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