Journal of Alzheimer's Disease - Volume 66, issue 4

Authors: Flanagan, Margaret E. | Cholerton, Brenna | Latimer, Caitlin S. | Hemmy, Laura S. | Edland, Steven D. | Montine, Kathleen S. | White, Lon R. | Montine, Thomas J.

Article Type: Research Article

Abstract: Transactive response binding protein-43 (TDP-43) cytoplasmic neuronal and glial aggregates (pathologic TDP-43) have been described in multiple brain diseases. We describe the associations between neuropathologically confirmed TDP-43 and cognition in two population-based cohorts: the Nun Study (NS) and the Honolulu-Asia Aging Study (HAAS). In the HAAS, there was a significant association between hippocampal sclerosis (HS) and TDP-43 (OR = 11.04, p  < 0.0001, 95% CI 3.57–34.13). In the NS, there were significant associations between TDP-43 and HS (OR = 16.44, p  > 0.001 95%, CI 7.10–38.00) and Alzheimer’s disease (AD) severity (OR = 1.74, p  = 0.009, 95% CI 1.15–2.64). When cognitive scores were added to the model, HS …remained significant but the other variables were not. When HS was removed from the model, the overall model remained significant and the associations between cognitive performance and TDP-43 (OR = 2.11, p  = 0.022, 95% CI 1.11–4.02) were significant. In the NS, there was a significant association between cognitive performance and TDP-43 (OR 1.94 p  = 0.005, 95% CI 1.22–3.09) (HS remained significant, but AD did not). When HS was removed from the model, only CERAD was significant (OR = 2.43 p  < 0.001, 95% CI 1.58–3.74). These results support a consistent association between pathologic TDP-43, HS, and the development of cognitive impairment in two large studies of brain aging, while the relationship between AD pathology and TDP-43 may vary according to cohort-specific features. Show more

Keywords: Alzheimer’s disease, associations, hippocampal sclerosis, TDP43

DOI: 10.3233/JAD-180162

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1549-1558, 2018

Authors: Xie, Yan-Chun | Yao, Zhao-Hui | Yao, Xiao-Li | Pan, Jian-Zhen | Zhang, Shao-Feng | Zhang, Yong | Hu, Ji-Chang

Article Type: Research Article

Abstract: Chronic cerebral hypoperfusion (CCH) affects the aging population and especially patients with neurodegenerative diseases, such as Alzheimer’s disease or Parkinson’s disease. CCH is closely related to the cognitive dysfunction in these diseases. Glucagon-like peptide-2 receptor (GLP2R) mRNA and protein are highly expressed in the gut and in hippocampal neurons. This receptor is involved in the regulation of food intake and the control of energy balance and glucose homeostasis. The present study employed behavioral techniques, electrophysiology, western blotting, immunohistochemistry, quantitative real time polymerase chain reaction (qRT-PCR), and Golgi staining to investigate whether the expression of GLP2R changes after CCH and whether …GLP2R is involved in cognitive impairment caused by CCH. Our findings show that CCH significantly decreased hippocampal GLP2R mRNA and protein levels. GLP2R upregulation could prevent CCH-induced cognitive impairment. It also improved the CCH-induced impairment of long-term potentiation and long-term depression. Additionally, GLP2R modulated after CCH the AKT-mTOR-p70S6K pathway in the hippocampus. Moreover, an upregulation of the GLP2R increased the neurogenesis in the dentate gyrus, neuronal activity, and density of dendritic spines and mushroom spines in hippocampal neurons. Our findings reveal the involvement of GLP2R via a modulation of the AKT-mTOR-p70S6K pathway in the mechanisms underlying CCH-induced impairments of spatial learning and memory. We suggest that the GLP2R and the AKT-mTOR-p70S6K pathway in the hippocampus are promising targets to treat cognition deficits in CCH. Show more

Keywords: Chronic cerebral hypoperfusion, cognitive dysfunction, glucagon-like peptide-2 receptor, neural plasticity

DOI: 10.3233/JAD-180782

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1559-1576, 2018

Authors: Gambogi, Leandro Boson | Guimarães, Henrique Cerqueira | de Souza, Leonardo Cruz | Caramelli, Paulo

Article Type: Research Article

Abstract: Background: The behavioral variant frontotemporal dementia (bvFTD) shares some clinical features with severe mental disorders, such as bipolar affective disorder (BAD), schizophrenia (SCZ), and schizoaffective disorder (SZA), and at least for a small subgroup of patients, these conditions may share similar pathological genetic mutations. Objectives: To investigate the frequency of a past medical history satisfying diagnostic criteria for BAD, SCZ, and SZA in a bvFTD outpatient sample, and to compare the clinical profile of patients with and without a positive history. Methods: Cross-sectional study in which participants were consecutively selected after receiving a diagnosis of probable …bvFTD and had a caregiver interviewed with SCID-I. The sample was categorized into two groups: with (bvFTD+) or without (bvFTD–) prior medical history satisfying diagnostic criteria for BAD/SCZ/SZA. Subjects went through cognitive, functional, and neuropsychiatric evaluations. Results: Overall, 46 bvFTD patients were included; bvFTD+ patients accounted for 36.9% of the sample. The main nosology fulfilling criteria was BAD (76.5%). The groups differed in Neuropsychiatric Inventory scores (p  = 0.01), use of antipsychotics (p  = 0.01), family history of psychosis (p  = 0.01), presence of primitive reflexes (p  = 0.04), Frontal Assessment Battery performance (p  = 0.01), Ekman’s facial emotion recognition test (p  = 0.03), frequency of apathy (p  = 0.03), and stereotyped behavior (p  = 0.01). All these parameters were more frequent/worse in the bvFTD+ group. Conclusions: A prior medical history compatible with BAD/SCZ/SZA was found in more than 1/3 of this sample of bvFTD patients and was associated with subtle distinctive clinical features. Show more

Keywords: Bipolar disorder, dementia, schizoaffective disorder, schizophrenia

DOI: 10.3233/JAD-180528

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1577-1585, 2018

Authors: Boespflug, Erin L. | Simon, Matthew J. | Leonard, Emmalyn | Grafe, Marjorie | Woltjer, Randall | Silbert, Lisa C. | Kaye, Jeffrey A. | Iliff, Jeffrey J.

Article Type: Research Article

Abstract: Waste clearance from the brain parenchyma occurs along perivascular pathways. Enlargement of the perivascular space (ePVS) is associated with pathologic features of Alzheimer’s disease (AD), although the mechanisms and implications of this dilation are unclear. Fluid exchange along the cerebral vasculature is dependent on the perivascular astrocytic water channel aquaporin-4 (AQP4) and loss of perivascular AQP4 localization is found in AD. We directly measured ePVS in postmortem samples of pathologically characterized tissue from participants who were cognitively intact or had AD or mixed dementia (vascular lesions with AD). We found that both AD and mixed dementia groups had significantly increased …ePVS compared to cognitively intact subjects. In addition, we found increased global AQP4 expression of the AD group over both control and mixed dementia groups and a qualitative reduction in perivascular localization of AQP4 in the AD group. Among these cases, increasing ePVS burden was associated with the presence of tau and amyloid-β pathology. These findings are consistent with the existing evidence of ePVS in AD and provide novel information regarding differences in AD and vascular dementia and the potential role of astroglial pathology in ePVS. Show more

Keywords: Amyloid, aquaporin-4, astrocytes, cerebrovascular disease, glymphatic, perivascular space, virchow-robin space

DOI: 10.3233/JAD-180367

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1587-1597, 2018

Authors: Shea, Yat-Fung | Barker, Warren | Greig-Gusto, Maria T. | Loewenstein, David A. | DeKosky, Steven T. | Duara, Ranjan

Article Type: Research Article

Abstract: Background: The impact of amyloid positron emission tomography (Aβ-PET) in a “real-world” memory disorders clinic remains poorly studied. Objective: We studied the impact of Aβ-PET in diagnosis and management in the memory clinic and factors making the most impact in diagnosis and management. Methods: We studied 102 patients who had presented at a memory disorders clinic (the Wien Center for Alzheimer’s Disease and Memory Disorders, Miami Beach, FL) and had a diagnostic work-up for cognitive complaints, including Aβ-PET scans. Results: Following Aβ-PET, changes were made in diagnosis (37.3%), in specific treatments for Alzheimer’s disease …(26.5%) and in psychiatric treatments (25.5%). The agreement between diagnosis pre-Aβ-PET versus post-Aβ-PET diagnosis was only fair, with a Cohen’s kappa of 0.23 (95% CI 0–0.42). Patients with MRI findings suggestive of AD (medial temporal and/or parietal atrophy) were more frequently amyloid positive than amyloid negative (66.2% versus 33.8%, p  = 0.04). Among patients with atypical clinical features for AD, but with MRI findings suggestive of AD, an amyloid negative PET scan had a greater impact than an amyloid positive PET scan on diagnosis (84.2% versus 17.1%, p  < 0.001), management (84.2% versus 40%, p  < 0.01) and discussion of results and advice on lifestyle (73.7% versus 22.9%, p  < 0.001). Conclusions: We conclude that MRI features suggestive of AD predict a positive amyloid PET scan. However, among those with MRI features suggestive of AD but with atypical clinical features of AD, the clinical impact on diagnosis and management is greater for an amyloid negative than an amyloid positive Aβ-PET scans. Show more

Keywords: Alzheimer’s disease, amyloid imaging, diagnosis, management, memory clinic, positron emission tomography

DOI: 10.3233/JAD-180683

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1599-1608, 2018

Authors: Thyrian, Jochen René | Michalowsky, Bernhard | Hertel, Johannes | Wübbeler, Markus | Gräske, Johannes | Holle, Bernhard | Schäfer-Walkmann, Susanne | Wolf-Ostermann, Karin | Hoffmann, Wolfgang

Article Type: Research Article

Abstract: Background: There is no common definition for the Dementia Care Network (DCN). They are heterogeneous and there is no general, longitudinal evidence for the effects of DCN. Objective: We describe changes in utilization of health services by people served by dementia care networks in Germany and factors associated with those changes over time. Methods: Primary data was assessed in 560 people with dementia (PwD) and their caregivers supported by DCN in Germany; sociodemographic and clinical variables, utilization of services; DCN were characterized according to governance. The design: observational study with face-to-face interviews at two time points …over a period of one year. Data was assessed via semi-structured interviews at the participants’ homes. Results: Utilization of health services in this study is consistently higher than reported for the general population and does not significantly change over time. The strongest predictor of utilization of any service after one year was the use of this service at baseline (OR from 3.23 to 44.16). Higher activities of daily functioning increased the chances to utilize specialist physicians (OR = 1.32; 95% -CI: 1.08–1.63) or occupational therapy (OR = 1.24; 95% -CI: 1.02–1.50) significantly. Being a female decreased chances to utilize specialist physicians (OR = 0.57; 95% -CI: 0.37–0.87) and increased the chances to utilize no services (OR = 2.08; 95% -CI: 1.29–3.33). Conclusion: While health care acknowledges the importance and benefits of dementia care networks (i.e., in Germany, the results were considered in new German legislation (SGB XI)), further research is needed to define this kind of service delivery to facilitate comparison as well as promote evidence-based implementation. Show more

Keywords: Care network, dementia, Germany, health services

DOI: 10.3233/JAD-180758

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1609-1617, 2018

Authors: Penninkilampi, Ross | Casey, Anne-Nicole | Singh, Maria Fiatarone | Brodaty, Henry

Article Type: Research Article

Abstract: It has been reported that social engagement may be associated with dementia risk. We searched PubMed, EMBASE, PsycINFO, CINAHL, LILACS, Biomed Central, Scopus, and Web of Science from January 2012 – May 2017, supplemented by extraction from previous reviews. We included cohort and case-control studies examining the association between social engagement or loneliness and dementia risk, pooling data using a random-effects model. Registered: PROSPERO (CRD42017067074). We included 31 cohort and 2 case-control studies comprising 2,370,452 participants. Poor social engagement indices were associated with increased dementia risk, including having a poor social network (RR = 1.59, 95% CI 1.31–1.96; I2  = 0.00%) and poor …social support (RR = 1.28, 95% CI 1.01–1.62; I2  = 55.51%). In long-term studies (≥10 years), good social engagement was modestly protective (RR = 0.88, 95% CI 0.80–0.96; I2  = 0.00%). Loneliness was non-significantly associated with increased risk (RR = 1.38, 95% CI 0.98–1.94; I2  = 45.32). Our findings encourage interventions targeting social isolation and disengagement for dementia prevention. Show more

Keywords: Alzheimer’s disease, dementia, engagement, loneliness, meta-analysis, socialization, social isolation, systematic review

DOI: 10.3233/JAD-180439

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1619-1633, 2018

Authors: Francis, Paul T. | Costello, Helen | Hayes, Gillian M.

Article Type: Research Article

Abstract: Brain banking has a long and distinguished past, contributing greatly to our understanding of human neurological and psychiatric conditions. Brain banks have been operationally diverse, collecting primarily end stage disease, with variable quality clinical data available, yet it is now recognized the most informative brain donations are from those in longitudinally studied cohorts. The Brains for Dementia Research (BDR) cohort and program was for planned brain donation across five UK brain banks and one donation point, with standardized operating procedures, following longitudinal clinical and psychometric assessments for people with no cognitive impairment as well as those with dementia. Lay …representatives with experience of dementia were involved from inception of BDR and 74.5% of all enquiries about participation came through routes that were directly attributable to or influenced by lay representatives. Ten years after inception, this ongoing project has received over 700 brain donations from the recruited cohort of 3,276 potential brain donors. At cohort census for this paper, 72.2% of the living cohort have no cognitive impairment by assessment, whereas only 28.3% of the donated cohort were without cognitive impairment. It is important that brain banks are agile and reflect the changing needs of the research community, given that ‘big data’, readiness cohorts, and GWAS demand large sample numbers of highly characterized individuals to facilitate new approaches and understanding of pathological processes in dementia. Show more

Keywords: Brain donation, cohort, control, dementia, research tissue bank

DOI: 10.3233/JAD-180699

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1635-1644, 2018

Authors: Chen, Ben | Zhong, Xiaomei | Mai, Naikeng | Peng, Qi | Zhang, Min | Chen, Xinru | Wu, Zhangying | Zou, Laiquan | Liang, Wanyuan | Ouyang, Cong | Wu, Yujie | Ning, Yuping

Article Type: Research Article

Abstract: Olfactory identification (OI) deficits have been regarded as an indicator of cognitive impairment in the elderly, but few studies have analyzed the mixed effect of depression on OI. Since depression is common in the elderly and strongly associated with OI, we aimed to explore whether the comorbidity of depression and cognitive impairment may be associated with worse outcomes. In total, 153 elderly patients with depression and 154 normal elderly were recruited. Subjects underwent assessments of depression, cognitive function, and OI. Information on the factors that may affect OI performance was collected (age, sex, smoking history, diabetes, etc.). Correlation analysis showed …that several factors had a significant influence on OI performance in the elderly, including severity of depression, cognitive scores, age, sex, and years of education (p  < 0.05). Among the different cognitive domains, OI was positively associated with global cognition, memory, language, executive function, and attention performance (p  < 0.05). The multiple linear regression analysis indicated that memory scores, age, HAMD scores, and sex were the most relevant factors to OI scores across all elderly participants. The factorial analysis suggested that elderly with comorbidity of depression and cognitive impairment (memory deficits or language deficits) had worse OI impairment, and there was an interactive effect of depression and memory deficits on OI in elderly people. The present study suggested that the coexistence of depressive symptoms and cognitive impairment was associated with worse OI in the elderly. Studies exploring the association between OI and cognitive function should include an assessment of depression and adjust the interactive effects of depression. Show more

Keywords: Cognition, depression, geriatric, neuropsychology, olfactory

DOI: 10.3233/JAD-180760

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1645-1655, 2018

Authors: Syeda, Tauqeerunnisa | Sanchez-Tapia, Mónica | Pinedo-Vargas, Laura | Granados, Omar | Cuervo-Zanatta, Daniel | Rojas-Santiago, Eleazar | Díaz-Cintra, Sof&a | Torres, Nimbe | Perez-Cruz, Claudia

Article Type: Research Article

Abstract: Recent investigations have demonstrated an important role of gut microbiota (GM) in the pathogenesis of Alzheimer’s disease (AD). GM modulates a host’s health and disease by production of several substances, including lipopolysaccharides (LPS) and short-chain fatty acids (SCFAs), among others. Diet can modify the composition and diversity of GM, and ingestion of a healthy diet has been suggested to lower the risk to develop AD. We have previously shown that bioactive food (BF) ingestion can abate neuroinflammation and oxidative stress and improve cognition in obese rats, effects associated with GM composition. Therefore, BF can impact the gut-brain axis and improved …behavior. In this study, we aim to explore if inclusion of BF in the diet may impact central pathological markers of AD by modulation of the GM. Triple transgenic 3xTg-AD (TG) female mice were fed a combination of dried nopal, soy, chia oil, and turmeric for 7 months. We found that BF ingestion improved cognition and reduced Aβ aggregates and tau hyperphosphorylation. In addition, BF decreased MDA levels, astrocyte and microglial activation, PSD-95, synaptophysin, GluR1 and ARC protein levels in TG mice. Furthermore, TG mice fed BF showed increased levels of pGSK-3β . GM analysis revealed that pro-inflammatory bacteria were more abundant in TG mice compared to wild-type, while BF ingestion was able to restore the GM’s composition, LPS, and propionate levels to control values. Therefore, the neuroprotective effects of BF may be mediated, in part, by modulation of GM and the release of neurotoxic substances that alter brain function. Show more

Keywords: Lipopolysaccharide, microbiota, neuroinflammation, pro-inflammatory bacteria, propionate, sirt1

DOI: 10.3233/JAD-180556

Citation: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1657-1682, 2018