Journal of Alzheimer's Disease - Volume 84, issue 4

Authors: Ryu, Hui Jin | Moon, Yeonsil | Kim, Minyoung | Kim, Hee-Jin | Galvin, James E. | Han, Seol-Heui

Article Type: Research Article

Abstract: Background: The Quick Dementia Rating System (QDRS) is a brief and rapid dementia staging tool that does not require a trained rater. Objective: The purpose of this study is to demonstrate the validity, reliability, and diagnostic usefulness of the Korean version of the QDRS (K-QDRS). Methods: We collected a total of 411 subject-informant dyads including cognitively unimpaired (CU, n  = 22), mild cognitive impairment (MCI, n  = 198), and dementia (n  = 191). The Clinical Dementia Rating (CDR) scale, Korean version of the Mini-Mental State Examination (K-MMSE), Korean version of instrumental activity of daily living (K-IADL), Short Form of …the Geriatric Depression Scale, Caregiver-Administered Neuropsychiatric Inventory (CGA-NPI), and detailed neuropsychological tests were administered as gold standards of dementia staging, cognition, function, mood, and behavior. Results: Internal consistency of the K-QDRS was excellent with Cronbach’s alpha of 0.933. Concurrent validity was also satisfactory, with the K-QDRS correlating highly with the CDR Sum of Boxes (Pearson’s r  = 0.791), K-MMSE (Pearson’s r  = –0.518), K-IADL (Pearson’s r  = 0.727), and CGA-NPI (Pearson’s r  = 0.700). The K-QDRS was highly correlated with the global CDR, K-IADL, and CGA-NPI. We suggested two types of comparisons (for initial diagnosis and for follow-up evaluation). The cutoff scores for follow-up were 1.0 for MCI, 3.5 for very mild dementia, 6.5 for mild dementia, and 11.0 for moderate dementia. Conclusion: The K-QDRS is a valid and reliable dementia rating questionnaire and can be used, briefly and rapidly, in various settings like clinical practices, longitudinal cohort studies, and community primary care. Show more

Keywords: Activities of daily living, clinical dementia rating, cognition, dementia, neurocognitive disorders, screening

DOI: 10.3233/JAD-210584

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1645-1656, 2021

Authors: Gan, Jinghuan | Liu, Shuai | Wang, Xiao-Dan | Hu, Wenzheng | Lv, Yang | Niu, Jianping | Meng, Xinling | Chen, Yongjie | Shi, Zhihong | Ji, Yong

Article Type: Research Article

Abstract: Background: Dementia and hyperhidrosis (HH) are common in the elderly while there is little research to investigate the association between them. Objective: To clarify a possible association between HH and dementia in population of adults ≥65 years old in China. Methods: A cross-sectional survey for elderly adults ≥65 years old was conducted from April to December 2019. A total of 5,958 participants were analyzed after two phases investigation. Goodness-of-fit tests (Pearson and deviance) were used to estimate the dispersion parameter and examine the adequacy of the models. Logistic and linear regression analyses were used to evaluate …the association between HH and dementia. Results: The overall prevalence of all-cause dementia was 10.17%, that of dementia with Lewy bodies (DLB) was 1.41%, and HH was 14.97%. Prevalence rates of HH were higher in participants with dementia and DLB. There was a significant positive relationship between HH duration and MMSE score (r  = 0.207, p  < 0.001, Durbin-Watson test = 1.806). Participants with HH were 1.275 (95% CI: 1.015–1.601, p  = 0.037) times to have dementia, and 3.616 (95% CI: 2.267–5.767, p  < 0.001) times to suffer from DLB than those without HH. Pearson and deviance chi square tests did not indicate overdispersion (p  > 0.05 in the logistic regression models). Conclusion: HH was common in the Chinese population ≥65 years old. It can increase the risk of dementia, particularly in DLB, in the elderly. It is important to improve the awareness of HH among dermatologists and neurologists. Show more

Keywords: Autonomic nervous system dysfunction, cognitive impairment, dementia, dementia with Lewy bodies, hyperhidrosis

DOI: 10.3233/JAD-210611

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1657-1667, 2021

Authors: Rusanen, Minna | Selander, Tuomas | Kärkkäinen, Virve | Koivisto, Anne

Article Type: Research Article

Abstract: Background: Human-animal interactions are known to have many beneficial psychosocial and psychophysiological effects on persons with and without medical health conditions. There are no previous prospective studies with long follow-up times on the effects of domestic pets on the persons with Alzheimer’s disease (AD) living at home. Objective: To investigate the effects of pets on the activities of daily living (ADL), disease progression, and neuropsychiatric symptoms (NPS) during a five-year follow-up on the persons with AD. Methods: Altogether 223 home-dwelling persons (mean age 75.2 years) with very mild (CDR 0.5) or mild (CDR 1) AD at …baseline were included for this study. ADCS-ADL, NPI, MMSE, and CDR-SOB were measured at baseline, annually for three years and after five years. Results: Totally 40 (17.9%) participants had a pet. At the baseline, pet owners and non-pet owners had no significant differences in age, gender, or the ADCS-ADL, NPS, and CDR-SOB scores, while MMSE was lower in pet owners than non-pet owners (20.2 versus 21.7; p  = 0.009). Over the follow-up, pet owners had significantly better mean ADCS-ADL (57.5 versus 54.0; p  = 0.031), NPI (9.3 versus 13.0; p  = 0.038), and CDR-SOB scores (5.7 versus 6.6; p  = 0.004) compared to non-pet owners. The differences in the MMSE scores between the groups detected at baseline attenuated over time. Conclusion: Significant positive effects of the pets on ADL functions, NPS, and disease progression were detected over the whole follow-up suggesting that having a pet may support daily activity and slow the disease progression in AD. Show more

Keywords: Activities of daily living, Alzheimer’s disease, cognitive activity, dementia, neuropsychiatric symptoms, rating scales

DOI: 10.3233/JAD-210557

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1669-1675, 2021

Authors: Upīte, Jolanta | Brüning, Thomas | Möhle, Luisa | Brackhan, Mirjam | Bascuñana, Pablo | Jansone, Baiba | Pahnke, Jens

Article Type: Research Article

Abstract: Background: A wide range of techniques has been developed over the past decades to characterize amyloid-β (Aβ) pathology in mice. Until now, no method has been established to quantify spatial changes in Aβ plaque deposition due to targeted delivery of substances using ALZET® pumps. Objective: Development of a methodology to quantify the local distribution of Aβ plaques after intracerebral infusion of compounds. Methods: We have developed a toolbox to quantify Aβ plaques in relation to intracerebral injection channels using Zeiss AxioVision® and Microsoft Excel® software. For the proof of concept, intracerebral stereotactic surgery …was performed in 50-day-old APP-transgenic mice injected with PBS. At the age of 100 days, brains were collected for immunhistological analysis. Results: The toolbox can be used to analyze and evaluate Aβ plaques (number, size, and coverage) in specific brain areas based on their location relative to the point of the injection or the injection channel. The tool provides classification of Aβ plaques in pre-defined distance groups using two different approaches. Conclusion: This new analytic toolbox facilitates the analysis of long-term continuous intracerebral experimental compound infusions using ALZET® pumps. This method generates reliable data for Aβ deposition characterization in relation to the distribution of experimental compounds. Show more

Keywords: Alzheimer’s disease, amyloid-β, distributional activity, implantable infusion pump, histology, plaques, quantification, transgenic mice

DOI: 10.3233/JAD-215180

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1677-1690, 2021

Authors: Petkus, Andrew J. | Younan, Diana | Wang, Xinhui | Beavers, Daniel P. | Espeland, Mark A. | Gatz, Margaret | Gruenewald, Tara | Kaufman, Joel D. | Chui, Helena C. | Millstein, Joshua | Rapp, Stephen R. | Manson, JoAnn E. | Resnick, Susan M. | Wellenius, Gregory A. | Whitsel, Eric A. | Widaman, Keith | Chen, Jiu-Chiuan

Article Type: Research Article

Abstract: Background: Elucidating associations between exposures to ambient air pollutants and profiles of cognitive performance may provide insight into neurotoxic effects on the aging brain. Objective: We examined associations between empirically derived profiles of cognitive performance and residential concentrations of particulate matter of aerodynamic diameter < 2.5 (PM2.5 ) and nitrogen dioxide (NO2 ) in older women. Method: Women (N  = 2,142) from the Women’s Health Initiative Study of Cognitive Aging completed a neuropsychological assessment measuring attention, visuospatial, language, and episodic memory abilities. Average yearly concentrations of PM2.5 and NO2 were estimated at the participant’s addresses for …the 3 years prior to the assessment. Latent profile structural equation models identified subgroups of women exhibiting similar profiles across tests. Multinomial regressions examined associations between exposures and latent profile classification, controlling for covariates. Result: Five latent profiles were identified: low performance across multiple domains (poor multi-domain; n  = 282;13%), relatively poor verbal episodic memory (poor memory; n  = 216; 10%), average performance across all domains (average multi-domain; n  = 974; 45%), superior memory (n  = 381; 18%), and superior attention (n  = 332; 15%). Using women with average cognitive ability as the referent, higher PM2.5 (per interquartile range [IQR] = 3.64μ g/m3 ) was associated with greater odds of being classified in the poor memory (OR = 1.29; 95% Confidence Interval [CI] = 1.10–1.52) or superior attention (OR = 1.30; 95% CI = 1.10–1.53) profiles. NO2 (per IQR = 9.86 ppb) was associated with higher odds of being classified in the poor memory (OR = 1.38; 95% CI = 1.17–1.63) and lower odds of being classified with superior memory (OR = 0.81; 95% CI = 0.67–0.97). Conclusion: Exposure to PM2.5 and NO2 are associated with patterns of cognitive performance characterized by worse verbal episodic memory relative to performance in other domains. Show more

Keywords: Cognitive aging, latent class analysis, nitrogen dioxide, particulate matter, women

DOI: 10.3233/JAD-210518

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1691-1707, 2021

Authors: Jeong, Hee-Jeong | Lee, Young-Min | Park, Je-Min | Lee, Byung-Dae | Moon, Eunsoo | Suh, Hwagyu | Kim, Hak-Jin | Pak, Kyoungjune | Choi, Kyung-Un | Chung, Young-In

Article Type: Research Article

Abstract: Background: A long-term follow-up study in patients with amnestic mild cognitive impairment (aMCI) is needed to elucidate the association between regional brain volume and psychopathological mechanisms of Alzheimer’s disease with psychosis (AD + P). Objective: The purpose of this study was to investigate the effect of the thickness of the angular cingulate cortex (ACC) on the risk of AD + P conversion in patients with aMCI. Methods: This was a hospital-based prospective longitudinal study including 174 patients with aMCI. The main outcome measure was time-to-progression from aMCI to AD + P. Subregions of the ACC (rostral ACC, rACC; caudal ACC, cACC) and …hippocampus (HC) were measured as regions of interest with magnetic resonance imaging and the Freesurfer analysis at baseline. Survival analysis with time to incident AD + P as an event variable was calculated with Cox proportional hazards models using the subregions of the ACC and HC as a continuous variable. Results: Cox proportional hazard analyses showed that the risk of AD + P was associated with sub-regional ACC thickness but not HC volume: reduced cortical thickness of the left cACC (HR [95%CI], 0.224 [0.087–0.575], p  = 0.002), right cACC (HR [95%CI], 0.318 [0.132–0.768], p  = 0.011). This association of the cACC with the risk of AD also remained significant when adjusted for HC volume. Conclusion: We found that reduced cortical thickness of the cACC is a predictor of aMCI conversion to AD + P, independent of HC, suggesting that the ACC plays a vital role in the underlying pathogenesis of AD + P. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, anterior cingulate cortex, incident psychosis

DOI: 10.3233/JAD-215005

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1709-1717, 2021

Authors: Sakurai, Keita | Iwase, Tamaki | Kaneda, Daita | Uchida, Yuto | Inui, Shohei | Morimoto, Satoru | Kimura, Yasuyuki | Kato, Takashi | Nihashi, Takashi | Ito, Kengo | Hashizume, Yoshio

Article Type: Research Article

Abstract: Background: Although hippocampal atrophy is a well-known imaging biomarker of Alzheimer’s disease (AD), this finding is not useful to differentiate AD from argyrophilic grain disease (AGD) which is a common AD mimicker presenting with similar amnestic symptoms and medial temporal atrophy. Instead, we propose use of the “sloping shoulders sign”, defined as a distinct configuration of the bilateral hippocampal heads showing lateral and downward slopes on axial magnetic resonance imaging (MRI). Objective: We investigated the diagnostic utility of the “sloping shoulders sign” as a simple radiological discriminator of AD from AGD. Methods: Using axial and coronal …three-dimensional MRI, our newly proposed “sloping shoulders sign”, other quantitative indices including the axial hippocampal head angle (AHHA), and well-known medial temporal atrophy (MTA) score were evaluated in pathologically-proven 24 AD and 11 AGD patients. Results: Detection rate of the “sloping shoulders sign” was significantly higher in all AD groups (83%; 20/24) and AD with Braak neurofibrillary tangle V/VI stage subgroup (88%; 15/17) than in AGD patients (18% – 2/11; p  < 0.001 and p  < 0.001, respectively). In contrast to the MTA score, this sign as well as AHHA demonstrated higher diagnostic performance and reproducibility, especially to differentiate all AD patients from AGD ones (accuracies of 71.4% , 82.9% and 82.9%; Cohen’s kappa of 0.70 and 0.81, and intraclass correlation coefficient of 0.96, respectively). Conclusion: The “sloping shoulders sign” is useful to differentiate advanced-stage AD from AGD. Its simplicity and reproducibility based on visual inspection using axial MRI make it suitable for routine clinical practice. Show more

Keywords: Alzheimer’s disease, argyrophilic grain disease, hippocampus, magnetic resonance imaging, sloping shoulders sign

DOI: 10.3233/JAD-210638

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1719-1727, 2021

Authors: Galvin, James E. | Kleiman, Michael J. | Chrisphonte, Stephanie | Cohen, Iris | Disla, Shanell | Galvin, Conor B. | Greenfield, Keri K. | Moore, Claudia | Rawn, Susan | Riccio, Mary Lou | Rosenfeld, Amie | Simon, Judith | Walker, Marcia | Tolea, Magdalena I.

Article Type: Research Article

Abstract: Background: There is increasing interest in lifestyle modification and integrative medicine approaches to treat and/or prevent mild cognitive impairment (MCI) and Alzheimer’s disease and related dementias (ADRD). Objective: To address the need for a quantifiable measure of brain health, we created the Resilience Index (RI). Methods: This cross-sectional study analyzed 241 participants undergoing a comprehensive evaluation including the Clinical Dementia Rating and neuropsychological testing. Six lifestyle factors including physical activity, cognitive activity, social engagements, dietary patterns, mindfulness, and cognitive reserve were combined to derive the RI (possible range of scores: 1–378). Psychometric properties were determined. …Results: The participants (39 controls, 75 MCI, 127 ADRD) had a mean age of 74.6±9.5 years and a mean education of 15.8±2.6 years. The mean RI score was 138.2±35.6. The RI provided estimates of resilience across participant characteristics, cognitive staging, and ADRD etiologies. The RI showed moderate-to-strong correlations with clinical and cognitive measures and very good discrimination (AUC: 0.836; 95% CI: 0.774–0.897) between individuals with and without cognitive impairment (diagnostic odds ratio = 8.9). Individuals with high RI scores (> 143) had better cognitive, functional, and behavioral ratings than individuals with low RI scores. Within group analyses supported that controls, MCI, and mild ADRD cases with high RI had better cognitive, functional, and global outcomes than those with low RI. Conclusion: The RI is a brief, easy to administer, score and interpret assessment of brain health that incorporates six modifiable protective factors. Results from the RI could provide clinicians and researchers with a guide to develop personalized prevention plans to support brain health. Show more

Keywords: Alzheimer’s disease, brain health, cognitive activity, cognitive reserve, dementia, diet, lifestyle, mild cognitive impairment, mindfulness, physical activity, resilience, risk factors

DOI: 10.3233/JAD-215077

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1729-1746, 2021

Authors: Roy, Avik | Kundu, Madhuchhanda | Chakrabarti, Sudipta | Patel, Dhruv R. | Pahan, Kalipada

Article Type: Research Article

Abstract: Background: Doublecortin (DCX), a microtubule associated protein, has emerged as a central biomarker of hippocampal neurogenesis. However, molecular mechanisms by which DCX is regulated are poorly understood. Objective: Since sleep is involved with the acquisition of memory and oleamide or 9-Octadecenamide (OCT) is a sleep-inducing supplement in human, we examined whether OCT could upregulate DCX in hippocampal progenitor cells (HPCs). Methods: We employed real-time PCR, western blot, immunostaining, chromatin immunoprecipitation, lentiviral transduction in HPCs, and the calcium influx assay. Results: OCT directly upregulated the transcription of Dcx in HPCs via activation of peroxisome …proliferator-activated receptor α (PPARα ), a lipid-lowering transcription factor. We observed that, HPCs of Ppara -null mice displayed significant impairment in DCX expression and neuronal differentiation as compared to that of wild-type mice. Interestingly, treatment with OCT stimulated the differentiation process of HPCs in wild-type, but not Ppara -null mice. Reconstruction of PPARα in mouse Ppara -null HPCs restored the expression of DCX, which was further stimulated with OCT treatment. In contrast, a dominant-negative mutant of PPARα significantly attenuated the stimulatory effect of OCT on DCX expression and suppressed neuronal differentiation of human neural progenitor cells. Furthermore, RNA microarray, STRING, chromatin immunoprecipitation, site-directed mutagenesis, and promoter reporter assay have identified DCX as a new target of PPARα . Conclusion: These results indicate that OCT, a sleep supplement, directly controls the expression of DCX and suggest that OCT may be repurposed for stimulating the hippocampal neurogenesis. Show more

Keywords: Doublecortin, hippocampal progenitor cells, oleamide, PPARα

DOI: 10.3233/JAD-215124

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1747-1762, 2021

Authors: Sundermann, Erin E. | Barnes, Lisa L. | Bondi, Mark W. | Bennett, David A. | Salmon, David P. | Maki, Pauline M.

Article Type: Research Article

Abstract: Background Despite a female advantage in verbal memory, normative data for verbal memory tests used to diagnose Alzheimer’s disease (AD) dementia and amnestic mild cognitive impairment (aMCI) often are not sex-adjusted. Objective To determine whether sex-adjusted norms improve aMCI diagnostic accuracy when accuracy was evaluated by progression to AD dementia over time. Methods Non-sex-specific and sex-specific verbal memory test norms were incorporated into Jak/Bondi aMCI criteria and applied to older (age 65–90) non-demented women (N  = 1,036) and men (N  = 355) from the Rush Memory and Aging Project. Using sex-specific aMCI diagnosis as the “true” condition versus …non-sex-specific aMCI diagnosis as the “predicted” condition, we identified True Positives, False Positives, True Negatives, and False Negatives and compared AD dementia risk over 10 years among groups. Results Rates of aMCI were higher in men versus women (χ2  = 15.39, p  < 0.001) when determined based on typical diagnostic criteria, but this difference reversed when using sex-specific diagnostic criteria (χ2  = 8.38, p  = 0.004). We identified 8%of women as False Negatives and 12%of men as False Positives. Risk of incident AD dementia in False Positive men was significantly lower than in True Positive men (HR = 0.26, 95%CI = 0.12–0.58, p  = 0.001). Risk of incident AD dementia in False Negative women was substantially higher than in True Negative women (HR = 3.11, 95%CI = 2.09–4.63, p  < 0.001). Conclusion Results suggest that previous reports of higher aMCI rates in men versus women may be an artifact of non-sex-adjusted norms/cut-scores. Incorporation of sex-specific norms/cut-scores for verbal memory impairment into aMCI diagnostic criteria may improve diagnostic accuracy and avoid diagnostic errors in approximately 20%. Show more

Keywords: Amnestic mild cognitive impairment, diagnosis, incident Alzheimer’s disease, sex differences, verbal memory

DOI: 10.3233/JAD-215260

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1763-1770, 2021