Alzheimer’s disease. Methods: Behavioral assays, a brief access test, and a 48 h two-bottle preference test, to assess taste sensitivities were started from 12 months of age in mice that were confirmed to have impaired cognition. Results: In the assays, there was no significant difference in taste sensitivities between wild type and App knock-in mice. …Additionally, no apparent difference was observed in the expression of taste markers in their taste bud cells. Conclusion: We concluded that cognitive impairment might not greatly affect taste sensitivity. Show more

Keywords: Aging, App knock-in mice, donepezil, taste sensitivity

DOI: 10.3233/JAD-200284

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 997-1004, 2020

Authors: Fuentes, Manuel | Klostermann, Arne | Kleineidam, Luca | Bauer, Chris | Schuchhardt, Johannes | Maier, Wolfgang | Jessen, Frank | Frölich, Lutz | Wiltfang, Jens | Kornhuber, Johannes | Klöppel, Stefan | Schieting, Vera | Teipel, Stefan J. | Wagner, Michael | Peters, Oliver

Article Type: Research Article

Abstract: Background: Cognitive functions and activities of daily living (ADL) become increasingly impaired with progressing Alzheimer’s disease. However, the temporal dynamics of this decline are inconsistent. Objective: To gain insight into the classical temporal cascade of specific cognitive and ADL changes, which may aid in improving detection of an impending clinical deterioration in patients, and to select ADL items and tests most sensitive to change in a specific disease stage. Methods: Patients with mild Alzheimer’s dementia (AD; MMSE = 23.9±2.88) were followed at 12 and 24 months. Lead-lag analysis of changes in cognitive and functional outcome measures (CDR-SOB, 12 …neuropsychological subtest scores from the CERAD + test battery, 25 Bayer-ADL items) was applied to rank the temporal sequence of changes on an ordinal scale. Results: Of 164 patients with mild AD, moderate disease progression was identified in 84 patients over 24 months (Δ MMSE 5.8±8.64; Δ CDR-SOB 4.32±4.03). Ten Bayer-ADL item measures were altered early in moderate progressors and included in a new ADL composite score. Accordingly, the new ADL score surpassed all neuropsychological measures in repeated lead-lag analysis. The Bayer-ADL total score, TMT-A, and MMSE were lagging variables in all lead-lag analyses. Conclusion: Short-term clinical deterioration in mild AD is initially preceded by changes (i.e., decline) in a well-defined set of ADL and not in classical cognitive measures. Show more

Keywords: Alzheimer’s disease, bayer activities of daily living scale, cognitive changes, disease progression, functional changes, lead and lag analysis

DOI: 10.3233/JAD-200230

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 1005-1015, 2020

Authors: Naude, James P. | Gill, Sascha | Hu, Sophie | McGirr, Alexander | Forkert, Nils D. | Monchi, Oury | Stys, Peter K. | Smith, Eric E. | Ismail, Zahinoor | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Assessing neuropsychiatric symptoms (NPS) in older adults is important for determining dementia risk. Mild behavioral impairment (MBI) is an at-risk state for cognitive decline and dementia, characterized by emergent NPS in later life. MBI has significantly higher dementia incidence than late life psychiatric conditions. However, its utility as a proxy for neurodegeneration has not been demonstrated. Plasma neurofilament light (NfL) is a validated biomarker of axonal damage, and has been shown to associate with hallmarks of neurodegeneration. Objective: The purpose of this investigation was to identify associations between NfL rate of change and the presence of MBI …symptomatology. Methods: We evaluated the association of MBI with changes in NfL in a cohort (n  = 584; MBI + n = 190, MBI– n  = 394) of non-demented participants from the Alzheimer’s Disease Neuroimaging Initiative. MBI was determined by transforming Neuropsychiatric Inventory Questionnaire items using a published algorithm. Change in NfL was calculated over 2 years. Results: Time*MBI status was the only significant interaction to predict change in NfL concentrations (F (1,574) = 4.59, p  = 0.032), even after controlling for age, mild cognitive impairment, and demographics. Analyses reclassifying 64 participants with new onset MBI over 2 years similarly demonstrated greater increases in NfL (F (1,574) = 5.82, p  = 0.016). Conclusion: These findings suggest MBI is a clinical proxy of early phase neurodegeneration with putative utility in identifying those at dementia risk. MBI can be used as a case ascertainment approach to capture those at high risk for cognitive decline and dementia, and is an important construct for clinicians dealing with cognitive and neuropsychiatric symptomatology in older adults. Show more

Keywords: Alzheimer’s disease, mild behavioral impairment, mild cognitive impairment, neurodegeneration, neurofilament light, neuropsychiatric symptoms

DOI: 10.3233/JAD-200011

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 1017-1027, 2020

Authors: Hayashi, Kentaro | Gonzales, Tina K. | Kapoor, Amita | Ziegler, Toni E. | Meethal, Sivan Vadakkadath | Atwood, Craig S.

Article Type: Research Article

Abstract: Background: While sex hormones are essential for normal cognitive health, those individuals with greater endocrine dyscrasia around menopause and with andropause are more likely to develop cognitive loss and Alzheimer’s disease (AD). Objective: To assess whether circulating sex hormones may provide an etiologically significant, surrogate biomarker, for cognitive decline. Methods: Plasma (n  = 152) and serum (n  = 107) samples from age- and gender-matched AD and control subjects from the Wisconsin Alzheimer’s Disease Research Center (ADRC) were analyzed for 11 steroids and follicle-stimulating hormone. Logistic regression (LR), correlation analyses, and recursive partitioning (RP) were used to examine the …interactions of hormones and hormone ratios and their association with AD. Models generated were then tested on an additional 43 ADRC samples. Results: The wide variation and substantial overlap in the concentrations of all circulating sex steroids across control and AD groups precluded their use for predicting AD. Classification tree analyses (RP) revealed interactions among single hormones and hormone ratios that associated with AD status, the most predictive including only the hormone ratios identified by LR. The strongest associations were observed between cortisol, cortisone, and androstenedione with AD, with contributions from progesterone and 17β-estradiol. Utilizing this model, we correctly predicted 81% of AD test cases and 64% of control test cases. Conclusion: We have developed a diagnostic model for AD, the Wisconsin Hormone Algorithm Test for Cognition (WHAT-Cog), that utilizes classification tree analyses of hormone ratios. Further refinement of this technology could provide a quick and cheap diagnostic method for screening those with AD. Show more

Keywords: Alzheimer’s disease, blood, classification tree, diagnostic, follicle-stimulating hormone, hormone ratio, model, prediction, recursive partitioning, steroids

DOI: 10.3233/JAD-200418

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 1029-1046, 2020

Authors: Griswold, Anthony J. | Sivasankaran, Sathesh K. | Van Booven, Derek | Gardner, Olivia K. | Rajabli, Farid | Whitehead, Patrice L. | Hamilton-Nelson, Kara L. | Adams, Larry D. | Scott, Aja M. | Hofmann, Natalia K. | Vance, Jeffery M. | Cuccaro, Michael L. | Bush, William S. | Martin, Eden R. | Byrd, Goldie S. | Haines, Jonathan L. | Pericak-Vance, Margaret A. | Beecham, Gary W.

Article Type: Research Article

Abstract: Background: Significant work has identified genetic variants conferring risk and protection for Alzheimer’s disease (AD), but functional effects of these variants is lacking, particularly in under-represented ancestral populations. Expression studies performed in easily accessible tissue, such as whole blood, can recapitulate some transcriptional changes occurring in brain and help to identify mechanisms underlying neurodegenerative processes. Objective: We aimed to identify transcriptional differences between AD cases and controls in a cohort of diverse ancestry. Methods: We analyzed the protein coding transcriptome using RNA sequencing from peripheral blood collected from 234 African American (AA) (115 AD, 119 controls) …and 240 non-Hispanic Whites (NHW) (121 AD, 119 controls). To identify case-control differentially expressed genes and pathways, we performed stratified, joint, and interaction analyses using linear regression models within and across ancestral groups followed by pathway and gene set enrichment analyses. Results: Overall, we identified 418 (291 upregulated, 127 downregulated) and 488 genes (352 upregulated, 136 downregulated) differentially expressed in the AA and NHW datasets, respectively, with only 16 genes commonly differentially expressed in both ancestral groups. Joint analyses provided greater power to detect case-control differences and identified 1,102 differentially expressed genes between cases and controls (812 upregulated, 290 downregulated). Interaction analysis identified only 27 genes with different effects in AA compared to NHW. Pathway and gene-set enrichment analyses revealed differences in immune response-related pathways that were enriched across the analyses despite different underlying gene sets. Conclusion: These results support the hypothesis of converging underlying pathophysiological processes in AD across ancestral groups. Show more

Keywords: Gene expression profiling, population characteristics, RNA, transcriptome

DOI: 10.3233/JAD-190855

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 1047-1060, 2020

Authors: Muurling, Marijn | Rhodius-Meester, Hanneke F.M. | Pärkkä, Juha | van Gils, Mark | Frederiksen, Kristian S. | Bruun, Marie | Hasselbalch, Steen G. | Soininen, Hilkka | Herukka, Sanna-Kaisa | Hallikainen, Merja | Teunissen, Charlotte E. | Visser, Pieter Jelle | Scheltens, Philip | van der Flier, Wiesje M. | Mattila, Jussi | Lötjönen, Jyrki | de Boer, Casper

Article Type: Research Article

Abstract: Background: Gait analysis with accelerometers is a relatively inexpensive and easy to use method to potentially support clinical diagnoses of Alzheimer’s disease and other dementias. It is not clear, however, which gait features are most informative and how these measures relate to Alzheimer’s disease pathology. Objective: In this study, we tested if calculated features of gait 1) differ between cognitively normal subjects (CN), mild cognitive impairment (MCI) patients, and dementia patients, 2) are correlated with cerebrospinal fluid (CSF) biomarkers related to Alzheimer’s disease, and 3) predict cognitive decline. Methods: Gait was measured using tri-axial accelerometers attached …to the fifth lumbar vertebra (L5) in 58 CN, 58 MCI, and 26 dementia participants, while performing a walk and dual task. Ten gait features were calculated from the vertical L5 accelerations, following principal component analysis clustered in four domains, namely pace, rhythm, time variability, and length variability. Cognitive decline over time was measured using MMSE, and CSF biomarkers were available in a sub-group. Results: Linear mixed models showed that dementia patients had lower pace scores than MCI patients and CN subjects (p  < 0.05). In addition, we found associations between the rhythm domain and CSF-tau, especially in the dual task. Gait was not associated with CSF Aβ42 levels and cognitive decline over time as measured with the MMSE. Conclusion: These findings suggest that gait — particularly measures related to pace and rhythm — are altered in dementia and have a direct link with measures of neurodegeneration. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, dementia, gait analysis, tau proteins

DOI: 10.3233/JAD-200225

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 1061-1070, 2020

Authors: Liang, Yingxia | Raven, Frank | Ward, Joseph F. | Zhen, Sherri | Zhang, Siyi | Sun, Haoqi | Miller, Sean J. | Choi, Se Hoon | Tanzi, Rudolph E. | Zhang, Can

Article Type: Research Article

Abstract: Background: The amyloid cascade hypothesis of Alzheimer’s disease (AD) posits that amyloid-β (Aβ) protein accumulation underlies the pathogenesis of the disease by leading to the formation of amyloid plaques, a pathologic hallmark of AD. Aβ is a proteolytic product of amyloid-β protein precursor (AβPP; APP), which is expressed in both neurons and astrocytes. Although considerable evidence shows that astrocytes may play critical roles in the pathogenesis of AD, the longitudinal changes of amyloid plaques in relationship to AβPP expression in astrocytes and cellular consequences are largely unknown. Objective: Here, we aimed to investigate astrocyte-related pathological changes of Aβ …and AβPP using immunohistochemistry and biochemical studies in both animal and cell models. Methods/Results: We utilized 5XFAD transgenic mice and found age-dependent upregulation of AβPP in astrocytes demonstrated with astrocytic reactive properties, which followed appearance of amyloid plaques in the brain. We also observed that AβPP proteins presented well-defined punctate immuno reactivity in young animals, whereas AβPP staining showed disrupted structures surrounding amyloid plaques in older mice. Moreover, we utilized astrocyte cell models and showed that pretreatment of Aβ42 resulted in downstream astrocyte autonomous changes, including up regulation in AβPP and BACE1 levels, as well as prolonged amyloidogenesis that could be reduced by pharmacological inhibition of BACE1. Conclusion: Collectively, our results show that age-dependent AβPP up regulation in astrocytes is a key feature in AD, which will not only provide novel insights for understanding AD progression, but also may offer new therapeutic strategies for treating AD. Show more

Keywords: Alzheimer’s disease, amyloid pathology, amyloid-β , amyloid-β protein precursor, amyloidogenesis, astrocyte, autonomous

DOI: 10.3233/JAD-200128

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 1071-1082, 2020

Authors: Kaur, Harpreet | Golovko, Svetlana | Golovko, Mikhail Y. | Singh, Surjeet | Darland, Diane C. | Combs, Colin K.

Article Type: Research Article

Abstract: Background: The intestinal microbiota and its metabolites, particularly short-chain fatty acids (SCFAs), have been implicated in immune function, host metabolism, and even behavior. Objective: This study was performed to investigate whether probiotic administration influences levels of intestinal microbiota and their metabolites in a fashion that may attenuate brain changes in a mouse model of Alzheimer’s disease (AD). Methods: C57BL/6 wild-type (WT) mice were compared to AppNL -G -F mice. The animals were treated with either vehicle or probiotic (VSL#3) for 8 weeks. Fecal microbiome analysis along with Aβ, GFAP, Iba-1, c-Fos, and Ki-67 immunohistochemistry …was done. SCFAs were analyzed in serum and brains using UPLC-MS/MS. Results: Probiotic (VSL#3) supplementation for 2 months resulted in altered microbiota in both WT and AppNL -G -F mice. An increase in serum SCFAs acetate, butyrate, and lactate were found in both genotypes following VSL#3 treatment. Propionate and isobutyrate were only increased in AppNL -G -F mice. Surprisingly, VSL#3 only increased lactate and acetate in brains of AppNL -G -F mice. No significant differences were observed between vehicle and VSL#3 fed AppNL -G -F hippocampal immunoreactivities of Aβ, GFAP, Iba-1, and Ki-67. However, hippocampal c-Fos staining increased in VSL#3 fed AppNL -G -F mice. Conclusion: These data demonstrate intestinal dysbiosis in the AppNL -G -F mouse model of AD. Probiotic VSL#3 feeding altered both serum and brain levels of lactate and acetate in AppNL -G -F mice correlating with increased expression of the neuronal activity marker, c-Fos. Show more

Keywords: Alzheimer’s disease, butyrate, gliosis, microbiota, plaques, probiotics, short chain fatty acids

DOI: 10.3233/JAD-200436

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 1083-1102, 2020

Authors: Duan, Wenna | Sehrawat, Parshant | Balachandrasekaran, Arvind | Bhumkar, Ashish B. | Boraste, Paresh B. | Becker, James T. | Kuller, Lewis H. | Lopez, Oscar L. | Gach, H. Michael | Dai, Weiying

Article Type: Research Article

Abstract: Background: Reliable cerebral blood flow (CBF) biomarkers using a noninvasive imaging technique are sought to facilitate early diagnosis and intervention in early Alzheimer’s disease (AD). Objective: We aim to identify brain regions in which CBF values are affected and related to cognitive decline in early AD using a large cohort. Methods: Perfusion MRIs using continuous arterial spin labeling were acquired at 1.5 T in 58 normal controls (NC), 50 mild cognitive impairments (MCI), and 40 AD subjects from the Cardiovascular Health Study Cognition Study. Regional absolute CBF and normalized CBF (nCBF) values, without and with correction …of partial volume effects, were compared across three groups. Association between regional CBF values and Modified Mini-Mental State Examination (3MSE) were investigated by multiple linear regression analyses adjusted for cardiovascular risk factors. Results: After correcting for partial volume effects and cardiovascular risk factors, ADs exhibited decreased nCBF with the strongest reduction in the bilateral posterior cingulate & precuneus region (p  < 0.001) compared to NCs, and the strongest reduction in the bilateral superior medial frontal region (p  < 0.001) compared to MCIs. MCIs exhibited the strongest nCBF decrease in the left hippocampus and nCBF increase in the right inferior frontal and insular region. The 3MSE scores within the symptomatic subjects were significantly associated with nCBF in the bilateral posterior and middle cingulate and parietal (p  < 0.001), bilateral superior medial frontal (p  < 0.001), bilateral temporoparietal (p  < 0.02), and right hippocampus (p  = 0.02) regions. Conclusion: Noninvasive perfusion MRI can detect functional changes across diagnostic class and serve as a staging biomarker of cognitive status. Show more

Keywords: Alzheimer’s disease, arterial spin labeling, cerebral blood flow, cognition

DOI: 10.3233/JAD-200034

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 1103-1120, 2020

Authors: Chatzistavraki, Maria | Papazafiri, Panagiota | Efthimiopoulos, Spiros

Article Type: Research Article

Abstract: Background: Coordinated calcium influx upon neuronal depolarization activates pathways that phosphorylate CaMKII, ERKs, and the transcription factor CREB and, therefore, expression of pro-survival and neuroprotective genes. Recent evidence indicates that amyloid-β protein precursor (AβPP) is trafficked to synapses and promotes their formation. At the synapse, AβPP interacts with synaptic proteins involved in vesicle exocytosis and affects calcium channel function. Objective: Herein, we examined the role of AβPP in depolarization-induced calcium-mediated signaling using acute cerebral slices from wild-type C57bl/6 mice and AβPP–/– C57bl/6 mice. Methods: Depolarization of acute cerebral slices from wild-type C57bl/6 and AβPP–/– C57bl/6 mice …was used to induce synaptic signaling. Protein levels were examined by western blot and calcium dynamics were assessed using primary neuronal cultures. Results: In the absence of AβPP, decreased pCaMKII and pERKs levels were observed. This decrease was sensitive to the inhibition of N- and P/Q-type Voltage Gated Calcium Channels (N- and P/Q-VGCCs) by ω -conotoxin GVIA and ω -conotoxin MVIIC, respectively, but not to inhibition of L-type VGCCs by nifedipine. However, the absence of AβPP did not result in a statistically significant decrease of pCREB, which is a known substrate of pERKs. Finally, using calcium imaging, we found that down regulation of AβPP in cortical neurons results in a decreased response to depolarization and altered kinetics of calcium response. Conclusion: AβPP regulates synaptic activity-mediated neuronal signaling by affecting N- and P/Q-VGCCs. Show more

Keywords: Alzheimer’s disease, amyloid-β protein precursor, AβPP, calcium, neuronal signaling, synapse

DOI: 10.3233/JAD-200290

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 1121-1133, 2020

Authors: Habiba, Umma | Merlin, Sam | Lim, Jeremiah K.H. | Wong, Vickie H.Y. | Nguyen, Christine T.O. | Morley, John W. | Bui, Bang V. | Tayebi, Mourad

Article Type: Research Article

Abstract: Background: Amyloid-β soluble oligomers (Aβo) are believed to be the cause of the pathophysiology underlying Alzheimer’s disease (AD) and are normally detected some two decades before clinical onset of the disease. Retinal pathology associated with AD pathogenesis has previously been reported, including ganglion cell loss, accumulation of Aβ deposits in the retina, and reduction of nerve fiber layer thickness as well as abnormalities of the microvasculature. Objective: This study’s aim is to better understand the relationship between brain and retinal Aβo deposition and in particular to quantify levels of the toxic Aβo as a function of age in …the retina of a rodent model of AD. Methods: Retinas and brain tissue from 5×FAD mice were stained with Congo red, Thioflavin-T (Th-T), and Aβ plaque-specific and Aβo-specific antibodies. Results: We show that retinas displayed an age-dependent increase of Th-T-specific amyloid fibrils. Staining with anti-Aβ antibody confirmed the presence of the Aβ plaques in all 5×FAD retinas tested. In contrast, staining with anti-Aβo antibody showed an age-dependent decrease of retinal Aβo. Of note, Aβo was observed mainly in the retinal nuclear layers. Finally, we confirmed the localization of Aβo to neurons, typically accumulating in late endosomes, indicating possible impairment of the endocytic pathway. Conclusion: Our results demonstrate the presence of intraneuronal Aβo in the retina and its accumulation inversely correlated with retinal Aβ plaque deposition, indicating an age-related conversion in this animal model. These results support the development of an early AD diagnostic test targeting Aβo in the eye. Show more

Keywords: Anti-oligomer antibody, Alzheimer’s disease, amyloid-β oligomers, retina, retinal immunodetection, 5×FAD mice

DOI: 10.3233/JAD-191346

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 1135-1150, 2020

Authors: Sy, Marie Charmaine C. | Espiritu, Adrian I. | Sy, Matthew Samuel C. | Jamora, Roland Dominic G. | Anlacan, Veeda Michelle M.

Article Type: Research Article

Abstract: Background: Scientific output in Southeast Asia (SEA) on the topic of dementia is postulated to be low in quality and quantity. It is also speculated that certain socioeconomic variables and measures of disease burden for dementia may play a significant role in driving the research output of a particular country. Objective: This study aimed to determine the research impact of published journal articles on dementia in SEA and its association with country-level socioeconomic factors and measures of disease burden for dementia. Methods: A systematic search was conducted using electronic healthcare databases. We included articles published on …dementia until August 2019 with at least 1 author affiliated with any SEA institution. We obtained bibliometric indices, relevant socioeconomic factors, and measures of disease burden for dementia from published sources. Results: One thousand six articles fulfilled the inclusion criteria. The majority of publications were related to Alzheimer’s disease (n  = 775, 77.0%). Singapore contributed the highest number of publications (n  = 457, 45.4%). Gross domestic product (GDP) per capita, % GDP for research and development, and total neurologists significantly correlated with several bibliometric indices. On the other hand, the measures of disease burden for dementia in SEA countries were not significantly associated with research productivity. Conclusion: Research productivity in SEA on dementia has substantially increased in recent years. Augmenting GDP per capita and expanding the apportionment of resources to research and development (R&D) may have a significant role in the advancement of dementia research in SEA. Show more

Keywords: Bibliometric analysis, burden of disease, dementia, scientometrics, socioeconomic factors, Southeast Asia

DOI: 10.3233/JAD-200355

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 1151-1160, 2020

Authors: Vergouw, Leonie J. M. | Geut, Hanneke | Breedveld, Guido | Kuipers, Demy J. S. | Quadri, Marialuisa | Netherlands Brain Bank | Rozemuller, Annemieke J. M. | van Swieten, John C. | de Jong, Frank Jan | van de Berg, Wilma D. J. | Bonifati, Vincenzo

Article Type: Research Article

Abstract: Background: Rare variants in the low-density lipoprotein receptor related protein 10 gene (LRP10 ) have recently been implicated in the etiology of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Objective: We searched for LRP10 variants in a new series of brain donors with dementia and Lewy pathology (LP) at autopsy, or dementia and parkinsonism without LP but with various other neurodegenerative pathologies. Methods: Sanger sequencing of LRP10 was performed in 233 donors collected by the Netherlands Brain Bank. Results: Rare, possibly pathogenic heterozygous LRP10 variants were present in …three patients: p.Gly453Ser in a patient with mixed Alzheimer’s disease (AD)/Lewy body disease (LBD), p.Arg151Cys in a DLB patient, and p.Gly326Asp in an AD patient without LP. All three patients had a positive family history for dementia or PD. Conclusion: Rare LRP10 variants are present in some patients with dementia and different brain pathologies including DLB, mixed AD/LBD, and AD. These findings suggest a role for LRP10 across a broad neurodegenerative spectrum. Show more

Keywords: Genetic predisposition to disease, genotype, LRP10, neuropathology, phenotype

DOI: 10.3233/JAD-200318

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 1161-1170, 2020

Authors: Sancesario, Giulia Maria | Di Lazzaro, Giulia | Alwardat, Mohammad | Biticchi, Benedetta | Basile, Valerio | Salimei, Chiara | Colona, Vito Luigi | Sinibaldi Salimei, Paola | Bernardini, Sergio | Mercuri, Nicola Biagio | Pisani, Antonio | Schirinzi, Tommaso

Article Type: Research Article

Abstract: Background: Synaptopathy is critical in pathophysiology of Parkinson’s disease (PD). Cerebrospinal fluid (CSF) levels of neurogranin (NG) and amyloid-β42 (Aβ42 ) are considered markers of synaptic dysfunction in neurodegenerative diseases. Objective: To evaluate the CSF synaptopathy-related biomarkers, especially the novel Aβ42 /NG ratio, in PD, establishing possible associations with cognitive level and other clinical parameters. Methods: Levels of NG, Aβ42 , amyloid-β40 , total and phosphorylated tau, and Aβ42 /NG ratio were measured in 30 PD patients and 30 controls and correlated with cognitive and motor parameters. The accuracy in distinguishing the cognitive status was …determined. Results: NG and Aβ42 were significantly reduced in PD, with higher NG levels in patients with worse cognition. The Aβ42 /NG ratio showed a direct correlation with Mini-Mental State Examination, independently from age and sex, and differentiated cognitively impaired patients with 92% sensitivity and 71.4% specificity, accuracy higher than NG alone. No correlations resulted with motor disturbances or therapy. Conclusions: The novel Aβ42 /NG ratio couples either presynaptic or postsynaptic markers of synaptic dysfunction, representing a potential global index of synaptopathy, useful to track cognitive functions in PD. Show more

Keywords: Cerebrospinal fluid biomarkers, cognitive, neurogranin, Parkinson’s disease

DOI: 10.3233/JAD-200344

Citation: Journal of Alzheimer's Disease, vol. 76, no. 3, pp. 1171-1178, 2020