Journal of Alzheimer's Disease - Volume 88, issue 3

Authors: Jester, Hannah M. | Gosrani, Saahj P. | Ding, Huiping | Zhou, Xueyan | Ko, Mei-Chuan | Ma, Tao

Article Type: Research Article

Abstract: Background: Sporadic or late onset Alzheimer’s disease (LOAD) is a multifactorial neurodegenerative disease with aging the most known risk factor. Non-human primates (NHPs) may serve as an excellent model to study LOAD because of their close similarity to humans in many aspects including neuroanatomy and neurodevelopment. Recent studies reveal AD-like pathology in old NHPs. Objective: In this pilot study, we took advantage of brain samples from 6 Cynomolgus macaques that were divided into two groups: middle aged (average age 14.81 years) and older (average age 19.33 years). We investigated whether AD-like brain pathologies are present in the NHPs. …Methods: We used immunohistochemical method to examine brain Aβ pathology and neuron density. We applied biochemical assays to measure tau phosphorylation and multiple signaling pathways indicated in AD. We performed electron microscopy experiments to study alterations of postsynaptic density and mitochondrial morphology in the brain of NHPs. Results: We found multiple AD-like pathological alteration in the prefrontal cortex (but not in the hippocampus) of the older NHPs including tau hyperphosphorylation, increased activity of AMP-activated protein kinase (AMPK), decreased expression of protein phosphatase 2A (PP2A), impairments in mitochondrial morphology, and postsynaptic densities formation. Conclusion: These findings may provide insights into the factors contributing to the development of LOAD, particularly during the early stage transitioning from middle to old age. Future endeavors are warranted to elucidate mechanisms underlying the regional (and perhaps cellular) vulnerability with aging and the functional correlation of such pathological changes in NHPs. Show more

Keywords: Aging, Alzheimer’s disease, AMPK, mitochondria, non-human primate, synapses

DOI: 10.3233/JAD-215303

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 957-970, 2022

Authors: Teichmann, Birgit | Gkioka, Mara | Kruse, Andreas | Tsolaki, Magda

Article Type: Research Article

Abstract: Background: Dementia is rapidly increasing worldwide due to demographic aging. More than two-thirds of patients are cared by family members. The quality of care depends on the caregivers’ attitude toward dementia influencing patient care decisions. Objective: The aim of this study is to examine the factors that influence the caregivers’ attitude and whether there is an association between participation in a psycho-educational program and attitude. Methods: We performed a cross-sectional study using a structured closed-ended questionnaire to retrieve socio-demographic information from caregivers and the persons with dementia (N = 86). The study included validated scales such as the …Dementia Attitude Scale, the Dementia Knowledge Assessment Tool 2, the Positive Aspects of Caregiving, the Zarit Burden Interview, the Confidence in Dementia Scale, and Spielberger’s State-Trait Anxiety Inventory, as well as a neuropsychological battery to assess the condition of people with dementia. Results: Our final model explains 55.6% of the total variance and shows a significant correlation of five factors with attitude toward dementia: confidence, behavioral and psychological symptoms of dementia, anxiety as a trait, positive aspects of caregiving, and dementia knowledge. The caregivers who participated in a psycho-educational program showed a significantly more positive attitude toward dementia, better dementia knowledge, higher confidence in dementia care, and lower anxiety as a state. Conclusion: The strong correlation of attitude and knowledge, as well as confidence in dementia care, supports the tripartite model of attitude, which hypothesizes the interrelation of affect, cognition, and behavior. Show more

Keywords: Anxiety, attitude, caregiver burden, dementia, family caregiver, knowledge

DOI: 10.3233/JAD-215731

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 971-984, 2022

Authors: Heffernan, Kevin S. | Stoner, Lee | Meyer, Michelle L. | Loprinzi, Paul D.

Article Type: Research Article

Abstract: Background: Aging-associated cognitive decline is greater in non-Hispanic Black (NHB) adults than non-Hispanic White (NHW) adults. An important risk factor for cognitive decline with aging is arterial stiffening, though the importance to racial variation remains poorly understood. Objective: We examined the association of an estimate of arterial stiffness with cognitive function in a bi-racial sample of 60–85-year-old adults (N  = 3,616, 26.5% NHB) enrolled in the National Health and Nutrition Examination Survey (NHANES) between 1999–2002 and 2011–2014. Methods: As a measure of vascular aging, pulse wave velocity was estimated (ePWV) using an equation incorporating age and mean …arterial pressure and expressed as m/s. Using the digit symbol substitution test (DSST), cognitive function was expressed as the number of correctly matched symbols (out of 133) within 120 s. Linear regression models examined associations between ePWV and DSST. Results: In models that adjusted for sex, education, smoking, body mass index, history of cardiovascular disease, and hypertension, ePWV was inversely associated with DSST score in NHB adults (β= –3.47, 95% CI = –3.9 to –3.0; p  < 0.001) and NHW adults (β= –3.51, 95% CI = –4.4 to –2.6; p  < 0.001). Conclusion: ePWV is inversely associated with a measure of cognitive function in older Black and White adults. ePWV may be a useful measure of vascular aging that can offer insight into cognitive aging. Show more

Keywords: Epidemiology, NHANES, survival, vascular stiffness

DOI: 10.3233/JAD-220042

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 985-993, 2022

Authors: Weissberger, Gali H. | Samek, Anya | Mosqueda, Laura | Nguyen, Annie L. | Lim, Aaron C. | Fenton, Laura | Han, S. Duke

Article Type: Research Article

Abstract: Background: Older age is associated with an increase in altruistic behaviors such as charitable giving. However, few studies have investigated the cognitive correlates of financial altruism in older adults. Objective: This study investigated the cognitive correlates of financial altruism measured using an altruistic choice paradigm in a community-based sample of older adults. Methods: In the present study, a sample of older adults (N  = 67; M age = 69.21, SD = 11.23; M education years = 15.97, SD  = 2.51; 58.2% female; 71.6% Non-Hispanic White) completed a comprehensive neuropsychological assessment and an altruistic choice paradigm in which they made decisions about allocating …money between themselves and an anonymous person. Results: In multiple linear regression analyses that controlled for age, education, and sex, financial altruism was negatively associated with performance on cognitive measures typically sensitive to early Alzheimer’s disease (including word list learning and recall, delayed story recall, and animal fluency). Conclusion: Findings of this study point to a negative relationship between financial altruism and cognitive functioning in older adults on measures known to be sensitive to Alzheimer’s disease. Findings also point to a potential link between financial exploitation risk and Alzheimer’s disease in older age. Show more

Keywords: Altruism, Alzheimer’s disease, cognition, economic factors, episodic memory

DOI: 10.3233/JAD-220187

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 995-1005, 2022

Authors: Horvath, Alexandra | Quinlan, Patrick | Eckerström, Carl | Åberg, N. David | Wallin, Anders | Svensson, Johan

Article Type: Research Article

Abstract: Background: Serum insulin-like growth factor-I (IGF-I) has shown some association with hippocampal volume in healthy subjects, but this relation has not been investigated in stable mild cognitive impairment (sMCI) or Alzheimer’s disease (AD). Objective: At a single memory clinic, we investigated whether serum IGF-I was associated with baseline magnetic resonance imaging (MRI)-estimated brain volumes and longitudinal alterations, defined as annualized changes, up to 6 years of follow-up. Methods: A prospective study of patients with sMCI (n  = 110) and AD (n  = 60). Brain regions included the hippocampus and amygdala as well as the temporal, parietal, frontal, and …occipital lobes, respectively. Results: Serum IGF-I was statistically similar in sMCI and AD patients (112 versus 123 ng/mL, p  = 0.31). In sMCI, serum IGF-I correlated positively with all baseline MRI variables except for the occipital lobe, and there was also a positive correlation between serum IGF-I and the annualized change in hippocampal volume (r s  = 0.32, p  = 0.02). Furthermore, sMCI patients having serum IGF-I above the median had lower annual loss of hippocampal volume than those with IGF-I below the median (p  = 0.02). In contrast, in AD patients, IGF-I did not associate with baseline levels or annualized changes in brain volumes. Conclusion: In sMCI patients, our results suggest that IGF-I exerted neuroprotective effects on the brain, thereby maintaining hippocampal volume. In AD, serum IGF-I did not associate with brain volumes, indicating that IGF-I could not induce neuroprotection in this disease. This supports the notion of IGF-I resistance in AD. Show more

Keywords: Alzheimer’s disease, brain region volume, hippocampus, insulin-like growth factor, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-220292

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 1007-1016, 2022

Authors: Tian, Jing | Wang, Tienju | Jia, Kun | Guo, Lan | Swerdlow, Russell H. | Du, Heng

Article Type: Research Article

Abstract: Background: Metabolic dysfunction links to cognitive deficits in Alzheimer’s disease (AD). Leptin is an anti-obesity hormone that modulates energy homeostasis and memory function. Although leptin deregulation is implicated in mouse models of AD-like brain pathology, clinical studies have shown inconsistent results regarding an association of leptin with the development of this neurodegenerative disorder. Objective: We investigated the changes of plasma leptin and the correlation of sex-stratified circulating leptin with cognitive performance, AD-related biological markers, and metabolic status in patients with AD and cognitively unimpaired (CU) counterparts. Methods: We used nonobese AD patients and CU controls in …a University of Kansas Medical Center (KUMC) cohort. Plasma leptin levels, circulating AD-related molecules and metabolic profiles were examined and analyzed. Results: In contrast to unchanged circulating leptin in females, male patients exhibited decreased plasma leptin levels compared with male CU counterparts. Moreover, plasma leptin showed no correlation with cognitive performance and AD blood biomarkers in patients with either sex. Of note, females but not males demonstrated an association of plasma leptin with body mass index, high density lipoprotein-cholesterol and its ratio with total cholesterol and triglycerides. Conclusion: Our findings suggest that leptin deficiency is associated with nonobese male AD patients, supporting systemic dysmetabolism in the development of this neurodegenerative disorder in certain populations. Although plasma leptin may have limited capacity to reflect disease severity or progression, future mechanistic studies on the regulation of leptin in nonobese patients with AD would deepen our understanding of the sex-related disparity of AD etiopathogenesis. Show more

Keywords: Alzheimer’s disease, blood biomarker, metabolism, plasma leptin, sex

DOI: 10.3233/JAD-220447

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 1017-1027, 2022

Authors: Leonhardi, Jakob | Barthel, Henryk | Speerforck, Sven | Dietzel, Jens | Schroeter, Matthias L. | Saur, Dorothee | Tiepolt, Solveig | Rullmann, Michael | Patt, Marianne | Claßen, Joseph | Schomerus, Georg | Sabri, Osama

Article Type: Research Article

Abstract: Background: Alzheimer’s disease and depression can start with combined cognitive and depressive symptoms [1, 2 ]. Accurate differential diagnosis is desired to initiate specific treatment. Objective: We investigated whether amyloid-β PET imaging can discriminate both entities. Methods: This retrospective observational study included 39 patients (20 female, age = 70±11years) with both cognitive and depressive symptoms who underwent amyloid-β PET imaging and in whom clinical follow-up data was available. Amyloid-β PET was carried out applying [18 F]Florbetaben or [11 C]PiB. The PET images were analyzed by standardized visual and relative-quantitative evaluation. Based on clinical follow-up (median of 2.4 years …[range 0.3 to 7.0 years, IQR = 3.7 years] after amyloid PET imaging which was not considered in obtaining a definite diagnosis), discrimination ability between AD-related depression and pseudo-dementia in depression/depression with other comorbidities was determined. Results: Visually, all 10 patients with pseudo-dementia in depression and all 15 patients with other depression were rated as amyloid-β-negative; 2 of 14 patients with AD-related depression were rated amyloid-β–negative. ROC curve analysis of the unified composite standardized uptake value ratios (cSUVRs) was able to discriminate pseudo-dementia in depression from AD-related depression with high accuracy (AUC = 0.92). Optimal [18 F]Florbetaben discrimination cSUVR threshold was 1.34. In congruence with the visual PET analysis, the resulting sensitivity of the relative-quantitative analysis was 86% with a specificity of 100%. Conclusion: Amyloid-β PET can differentiate AD-related depression and pseudo-dementia in depression. Prospective clinical studies are warranted to confirm this result and to potentially broaden the spectrum of clinical applications for amyloid-β PET imaging. Show more

Keywords: Alzheimer’s disease, amyloid-β, amyloid PET imaging, depression, [18F]florbetaben, mild cognitive impairment, pittsburgh compound B, pseudo-dementia

DOI: 10.3233/JAD-215619

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 1029-1035, 2022

Authors: Gan, Jinghuan | Liu, Shuai | Chen, Zhichao | Yang, Yaqi | Ma, Lingyun | Meng, Qingbo | Wang, Xiao-Dan | Liu, Chunyan | Li, Xudong | Zhang, Wei | Ji, Yong

Article Type: Research Article

Abstract: Background: Studies on plasma orexin-A levels in prodromal dementia with Lewy bodies (DLB) and the relationship with clinical manifestations are rare. Objective: To assess plasma orexin-A levels and evaluate the correlation with clinical features in patients with mild cognitive impairment with Lewy bodies (MCI-LB) and DLB. Methods: Plasma orexin-A levels were measured in 41 patients with MCI-LB, 53 with DLB, and 48 healthy controls (HCs). Informant-based history, neurological examinations, neuropsychological assessments, laboratory tests, and neuroimaging were collected and the correlation between orexin-A and various indicators evaluated. Results: Plasma orexin-A levels in patients with MCI-LB …(1.18±0.33 ng/mL, p  = 0.014) or DLB (1.20±0.44 ng/mL, p  = 0.011) were significantly higher than in HCs (1.02±0.32 ng/mL) and associated with gender and age. DLB patients with fluctuating cognition (FC) (1.01±0.23 versus 1.31±0.50, p  = 0.007) or parkinsonism (PARK) (0.98±0.19 versus 1.25±0.47, p  = 0.030) had significantly lower plasma orexin-A levels than subjects without FC or PARK. Plasma orexin-A levels were significantly negatively correlated with irritability and UPDRS-III scores and significantly positively correlated with disinhibition scores. Conclusion: This is the first report in which elevated plasma orexin-A levels were observed in patients with MCI-LB or DLB. In addition, lower orexin-A levels were found in patients with DLB and FC or PARK compared with HCs. The plasma orexin-A levels were associated with the presence of core features and motor and neuropsychiatric symptoms in patients with MCI-LB and DLB. Show more

Keywords: Dementia with lewy bodies, fluctuation, hypocretin, mild cognitive impairment with lewy bodies, orexin, parkinsonism

DOI: 10.3233/JAD-220082

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 1037-1048, 2022

Authors: Mielke, Michelle M. | Ransom, Jeanine E. | Mandrekar, Jay | Turcano, Pierpaolo | Savica, Rodolfo | Brown, Allen W.

Article Type: Research Article

Abstract: Background: Epidemiological studies examining associations between traumatic brain injury (TBI) and Alzheimer’s disease and related dementias (ADRD) have yielded conflicting results, which may be due to methodological differences. Objective: To examine the relationship between the presence and severity of TBI and risk of ADRD using a population-based cohort with medical record abstraction for confirmation of TBI and ADRD. Methods: All TBI events among Olmsted County, Minnesota residents aged > 40 years from 1985–1999 were confirmed by manual review and classified by severity. Each TBI case was randomly matched to two age-, sex-, and non-head injury population-based referents without …TBI. For TBI events with non-head trauma, the Trauma Mortality Prediction Model was applied to assign an overall measure of non-head injury severity and corresponding referents were matched on this variable. Medical records were manually abstracted to confirm ADRD diagnosis. Cox proportional hazards models examined the relationship between TBI and severity with risk of ADRD. Results: A total of 1,418 residents had a confirmed TBI (865 Possible, 450 Probable, and 103 Definite) and were matched to 2,836 referents. When combining all TBI severities, the risk of any ADRD was significantly higher for those with a confirmed TBI compared to referents (HR = 1.32, 95% CI: 1.11, 1.58). Stratifying by TBI severity, Probable (HR = 1.42, 95% CI: 1.05, 1.92) and Possible (HR = 1.29, 95% CI: 1.02–1.62) TBI was associated with an increased risk of ADRD, but not Definite TBI (HR = 1.22, 95% CI: 0.68, 2.18). Conclusion: Our analyses support including TBI as a potential risk factor for developing ADRD. Show more

Keywords: Alzheimer’s disease, dementia, epidemiology, Parkinson’s disease, population, traumatic brain injury

DOI: 10.3233/JAD-220159

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 1049-1059, 2022

Authors: Bukhbinder, Avram S. | Ling, Yaobin | Hasan, Omar | Jiang, Xiaoqian | Kim, Yejin | Phelps, Kamal N. | Schmandt, Rosemarie E. | Amran, Albert | Coburn, Ryan | Ramesh, Srivathsan | Xiao, Qian | Schulz, Paul E.

Article Type: Research Article

Abstract: Background: Prior studies have found a reduced risk of dementia of any etiology following influenza vaccination in selected populations, including veterans and patients with serious chronic health conditions. However, the effect of influenza vaccination on Alzheimer’s disease (AD) risk in a general cohort of older US adults has not been characterized. Objective: To compare the risk of incident AD between patients with and without prior influenza vaccination in a large US claims database. Methods: Deidentified claims data spanning September 1, 2009 through August 31, 2019 were used. Eligible patients were free of dementia during the 6-year …look-back period and≥65 years old by the start of follow-up. Propensity-score matching (PSM) was used to create flu-vaccinated and flu-unvaccinated cohorts with similar baseline demographics, medication usage, and comorbidities. Relative risk (RR) and absolute risk reduction (ARR) were estimated to assess the effect of influenza vaccination on AD risk during the 4-year follow-up. Results: From the unmatched sample of eligible patients (n  = 2,356,479), PSM produced a sample of 935,887 flu–vaccinated-unvaccinated matched pairs. The matched sample was 73.7 (SD, 8.7) years of age and 56.9% female, with median follow-up of 46 (IQR, 29–48) months; 5.1% (n  = 47,889) of the flu-vaccinated patients and 8.5% (n  = 79,630) of the flu-unvaccinated patients developed AD during follow-up. The RR was 0.60 (95% CI, 0.59–0.61) and ARR was 0.034 (95% CI, 0.033–0.035), corresponding to a number needed to treat of 29.4. Conclusion: This study demonstrates that influenza vaccination is associated with reduced AD risk in a nationwide sample of US adults aged 65 and older. Show more

Keywords: Alzheimer’s disease, cohort studies, incidence, influenza vaccines, pharmacoepidemiology, retrospective studies, vaccination

DOI: 10.3233/JAD-220361

Citation: Journal of Alzheimer's Disease, vol. 88, no. 3, pp. 1061-1074, 2022