Journal of Alzheimer's Disease - Volume 75, issue 4

Authors: Chen, Guanqun | Liu, Chunhua | Yang, Kun | Li, Yuxia | Sheng, Can | Xie, Yunyan | Hu, Xiaochen | Jiang, Jiehui | Han, Ying

Article Type: Research Article

Abstract: Background: Clinical research has demonstrated that brain reserve (BR) could exert positive effects on cognition for patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI). However, the effects of BR on cognition in individuals with subjective cognitive decline (SCD) are not clear. Objective: To examine cross-sectional effects of BR on cognition in SCD populations. Methods: One hundred forty-nine subjects were studied from the Sino Longitudinal Study on Cognitive Decline (SILCODE) study. Head circumference was used as a proxy of BR. Cognition was assessed across four domains (memory, executive, language, and general cognitive functions). Multiple linear …regression models were conducted to examine effects of BR on cognitive scores. Furthermore, we addressed the question that whether the degree of self-perception of cognitive decline modified the effect of BR on cognitive performance in SCD subjects. Results: We found a positive effect of BR on language cognition in subjects with SCD. Furthermore, the positive effect of BR on language cognition survived in SCD participants with a low degree of self-perception of cognitive decline while disappeared in SCD participants with a high degree of self-perception of cognitive decline. Conclusion: This study suggests that BR has the potential to delay or slow down cognitive decline in SCD individuals, especially for mild SCD. Show more

Keywords: Alzheimer’s disease, brain reserve, head circumference, subjective cognitive decline, subjective cognitive decline questionnaire

DOI: 10.3233/JAD-200005

Citation: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1203-1210, 2020

Authors: McKeever, Anna | Paris, Alvar F. | Cullen, James | Hayes, Lawrence | Ritchie, Craig W. | Ritchie, Karen | Waldman, Adam D. | Wells, Katie | Busza, Albert | Carriere, Isabelle | O’Brien, John T. | Su, Li

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) begins decades before the onset of dementia. There is a need to investigate biomarkers of early AD for use in clinical trials and to facilitate early intervention. Objective: We aimed to determine whether changes in hippocampal subfield volumes in healthy middle-aged adults were associated with risk of future dementia. Methods: We included 150 participants from the PREVENT-Dementia cohort, which recruited subjects aged 40–59 with or without a family history of dementia (FHD; included here were 81 with FHD and 69 without). Hippocampal subfield volumes were segmented from high resolution T2-weighted 3T MRI …images taken at baseline and 2-year follow-up. Results: FHD and greater 20 year-risk of dementia due to cardiovascular risk factors were both associated with lower CA1 volume. FHD was also associated with a relative increase in combined CA3, CA4, and dentate gyrus volume between baseline and follow-up. Conclusion: CA1 atrophy may commence as early as middle-age in those with a high risk of future dementia, while increases in CA3, CA4, and dentate gyrus volume may be a response to early AD in the form of inflammation or neurogenesis. Show more

Keywords: Alzheimer’s disease, APOE ɛ4, CA1, CA2, CA3, CA4, Dementia Risk Score, dentate gyrus, family history, pre-clinical

DOI: 10.3233/JAD-200238

Citation: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1211-1218, 2020

Authors: Andrade, Víctor | Cortés, Nicole | Pastor, Gabriela | Gonzalez, Andrea | Ramos-Escobar, Nicolás | Pastene, Edgar | Rojo, Leonel E. | Maccioni, Ricardo B.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a multifactorial disease, that involves neuroinflammatory processes in which microglial cells respond to “damage signals”. The latter includes oligomeric tau, iron, oxidative free radicals, and other molecules that promotes neuroinflammation in the brain, promoting neuronal death and cognitive impairment. Since AD is the first cause of dementia in the elderly, and its pharmacotherapy has limited efficacy, novel treatments are critical to improve the quality of life of AD patients. Multitarget therapy based on nutraceuticals has been proposed as a promising intervention based on evidence from clinical trials. Several studies have shown that epicatechin-derived polyphenols from …tea improve cognitive performance; also, the polyphenol molecule N-acetylcysteine (NAC) promotes neuroprotection. Objective: To develop an approach for a rational design of leading compounds against AD, based on specific semisynthetic epicatechin and catechin derivatives. Methods: We evaluated tau aggregation in vitro and neuritogenesis by confocal microscopy in mouse neuroblastoma cells (N2a), after exposing cells to either epicatechin-pyrogallol (EPIC-PYR), catechin-pyrogallol (CAT-PYR), catechin-phloroglucinol (CAT-PhG), and NAC. Results: We found that EPIC-PYR, CAT-PYR, and CAT-PhG inhibit human tau aggregation and significantly increase neuritogenesis in a dose-dependent manner. Interestingly, modification with a phloroglucinol group yielded the most potent molecule of those evaluated, suggesting that the phloroglucinol group may enhance neuroprotective activity of the catechin-derived compounds. Also, as observed with cathechins, NAC promotes neuritogenesis and inhibits tau self-aggregation, possibly through a different pathway. Conclusion: EPIC-PYR, CAT-PYR, CAT-PhG, and NAC increased the number of neurites in Na2 cell line and inhibits tau-self aggregation in vitro . Show more

Keywords: Alzheimer’s disease, bioactive compounds, molecular functions, molecular networks, natural compounds, polyphenols, prevalent neurological disorders, tau oligomerization

DOI: 10.3233/JAD-200067

Citation: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1219-1227, 2020

Authors: Yu, Lei | Mottola, Gary | Bennett, David A. | Boyle, Patricia A.

Article Type: Research Article

Abstract: Background: Financial and health literacy are associated with cognitive outcomes in old age. However, the extent to which confidence in financial and health literacy is related to cognitive health is unknown. Objective: This study tests the hypothesis that confidence is associated with cognitive outcomes above and beyond actual financial and health literacy. Methods: A total of 974 older adults underwent assessments of literacy and confidence in literacy, and were subsequently followed for annual clinical evaluations. Financial and health literacy were assessed via a series of items which were immediately followed by questions asking participants to rate …their confidence in accuracy of their response to the literacy items. Cox proportional hazards models examined the associations of financial and health literacy and confidence in literacy with incident Alzheimer’s disease (AD) dementia; and linear mixed models examined the associations with cognitive decline. Results: Participants on average were 81.2 years of age at literacy assessment. Over up to 9 years of annual follow-up, 175 (18%) developed AD dementia. After adjusting for demographics, higher confidence in financial literacy was associated with lower risk of AD dementia and slower decline in cognition. The results persisted after further adjusting for financial literacy performance. Similar findings were observed for confidence in health literacy. Further, older adults who expressed under-confidence relative to their actual level of financial and health literacy were more likely to develop AD dementia and experienced faster cognitive decline. Conclusion: Both domain-specific literacy and confidence in one’s financial and health knowledge are important determinants of cognitive health among community-dwelling older adults. Show more

Keywords: Alzheimer’s disease, cognition, confidence, heath and financial literacy

DOI: 10.3233/JAD-200001

Citation: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1229-1240, 2020

Authors: Luchsinger, José A. | Palta, Priya | Rippon, Brady | Sherwood, Greysi | Soto, Luisa | Ceballos, Fernando | Laing, Krystal | Igwe, Kay | He, Hengda | Razlighi, Qolamreza | Teresi, Jeanne | Moreno, Herman | Brickman, Adam M.

Article Type: Research Article

Abstract: Background: Type 2 diabetes is a dementia risk factor, but its relation to Alzheimer’s disease (AD), the most common cause of dementia, is unclear. Objective: Our primary objective was to examine the association of pre-diabetes and type 2 diabetes with brain amyloid-β (Aβ), the putative main culprit of AD. Our secondary objective was to examine the association of pre-diabetes and type 2 diabetes with neurodegeneration, cerebrovascular disease (CVD), and memory performance. Methods: We conducted a cross-sectional study of 350 late middle-aged Hispanics without dementia in New York City. We classified diabetes status as normal glucose tolerance …(NGT), pre-diabetes, and type 2 diabetes following American Diabetes Association criteria. Brain Aβ was ascertained as global Aβ standardized value uptake ratio using PET with 18 F-Florbetaben. Neurodegeneration was operationalized as cortical thickness in regions affected by AD using MRI. CVD was operationalized as white matter hyperintensity volume (WMH) on MRI, and memory as performance with the selective reminding test (SRT). Results: Mean age was 64.15±3.34 years, 72.00% were women, and 35.43% were APOE ɛ 4 carriers. Pre-diabetes, but not type 2 diabetes, was associated with higher Aβ compared with NGT. Type 2 diabetes treatment was related to lower Aβ. Type 2 diabetes was related to lower cortical thickness, higher WMH, and lower SRT score. Conclusion: Pre-diabetes, but not type 2 diabetes, is associated with higher brain Aβ in late middle age, and this observation could be explained by the relation of diabetes treatment with lower brain Aβ. Whether type 2 diabetes treatment lowers brain Aβ requires further study. Show more

Keywords: Amyloid, middle age, Hispanic, type 2 diabetes

DOI: 10.3233/JAD-200232

Citation: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1241-1252, 2020

Authors: Vecchio, Fabrizio | Miraglia, Francesca | Alù, Francesca | Menna, Matteo | Judica, Elda | Cotelli, Maria | Rossini, Paolo Maria

Article Type: Research Article

Abstract: Background: Several studies investigated clinical and instrumental differences to make diagnosis of dementia in general and in Alzheimer’s disease (AD) in particular with the aim to classify, at the individual level, AD patients and healthy controls cooperating with neuropsychological tests for an early diagnosis. Advanced network analysis of electroencephalographic (EEG) rhythms provides information on dynamic brain connectivity and could be used in classification processes. If successfully reached, this goal would add a low-cost, easily accessible, and non-invasive technique with neuropsychological tests. Objective: To investigate the possibility to automatically classify physiological versus pathological aging from cortical sources’ connectivity based …on a support vector machine (SVM) applied to EEG small-world parameter. Methods: A total of 295 subjects were recruited: 120 healthy volunteers and 175 AD. Graph theory functions were applied to undirected and weighted networks obtained by lagged linear coherence evaluated by eLORETA. A machine-learning classifier (SVM) was applied. EEG frequency bands were: delta (2–4 Hz), theta (4–8 Hz), alpha1 (8–10.5 Hz), alpha2 (10.5–13 Hz), beta1 (13–20 Hz), beta2 (20–30 Hz), and gamma (30–40 Hz). Results: The receiver operating characteristic curve showed AUC of 0.97±0.03 (indicating very high classification accuracy). The classifier showed 95% ±5% sensitivity, 96% ±3% specificity, and 95% ±3% accuracy for the classification. Conclusion: EEG connectivity analysis via a combination of source/connectivity biomarkers, highly correlating with neuropsychological AD diagnosis, could represent a promising tool in identification of AD patients. This approach represents a low-cost and non-invasive method, one that utilizes widely available techniques which, when combined, reach high sensitivity/specificity and optimal classification accuracy on an individual basis (0.97 of AUC). Show more

Keywords: Alzheimer’s disease, delta and alpha bands, EEG, functional connectivity, graph theory, LORETA, machine learning classifier, small-world, support vector machine

DOI: 10.3233/JAD-200171

Citation: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1253-1261, 2020

Authors: Tan, Edwin C.K. | Lexomboon, Duangjai | Häbel, Henrike | Fastbom, Johan | Eriksdotter, Maria | Johnell, Kristina | Sandborgh-Englund, Gunilla

Article Type: Research Article

Abstract: Background: Older adults with dementia often have poor oral health. Chronic use of xerogenic medications may contribute to adverse dental outcomes. Objective: To investigate the impact of xerogenic medication classes on the predicted risk for dental interventions in people with dementia. Methods: This was a population-based cohort study involving 30,955 individuals registered in the Swedish Dementia Registry (SveDem) from 2008 to 2015. Data were linked with other national registers. The exposure was xerogenic medication classes used in the three years prior to dementia diagnosis (baseline). The primary outcome was the composite of number of tooth extractions …and dental restorations over the three-year follow-up period. Secondary outcomes included the number of tooth extractions and number of dental restorations. Poisson regression models were used to estimate the association between the exposure and outcomes. Analyses were adjusted for age, gender, Mini-Mental State Examination, living arrangement, dementia disorder, average number of medications, Charlson’s comorbidity index, number of dental visits, and number of teeth. Results: After adjusting for potential covariates, the use of urological drugs (incidence rate ratio [IRR] 1.16, 95% CI 1.04–1.28), proton pump inhibitors (IRR 1.13, 95% CI 1.04–1.23), and opioids (IRR 1.19, 95% CI 1.06–1.34) were significantly associated with the primary composite outcome. Conclusion: The use of specific classes of xerogenic medications was associated with an increased risk for tooth extractions and restorations in people with dementia. The risks and benefits of xerogenic medications, in the context of oral health, should be carefully assessed in this vulnerable population. Show more

Keywords: Dementia, dental care, longitudinal studies, medication, polypharmacy, registers, tooth loss, xerostomia

DOI: 10.3233/JAD-200148

Citation: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1263-1271, 2020

Authors: Kawasaki, Aki | Ouanes, Sami | Crippa, Sylvain V. | Popp, Julius

Article Type: Research Article

Abstract: Background: Pathologic changes in cerebral and retinal structures governing the pupillary light reflex occur in Alzheimer’s disease (AD). Analysis of pupillary responses originating from different retinal cells may allow for non-invasive detection of cerebral AD pathology. Objective: This study aimed to quantify the pupil light reflex using a portable chromatic pupillometer in patients with early stage AD and compare their responses to those of a healthy control group. Methods: Participants in this case-control pilot study were recruited from a well-characterized cohort of elderly people participating in a larger prospective study on early AD. Cognitive testing, volumetric …brain imaging, and lumbar puncture were performed in all participants to define two groups: early AD, i.e., cognitively impaired subjects with biomarker-confirmed AD pathology, and control group of subjects with normal cognition and normal CSF biomarker profile. Pupil responses to red and blue light stimuli intended to activate cone photoreceptors and melanopsin ganglion cells were recorded under photopic conditions. Results: Sixteen patients with AD (mean age 77 years) and sixteen controls (mean age 71 years) were tested. Baseline pupil size was significantly smaller in AD patients. Pupillary contraction amplitude to all red and blue lights was also smaller in AD patients but did not reach statistical significance. The post-illumination pupillary response was the same between the two groups. Conclusion: Compared to healthy controls, we found only a smaller resting size of the pupil in patients with early AD. The pupillary dynamics to light stimulation remained relatively preserved. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid biomarkers, dementia, melanopsin ganglion cell, pupil, pupil light reflex

DOI: 10.3233/JAD-200120

Citation: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1273-1282, 2020

Authors: Gueib, Claire | Pop, Alina | Bannay, Aurélie | Nassau, Emeline | Fescharek, Reinhard | Gil, Roger | Luc, Amandine | Rivasseau Jonveaux, Thérèse

Article Type: Research Article

Abstract: Background: The environment of patients with Alzheimer’s disease and related disorders (ADRD) intensifies the consequences of cognitive impairment and exacerbates behavioral problems if inappropriate or, conversely, mitigate these problems if its design is tailored to the needs of these persons. Objective: We evaluate the impacts of hospitalization and of a specific healing garden on self-consciousness which represent a central impairment in ADRD. The self-consciousness questionnaire (SCQ), validated for its assessment at mild to moderate phases of the disease, explores the dimensions of personal identity, awareness of cognitive deficiencies, self-assessment of affective state, awareness of body representation, prospective memory, …capacity for introspection, and moral judgments. Methods: After having verified, by means of a preliminary study, its feasibility to the more advanced stages of the disease, this questionnaire allowed assessment of the impact of the environment by comparing, in routine care, patients hospitalized in a cognitive-behavioral unit who solely remain indoors with others who use the Art, Memory and Life healing garden. Results: A significant decrease in SCQ due to an increase in anosognosia during hospitalization was observed in the group that remained indoors. For the group using the garden, a positive effect on overall SCQ score was observed, as a result of a significant improvement in body representation as the driving parameter. Conclusion: Factors that are grounded in the hypotheses that spearheaded its conception, such as sensory enrichment, familiarity, contact with nature, scaffolding role for cognitive functions, supportive effect for social interactions, and the “Nancy hypotheses of beauty”, thus contribute to their validation. Show more

Keywords: Alzheimer’s disease, anosognosia, body representation, healing gardens, self-consciousness

DOI: 10.3233/JAD-190748

Citation: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1283-1300, 2020

Authors: Rai, Surya Prakash | Krohn, Markus | Pahnke, Jens

Article Type: Research Article

Abstract: Background: Spatial memory dysfunction has been demonstrated in mouse models of Alzheimer’s disease (AD) which is consistent with the clinical finding that the early signature of AD includes difficulties in the formation and/or storage of a memory. A stored memory—a long term memory—can be modulated via process called as memory retrieval that can either lead toward memory reconsolidation or even memory extinction. Objective: We aim to shed light on the fate of the spatial memory during memory reactivation and memory extinction using a water maze task. Methods: In Set-up I, we trained 3-month-old mice (wild-type mice …and mice with cerebral β-amyloidosis) and assessed the fate of remote memory after four months of retention interval (RI). In Set-up II, we performed an early-extensive training at 2 months of age, retrained the same mice at 3 months of age, introduced four months of RI, and finally assessed remote spatial memory at 7 months of age. Results: We find in β-amyloidosis mice that memory reactivation problems were detectable at 7 months of age and were alleviated by cognitive overtraining. Similarly, forgetting of remote spatial memory was also minimized by cognitive overtraining. Finally, we show that the cognitive training facilitates the recovery of the reactivated spatial memory while reducing the ability to form new spatial memory in AD mice. Conclusion: This result may explain the rationality behind the cognitive reserve observed in AD patients and elderly with severe β-amyloidosis not corresponding to the actual low dementia symptoms. Show more

Keywords: Alzheimer’s disease, APP transgene, cognitive flexibility, cognitive reserve, memory extinction, memory reconsolidation, memory retrieval, remote memory, water maze

DOI: 10.3233/JAD-200161

Citation: Journal of Alzheimer's Disease, vol. 75, no. 4, pp. 1301-1317, 2020