Journal of Alzheimer's Disease - Volume 81, issue 4

Authors: Zweig, Jonathan A. | Brandes, Mikah S. | Brumbach, Barbara H. | Caruso, Maya | Wright, Kirsten M. | Quinn, Joseph F. | Soumyanath, Amala | Gray, Nora E.

Article Type: Research Article

Abstract: Background: The medicinal herb Centella asiatica has been long been used for its neuroprotective and cognitive enhancing effects. We have previously shown that two weeks of treatment with a water extract of Centella asiatica (CAW) improves cognition and activates the endogenous antioxidant response pathway without altering amyloid-β (Aβ) plaque burden. Objective: Here, we assess the effect of long-term treatment of CAW in the 5xFAD mouse model of Aβ accumulation. Methods: Four-month-old 5xFAD mice were treated with CAW in their drinking water (2 g/L) for three months at which point they underwent cognitive testing as well …as analysis of Aβ plaque levels and antioxidant and synaptic gene expression. In order to confirm the involvement of the antioxidant regulatory transcription factor NRF2 on the effects of CAW on synaptic plasticity, neurons isolated from 5xFAD mice were also treated with CAW and the targeted inhibitor ML385. Results: Three months of treatment with CAW improved spatial and contextual memory as well as executive function in 5xFAD mice. This improvement was accompanied by increased antioxidant gene expression and a decrease in Aβ plaque burden relative to untreated 5xFAD animals. In isolated neurons, treatment with ML385 blocked the effects of CAW on dendritic arborization and synaptic gene expression. Conclusion: These results suggest that prolonged CAW exposure could be beneficial in Alzheimer’s disease and that these effects likely involve NRF2 activation. Moreover, these findings suggest that targeting NRF2 itself may be a relevant therapeutic strategy for improving synaptic plasticity and cognitive function in Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, amyloid-β, centella asiatica, cognition, NRF2

DOI: 10.3233/JAD-210271

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1453-1468, 2021

Authors: Huo, Qingwei | Tabassum, Sidra | Chen, Ming | Sun, Mengyao | Deng, Yueming | Zheng, Xingzhi | Li, Yi | Chen, Jian | Long, Cheng | Yang, Li

Article Type: Research Article

Abstract: Background: Neuropathological features of Alzheimer’s disease are characterized by the deposition of amyloid-β (Aβ) plaques and impairments in synaptic activity and memory. However, we know little about the physiological role of amyloid-β protein precursor (AβPP) from which Aβ derives. Objective: Evaluate APP deficiency induced alterations in neuronal electrical activity and mitochondrial protein expression. Methods: Utilizing electrophysiological, biochemical, pharmacological, and behavioral tests, we revealed aberrant local field potential (LFP), extracellular neuronal firing and levels of mitochondrial proteins. Result: We show that APP knockout (APP-/- ) leads to increased gamma oscillations in the medial prefrontal cortex …(mPFC) at 1-2 months old, which can be restored by baclofen (Bac), a γ-aminobutyric acid type B receptor (GABAB R) agonist. A higher dose and longer exposure time is required for Bac to suppress neuronal firing in APP-/- mice than in wild type animals, indicating enhanced GABAB R mediated activity in the mPFC of APP-/- mice. In line with increased GABAB R function, the glutamine synthetase inhibitor, L-methionine sulfonate, significantly increases GABAB R levels in the mPFC of APP-/- mice and this is associated with a significantly lower incidence of death. The results suggest that APP-/- mice developed stronger GABAB R mediated inhibition. Using HEK 293 as an expression system, we uncover that AβPP functions to suppress GABAB R expression. Furthermore, APP-/- mice show abnormal expression of several mitochondrial proteins. Conclusion: APP deficiency leads to both abnormal network activity involving defected GABAB R and mitochondrial dysfunction, suggesting critical role of AβPP in synaptic and network function. Show more

Keywords: Amyloid-β precursor protein, GABABR, gamma oscillations, L-methionine sulfonate, medial prefrontal cortex, mitochondria, spikes

DOI: 10.3233/JAD-201557

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1469-1482, 2021

Authors: Leroy, Victoire | Chen, Yaohua | Demnitz, Naiara | Pasquier, Florence | Krolak-Salmon, Pierre | Fougère, Bertrand | Puisieux, Françcois

Article Type: Research Article

Abstract: Background: Falls are a major health problem in older persons but are still under-diagnosed and challenging to prevent. Current guidelines do not target high-risk populations, especially people living with dementia. In France, people with neurocognitive disorders are mainly referred to memory clinics (MCs). Objective: We aimed to survey the routine practice of physicians working in MCs regarding fall risk assessment. Methods: We conducted a cross-sectional survey in France from January to May 2019 among physicians working in MCs, through an anonymous online questionnaire: twenty-seven questions about the physician’s background and their practice of fall risk assessment, …especially use of clinical and paraclinical tools. We compared the results according to the age and the specialty of the physician. Results: We obtained 171 responses with a majority of women (60%) and geriatricians (78%). All age classes and all French regions were represented. Most of respondents (98.8%) stated that they address gait and/or falls in outpatient clinic and 95.9%in day hospitals. When asked about how they assess fall risk, fall history (83%) and gait examination (68.4%) were the most widely used, while orthostatic hypotension (24%) and clinical standardized tests (25.7%) were less common. Among standardized tests, One-leg Balance, Timed Up and Go Test, and gait speed measurements were the most used. Geriatricians had more complete fall risk assessment than neurologists (e.g., 56%versus 13%for use of standardized tests, p  < 0.0001). Conclusion: Almost all physicians addressed the question of fall in MC, but practices are widely heterogeneous. Further investigations are needed to standardize fall risk assessment in MCs. Show more

Keywords: Assessment, fall risk, memory clinic, routine practice, survey

DOI: 10.3233/JAD-201585

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1483-1491, 2021

Authors: Pillai, Jagan A. | Kou, Lei | Bena, James | Penn, Lisa | Leverenz, James B.

Article Type: Research Article

Abstract: Background: There is significant interest in understanding the role of modifiable vascular risk factors contributing to dementia risk across age groups. Objective: Risk of dementia onset was assessed in relation to vascular risk factors of hypertension and hypercholesterolemia among cognitively normal APOE ɛ 4 carriers and non-carriers. Methods: In a sample of prospectively characterized longitudinal cohort from the National Alzheimer’s Coordinating Center database, 9,349 participants met criteria for normal cognition at baseline, had a CDR-Global (CDR-G) score of zero, and had concomitant data on APOE ɛ 4 status and medical co-morbidities including histories of …hypertension and hypercholesterolemia. Multivariable Cox proportional hazards models adjusted for well-known potential confounders were used to compare dementia onset among APOE ɛ 4 carriers and non-carriers by young (≤65 years) and old (> 65 year) age groups. Results: 519 participants converted to dementia within an average follow up of 5.97 years. Among older APOE ɛ 4 carriers, hypercholesterolemia was related to lower risk of dementia (HR (95% CI), 0.68 (0.49–0.94), p  = 0.02). Among older APOE ɛ 4 non-carriers, hypertension was related to higher risk of dementia (HR (95% CI), 1.44 (1.13–1.82), p  = 0.003). These results were corroborated among a subset with autopsy data characterizing underlying neuropathology. Among younger participants, vascular risk factors did not impact dementia risk, likely from a lower frequency of vascular and Alzheimer’s as etiologies of dementia among this cohort. Conclusion: A history of hypercholesterolemia related to a lower risk of dementia among older APOE ɛ 4 carriers, while hypertension related to a higher risk of dementia among older APOE ɛ 4 non-carriers. Show more

Keywords: APOE ɛ4, dementia, dementia risk, depression, hypercholesterolemia, hypertension, longitudinal cohort study, mixed dementia, neuropathology, normal cognition cohort

DOI: 10.3233/JAD-201609

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1493-1504, 2021

Authors: Dekker, Alain D. | Ulgiati, Aurora M. | Groen, Henk | Boxelaar, Vincent A. | Sacco, Silvia | Falquero, Ségolène | Carfi, Angelo | di Paola, Antonella | Benejam, Bessy | Valldeneu, Silvia | Fopma, Roelie | Oosterik, Marjo | Hermelink, Marloes | Beugelsdijk, Gonny | Schippers, Mieke | Henstra, Hepie | Scholten-Kuiper, Martine | Willink-Vos, Judith | de Ruiter, Lisa | Willems, Liesbeth | Loonstra-de Jong, Anneke | Coppus, Antonia M.W. | Tollenaere, Marleen | Fortea, Juan | Onder, Graziano | Rebillat, Anne-Sophie | Van Dam, Debby | De Deyn, Peter P.

Article Type: Research Article

Abstract: Background: People with Down syndrome (DS) are at high risk to develop Alzheimer’s disease dementia (AD). Behavioral and psychological symptoms of dementia (BPSD) are common and may also serve as early signals for dementia. However, comprehensive evaluation scales for BPSD, adapted to DS, are lacking. Therefore, we previously developed the BPSD-DS scale to identify behavioral changes between the last six months and pre-existing life-long characteristic behavior. Objective: To optimize and further study the scale (discriminative ability and reliability) in a large representative DS study population. Methods: Optimization was based on item irrelevance and clinical experiences …obtained in the initial study. Using the shortened and refined BPSD-DS II , informant interviews were conducted to evaluate 524 individuals with DS grouped according to dementia status: no dementia (DS, N = 292), questionable dementia (DS + Q, N = 119), and clinically diagnosed dementia (DS + AD, N = 113). Results: Comparing item change scores between groups revealed prominent changes in frequency and severity for anxious, sleep-related, irritable, restless/stereotypic, apathetic, depressive, and eating/drinking behavior. For most items, the proportion of individuals displaying an increased frequency was highest in DS + AD, intermediate in DS + Q, and lowest in DS. For various items within sections about anxious, sleep-related, irritable, apathetic, and depressive behaviors, the proportion of individuals showing an increased frequency was already substantial in DS + Q, suggesting that these changes may serve as early signals of AD in DS. Reliability data were promising. Conclusion: The optimized scale yields largely similar results as obtained with the initial version. Systematically evaluating BPSD in DS may increase understanding of changes among caregivers and (timely) adaptation of care/treatment. Show more

Keywords: Alzheimer’s disease, behavior, behavioral and psychological symptoms of dementia, dementia, Down syndrome, intellectual disabilities, neuropsychiatric symptoms, trisomy 21

DOI: 10.3233/JAD-201427

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1505-1527, 2021

Authors: Szlejf, Claudia | Suemoto, Claudia Kimie | Janovsky, Carolina Castro Porto Silva | Bertola, Laiss | Barreto, Sandhi Maria | Lotufo, Paulo Andrade | Benseñor, Isabela Martins

Article Type: Research Article

Abstract: Background: Subtle thyroid alterations have a controversial role in cognition. Objective: We investigated the longitudinal association of baseline thyroid function, thyrotropin (TSH), and thyroxine (FT4) levels with cognitive performance after 4 years of follow-up in middle-aged and older adults without overt thyroid dysfunction. Methods: We included 4,473 individuals, age≥55 years at the second study wave, without overt thyroid dysfunction at baseline. Individuals were divided according to thyroid function and TSH and FT4 tertiles. Cognition was assessed at baseline and after 4 years of follow-up by the word recall (DWR), semantic verbal fluency (SVF), and trail making …(TMT) tests. The longitudinal association of thyroid function and TSH and FT4 tertiles with cognitive performance was investigated using generalized estimating equations adjusted for sociodemographic characteristics, lifestyle, cardiovascular risk factors and depression. Results: There was no longitudinal association of thyroid function and TSH and FT4 baseline levels with performance on the cognitive tests. However, there was a baseline cross-sectional U-shaped association of FT4 tertiles with poorer performance in the SVF (first FT4 tertile: β = –0.11, 95% CI = –0.17; –0.04; third FT4 tertile: β = –0.10, 95% CI = –0.17; –0.04) and of the third FT4 tertile with poorer performance in the DWR (β = –0.09, 95% CI = –0.16; –0.02). Conclusion: Thyroid function and hormone levels were not associated with cognitive decline during 4 years of follow-up in middle-aged and older adults without overt thyroid dysfunction. Future studies with longer follow-up could clarify the implications of subtle thyroid alterations in cognition. Show more

Keywords: Cognition, free thyroxine, older adults, thyroid function, thyrotropin

DOI: 10.3233/JAD-210018

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1529-1540, 2021

Authors: Alegret, Montserrat | Espinosa, Ana | Ortega, Gemma | Pérez-Cordón, Alba | Sanabria, Ángela | Hernández, Isabel | Marquié, Marta | Rosende-Roca, Maitée | Mauleón, Ana | Abdelnour, Carla | Vargas, Liliana | de Antonio, Ester Esteban | López-Cuevas, Rogelio | Tartari, Juan Pablo | Alarcón-Martín, Emilio | Tárraga, Lluís | Ruiz, Agustín | Boada, Mercè | Valero, Sergi

Article Type: Research Article

Abstract: Background: Over the last decade, teleneuropsychology has increased substantially. There is a need for valid neuropsychological batteries to be administered home-to-home. Since 2006, the neuropsychological battery of Fundació ACE (NBACE) has been administered face-to-face in our clinical settings. Recently, we adapted the NBACE for teleneuropsychology use to be administered home-to-home (NBACEtn). Objective: The aims of the present study are: 1) to determine the home-to-home NBACE equivalence compared to its original face-to-face version; and 2) to examine home-to-home NBACE discriminant capacity by differentiating among cognitively healthy, mild cognitive impairment, or mild dementia subjects and comparing it with the face-to-face …version. Methods: Data from 338 individuals assessed home-to-home (NBACEtn) were contrasted with 7,990 participants assessed with its face-to-face version (NBACE). Exploratory and confirmatory factorial structure, and invariance analysis of the two versions of the battery were performed. Results: Exploratory and confirmatory factor analysis supported the four-factor model (attention, memory, executive, and visuospatial/constructional functions). Configural, metric, and scalar measurement invariance was found between home-to-home and face-to-face NBACE versions. Significant differences in most of the neuropsychological variables assessed were observed between the three clinical groups in both versions of administration. No differences were found between the technological devices used by participants (computer or tablet and mobile devices). Conclusion: For the first time, invariance analysis findings were addressed by determining a teleneuropsychological battery’s equivalence in comparison with its face-to-face version. This study amplifies the neuropsychological assessment’s applicability using a home-to-home format, maintaining the original measure’s structure, interpretability, and discriminant capacity. Show more

Keywords: Alzheimer’s disease, cognitive impairment, construct validity, face-to-face, home-to-home, invariance, neuropsychological assessment, telemedicine, teleneuropsychology

DOI: 10.3233/JAD-201389

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1541-1553, 2021

Authors: Molad, Jeremy | Hallevi, Hen | Korczyn, Amos D. | Seyman, Estelle | Bornstein, Natan M. | Niry, Dana | Eldor, Roy | Ben Assayag, Einor

Article Type: Research Article

Abstract: Background: Migraine is known to mildly increase the risk for ischemic stroke and is associated with vascular MRI markers. However, the potential effect of chronic headache (CH) on stroke outcomes has not been studied. Objective: We aimed to assess the interrelation between CH and post-stroke cognitive impairment. Methods: Data from 455 patients with a first ever stroke from the TABASCO study was available. All patients underwent 3T brain MRI, blood analysis, and a serial cognitive assessment at baseline and 6, 12, and 24 months after. Results: Eighty-five (18.7%) patients reported suffering from CH, of …whom 53 (62.4%) reported symptoms of photophobia or nausea, and 34 (40%) reported an aura. CH was associated with female sex, lower prevalence of T2DM (p  < 0.001), and lower HbA1C levels (p  < 0.001). Multiple regression analysis, controlling for age, sex, education, vascular risk factors, and the presence of acute lesions in MRI, revealed that CH was an independent predictor of better cognitive scores 6, 12, and 24 months post-stroke (p  = 0.015, p  = 0.01, and p  = 0.012, respectively). Stroke patients suffering from CH had also higher normalized gray, white matter, and thalamus volumes, and better white matter microstructural integrity (p  < 0.001, p  = 0.037, p  < 0.001, p  = 0.008, respectively) Conclusion: In this study, CH was consistently associated with better long term cognitive scores among post stroke subjects. These surprising findings may partially arise from the higher prevalence of T2DM among subjects without CH, that may represent the existence of chronic cerebrovascular disease, and may reflect mechanisms involving glucose metabolism. Show more

Keywords: Chronic headache, migraine, post-stoke cognitive impairment, stroke, TABASCO

DOI: 10.3233/JAD-210077

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1555-1566, 2021

Authors: Chekani, Farid | Pike, James | Jones, Eddie | Husbands, Joseph | Khandker, Rezaul K.

Article Type: Research Article

Abstract: Background: Dementia is commonly accompanied by neurobehavioral symptoms; however, the relationship between such symptoms and health-related outcomes is unclear. Objective: To investigate the impact of specific neurobehavioral symptoms in dementia on healthcare resource use (HCRU), patient quality of life (QoL), and caregiver burden. Methods: Data were taken from the 2015/16 Adelphi Real World Dementia Disease Specific Programme™, a point-in-time survey of physicians and their consulting dementia patients. Multiple regression analyses were used to examine associations between patient symptom groups and health-related outcomes. Results: Each patient symptom group of interest (patients with agitation/aggression and related …symptoms [AARS] with psychosis, patients with AARS without psychosis, and patients with other behavioral symptoms) had a positive association with HCRU variables (i.e., HCRU was greater), a negative association with proxy measures of patient QoL (i.e., QoL was decreased), and a positive association with caregiver burden (i.e., burden was greater) compared with patients with no behavioral symptoms (control group). The magnitude of effect was generally greatest in patients with AARS with psychosis. Regression analysis covariates that were found to be most often significantly related to the outcomes were dementia severity and the patients’ living situation (i.e., whether they were in nursing homes or living in the community). Conclusion: Combinations of behavioral symptoms, particularly involving AARS plus psychosis, may have a detrimental impact on health-related outcomes such as HCRU, patient QoL, and caregiver burden in dementia. Our results have implications for intervention development in patients who report clusters of symptoms and caregivers, and for identifying at-risk individuals. Show more

Keywords: Aggression, agitation, behavioral symptoms, burden, caregivers, cognitive impairment, dementia, healthcare resource use, quality of life

DOI: 10.3233/JAD-201483

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1567-1578, 2021

Authors: Nakamura, Shin | Yomota, Satoshi | Ito, Hitomi | Akinaga, Nobuyuki | Hori, Ayaka | Chinomi, Kenta | Suzuki, Hideaki | Uchida, Kazuhiko | Asada, Takashi

Article Type: Research Article

Abstract: Background: Maintaining cognitive function is integral to a healthy social life in the aged. Although neuropsychological tests and brain imaging methods can assess cognitive dysfunction, these techniques are subjective, psychologically burdensome, and cannot be conducted easily. Objective: We sought to develop an objective, low-burden novel cognitive function scale based on functional near-infrared spectroscopy (fNIRS) of hemodynamic changes in the cerebral cortex during daily task performance. Methods: A total of 63 participants (aged 60–80 years) identified as non-dementia controls (NDC) or with mild cognitive impairment (MCI) were recruited and randomly assigned to training and test data sets. …Explanatory variables were hemodynamic responses during low-burden sensory and simple tasks without higher-order brain functioning. Results: A logistic regression analysis of the fNIRS index in NDCs and MCI patients revealed area under the curve, sensitivity, specificity, and holdout results of 0.98, 94%, 88%, and 62% respectively. Correlation between fNIRS index and MCI odds showed positive linearity (R2  = 0.96). Conclusion: Positive correlation between the fNIRS index and MCI odds indicated effectiveness of this fNIRS measurement. Although additional experiments are necessary, the fNIRS index representing degree of cognitive decline can be an onsite monitoring tool to assess cognitive status. Show more

Keywords: Cognitive dysfunction, functional neuroimaging, mental status and dementia tests, neuropsychological tests, neurovascular coupling, spectroscopy near-infrared

DOI: 10.3233/JAD-210072

Citation: Journal of Alzheimer's Disease, vol. 81, no. 4, pp. 1579-1588, 2021