Journal of Alzheimer's Disease - Volume 49, issue 4

Authors: Weekman, Erica M. | Wilcock, Donna M.

Article Type: Research Article

Abstract: The neurovascular unit, which consists of astrocytic end-feet, neurons, pericytes, and endothelial cells, plays a key role in maintaining brain homeostasis by forming the blood-brain barrier and carefully controlling local cerebral blood flow. When the blood-brain barrier is disrupted, blood components can leak into the brain, damage the surrounding tissue and lead to cognitive impairment. This disruption in the blood-brain barrier and subsequent impairment in cognition are common after stroke and during cerebral amyloid angiopathy and Alzheimer’s disease. Matrix metalloproteinases are proteases that degrade the extracellular matrix as well as tight junctions between endothelial cells and have been implicated in …blood-brain barrier breakdown in neurodegenerative diseases. This review will focus on the roles of MMP2 and MMP9 in dementia, primarily post-stroke events that lead to dementia, cerebral amyloid angiopathy, and Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease,, cerebral amyloid angiopathy, hemorrhagic transformation, matrix metalloproteinases, stroke, vascular cognitive impairment

DOI: 10.3233/JAD-150759

Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 893-903, 2016

Authors: Rüb, Udo | Stratmann, Katharina | Heinsen, Helmut | Del Turco, Domenico | Ghebremedhin, Estifanos | Seidel, Kay | den Dunnen, Wilfred | Korf, Horst-Werner

Article Type: Review Article

Abstract: In spite of considerable progress in neuropathological research on Alzheimer’s disease (AD), knowledge regarding the exact pathoanatomical distribution of the tau cytoskeletal pathology in the thalamus of AD patients in the advanced Braak and Braak AD stages V or VI of the cortical cytoskeletal pathology is still fragmentary. Investigation of serial 100 μm-thick brain tissue sections through the thalamus of clinically diagnosed AD patients with Braak and Braak AD stage V or VI cytoskeletal pathologies immunostained with the anti-tau AT8 antibody, along with the affection of the extraterritorial reticular nucleus of the thalamus, reveals a consistent and severe tau immunoreactive …cytoskeletal pathology in the limbic nuclei of the thalamus (e.g., paraventricular, anterodorsal and laterodorsal nuclei, limitans-suprageniculate complex). The thalamic nuclei integrated into the associative networks of the human brain (e.g., ventral anterior and mediodorsal nuclei) are only mildly affected, while its motor precerebellar (ventral lateral nucleus) and sensory nuclei (e.g., lateral and medial geniculate bodies, ventral posterior medial and lateral nuclei, parvocellular part of the ventral posterior medial nucleus) are more or less spared. The highly stereotypical and characteristic thalamic distribution pattern of the AD-related tau cytoskeletal pathology represents an anatomical mirror of the hierarchical topographic distribution of the cytoskeletal pathology in the interconnected regions of the cerebral cortex of AD patients. These pathoanatomical parallels support the pathophysiological concept of a transneuronal spread of the disease process of AD along anatomical pathways. The AD-related tau cytoskeletal pathology in the thalamus most likely contributes substantially to the neuropsychiatric disease symptoms (e.g., dementia), attention deficits, oculomotor dysfunctions, altered non-discriminative aspects of pain experience of AD patients, and the disruption of their waking and sleeping patterns. Show more

Keywords: Alzheimer’s disease, cytoskeletal pathology, pathoanatomy, tau, thalamus

DOI: 10.3233/JAD-150639

Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 905-915, 2016

Authors: Tang, Hui-Dong | Zhou, Yi | Gao, Xiang | Liang, Liang | Hou, Miao-Miao | Qiao, Yuan | Ma, Jian-Fang | Chen, Sheng-Di

Article Type: Research Article

Abstract: Background: China is facing a continuously rising numbers of people with cognitive impairment (CI). Objectives: To investigate the prevalence and risk factors of CI among elderly people living in rural and urban communities. Methods: We conducted a face-to-face survey of CI on 7,900 individuals aged 50 years or older meeting inclusion criteria in the Malu (rural community, n  = 4,429) and Wuliqiao (urban community, n  = 3,471) communities of Shanghai. The Mini-Mental State Examination (MMSE) was used to evaluate the cognitive function. Information on demographic features and potential risk factors for CI was collected during the interview. Multivariate …logistic regression was performed to identify risk factors associated with CI. Results: Based on the education modified MMSE score, we identified 329 CI cases in rural community and 227 in urban community. The prevalence of CI was 7.43% in rural population and 6.54% in urban population (p  = 0.13). In the urban population, risk of having CI was associated with age (OR = 1.04; 95% CI: 1.01–1.08), lack of physical activities (OR = 2.25; 95% CI: 1.11–4.57), presence of diabetes mellitus (OR = 1.79; 95% CI: 1.04–3.07), and having three or more children (OR = 2.39; 95% CI: 1.27–4.50). In contrast, factors associated with rural populations included female gender (OR = 2.03; 95% CI: 1.08–3.82), age (OR = 1.06; 95% CI: 1.03–1.08), exposure to pesticides (OR = 4.68; 95% CI: 1.27–17.21), history of encephalitis or meningitis (OR = 6.02; 95% CI: 1.92–18.85) and head trauma (OR = 1.89; 95% CI: 1.10–3.24). Conclusions: Urban rural and populations showed different risk factors for CI, suggesting that different preventive strategies in these areas should be performed. Show more

Keywords: Cognitive impairment, prevalence, risk factors, rural population, urban population

DOI: 10.3233/JAD-150748

Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 917-925, 2016

Authors: Rosenberger, Andrea F.N. | Hilhorst, Riet | Coart, Elisabeth | García Barrado, Leandro | Naji, Faris | Rozemuller, Annemieke J.M. | van der Flier, Wiesje M. | Scheltens, Philip | Hoozemans, Jeroen J.M. | van der Vies, Saskia M.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is characterized by a long pre-clinical phase (20–30 years), during which significant brain pathology manifests itself. Disease mechanisms associated with pathological hallmarks remain elusive. Most processes associated with AD pathogenesis, such as inflammation, synaptic dysfunction, and hyper-phosphorylation of tau are dependent on protein kinase activity. The objective of this study was to determine the involvement of protein kinases in AD pathogenesis. Protein kinase activity was determined in postmortem hippocampal brain tissue of 60 patients at various stages of AD and 40 non-demented controls (Braak stages 0-VI) using a peptide-based microarray platform. We observed an overall decrease of …protein kinase activity that correlated with disease progression. The phosphorylation of 96.7% of the serine/threonine peptides and 37.5% of the tyrosine peptides on the microarray decreased significantly with increased Braak stage (p -value <0.01). Decreased activity was evident at pre-clinical stages of AD pathology (Braak I-II). Increased phosphorylation was not observed for any peptide. STRING analysis in combination with pathway analysis and identification of kinases responsible for peptide phosphorylation showed the interactions between well-known proteins in AD pathology, including the Ephrin-receptor A1 (EphA1), a risk gene for AD, and sarcoma tyrosine kinase (Src), which is involved in memory formation. Additionally, kinases that have not previously been associated with AD were identified, e.g., protein tyrosine kinase 6 (PTK6/BRK), feline sarcoma oncogene kinase (FES), and fyn-associated tyrosine kinase (FRK). The identified protein kinases are new biomarkers and potential drug targets for early (pre-clinical) intervention. Show more

Keywords: Alzheimer’s disease, peptide microarray analysis, phospho-peptides, postmortem changes, protein kinase activity, signaling pathways

DOI: 10.3233/JAD-150429

Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 927-943, 2016

Authors: Lange, Catharina | Suppa, Per | Frings, Lars | Brenner, Winfried | Spies, Lothar | Buchert, Ralph | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Positron emission tomography (PET) with the glucose analog F-18-fluorodeoxyglucose (FDG) is widely used in the diagnosis of neurodegenerative diseases. Guidelines recommend voxel-based statistical testing to support visual evaluation of the PET images. However, the performance of voxel-based testing strongly depends on each single preprocessing step involved. Objective: To optimize the processing pipeline of voxel-based testing for the prognosis of dementia in subjects with amnestic mild cognitive impairment (MCI). Methods: The study included 108 ADNI MCI subjects grouped as ‘stable MCI’ (n  = 77) or ‘MCI-to-AD converter’ according to their diagnostic trajectory over 3 years. Thirty-two ADNI …normals served as controls. Voxel-based testing was performed with the statistical parametric mapping software (SPM8) starting with default settings. The following modifications were added step-by-step: (i) motion correction, (ii) custom-made FDG template, (iii) different reference regions for intensity scaling, and (iv) smoothing was varied between 8 and 18 mm. The t-sum score for hypometabolism within a predefined AD mask was compared between the different settings using receiver operating characteristic (ROC) analysis with respect to differentiation between ‘stable MCI’ and ‘MCI-to-AD converter’. The area (AUC) under the ROC curve was used as performance measure. Results: The default setting provided an AUC of 0.728. The modifications of the processing pipeline improved the AUC up to 0.832 (p  = 0.046). Improvement of the AUC was confirmed in an independent validation sample of 241 ADNI MCI subjects (p  = 0.048). Conclusion: The prognostic value of voxel-based single subject analysis of brain FDG PET in MCI subjects can be improved considerably by optimizing the processing pipeline. Show more

Keywords: Alzheimer’s Disease Neuroimaging Initiative, F-18-fluorodeoxyglucose, intensity scaling, mild cognitive impairment, positron emission tomography, processing pipeline, prognosis, single subject analysis, statistical parametric mapping, template

DOI: 10.3233/JAD-150814

Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 945-959, 2016

Authors: Xie, Haiqun | Zhang, Chengguo | Wang, Yukai | Huang, Shuyun | Cui, Wei | Yang, Wenbin | Koski, Lisa | Xu, Xiping | Li, Youbao | Zheng, Meili | He, Mingli | Fu, Jia | Shi, Xiuli | Wang, Kai | Tang, Genfu | Wang, Binyan | Huo, Yong

Article Type: Research Article

Abstract: Background: Dementia is increasingly prevalent due to rapid aging of the population, but under-recognized among people with low education levels. This is partly due to a lack of appropriate and precise normative data, which underestimates cognitive aging in the use of screening tools for dementia. Objective: We aimed to improve the precision of screening for cognitive impairment, by characterizing the patterns of cognitive aging and derived normative data of the Mini-Mental State Examination (MMSE) for illiterate and low-educated populations. Methods: This community-based study included data from 2,280 individuals aged 40 years or older from two rural …areas. Multiple linear modeling examined the effect of aging on cognition reflected by the MMSE, stratified by education level and gender. Threshold effect of age on cognition was performed using a smoothing function. Results: The majority of participants (60.4%) were illiterate or had attended only primary school (24.6%). The effect of aging on cognition varied by gender and education. Primary-school educated females and males remained cognitively stable up to 62 and 71 years of age, respectively, with MMSE score declining 0.4 and 0.8 points/year in females and males thereafter. Illiterates females scored 2.3 points lower than illiterate males, and scores for both declined 0.2 points/year. According to these results, normative data stratified by age, education and gender was generated. Conclusion: This study suggests gender and educational differences exist in cognitive aging among adults with limited or no formal education. To improve screening precision for cognitive impairment with the use of MMSE in low-educated population, age, gender, and education level should be considered. Show more

Keywords: Aging, cognitive impairment, gender, MMSE, norms

DOI: 10.3233/JAD-143066

Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 961-969, 2016

Authors: Liu, Guosong | Weinger, Jason G. | Lu, Zhong-Lin | Xue, Feng | Sadeghpour, Safa

Article Type: Research Article

Abstract: Background: Cognitive impairment is a major problem in elderly, affecting quality of life. Pre-clinical studies show that MMFS-01, a synapse density enhancer, is effective at reversing cognitive decline in aging rodents. Objective: Since brain atrophy during aging is strongly associated with both cognitive decline and sleep disorder, we evaluated the efficacy of MMFS-01 in its ability to reverse cognitive impairment and improve sleep. Methods: We conducted a randomized, double-blind, placebo-controlled, parallel-designed trial in older adult subjects (age 50–70) with cognitive impairment. Subjects were treated with MMFS-01 (n  = 23) or placebo (n  = 21) for 12 weeks and …cognitive ability, sleep quality, and emotion were evaluated. Overall cognitive ability was determined by a composite score of tests in four major cognitive domains. Results: With MMFS-01 treatment, overall cognitive ability improved significantly relative to placebo (p  = 0.003; Cohen’s d  = 0.91). Cognitive fluctuation was also reduced. The study population had more severe executive function deficits than age-matched controls from normative data and MMFS-01 treatment nearly restored their impaired executive function, demonstrating that MMFS-01 may be clinically significant. Due to the strong placebo effects on sleep and anxiety, the effects of MMFS-01 on sleep and anxiety could not be determined. Conclusions: The current study demonstrates the potential of MMFS-01 for treating cognitive impairment in older adults. Show more

Keywords: Alzheimer’s disease, cognitive impairment, cognition, composite score, L-threonate, magnesium, mild cognitive impairment, randomized clinical trial, sleep disorder, synaptic density

DOI: 10.3233/JAD-150538

Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 971-990, 2016

Authors: Kim, Sungeun | Nho, Kwangsik | Ramanan, Vijay K. | Lai, Dongbing | Foroud, Tatiana M. | Lane, Katie | Murrell, Jill R. | Gao, Sujuan | Hall, Kathleen S. | Unverzagt, Frederick W. | Baiyewu, Olusegun | Ogunniyi, Adesola | Gureje, Oye | Kling, Mitchel A. | Doraiswamy, P. Murali | Kaddurah-Daouk, Rima | Hendrie, Hugh C. | Saykin, Andrew J.

Article Type: Research Article

Abstract: Plasma homocysteine, a metabolite involved in key cellular methylation processes seems to be implicated in cognitive functions and cardiovascular health with its high levels representing a potential modifiable risk factor for Alzheimer’s disease (AD) and other dementias. A better understanding of the genetic factors regulating homocysteine levels, particularly in non-white populations, may help in risk stratification analyses of existing clinical trials and may point to novel targets for homocysteine-lowering therapy. To identify genetic influences on plasma homocysteine levels in individuals with African ancestry, we performed a targeted gene and pathway-based analysis using a priori biological information and then to …identify new association performed a genome-wide association study. All analyses used combined data from the African American and Yoruba cohorts from the Indianapolis-Ibadan Dementia Project. Targeted analyses demonstrated significant associations of homocysteine and variants within the CBS (Cystathionine beta-Synthase) gene. We identified a novel genome-wide significant association of the AD risk gene CD2AP (CD2-associated protein) with plasma homocysteine levels in both cohorts. Minor allele (T) carriers of identified CD2AP variant (rs6940729) exhibited decreased homocysteine level. Pathway enrichment analysis identified several interesting pathways including the GABA receptor activation pathway. This is noteworthy given the known antagonistic effect of homocysteine on GABA receptors. These findings identify several new targets warranting further investigation in relation to the role of homocysteine in neurodegeneration. Show more

Keywords: African Continental Ancestry Group, CD2-associated protein, cystathionine beta-synthase, genome-wide association study, homocysteine, metabolic networks and pathways, metabolomics

DOI: 10.3233/JAD-150651

Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 991-1003, 2016

Authors: Lee, Geon-Hwi | Jang, Byungki | Choi, Hong-Seok | Kim, Hee-Jun | Park, Jeong-Ho | Jeon, Yong-Chul | Carp, Richard I. | Kim, Yong-Sun | Choi, Eun-Kyoung

Article Type: Research Article

Abstract: Prion infection leads to neuronal cell death, glial cell activation, and the accumulation of misfolded prion proteins. However, the altered cellular environments in animals with prion diseases are poorly understood. In the central nervous system, cells connect the cytoplasm of adjacent cells via connexin (Cx)-assembled gap junction channels to allow the direct exchange of small molecules, including ions, neurotransmitters, and signaling molecules, which regulate the activities of the connected cells. Here, we investigate the role of Cx43 in the pathogenesis of prion diseases. Upregulated Cx43 expression, which was dependent on c-Jun N-Terminal Kinase (JNK)/c-Jun signaling cascades, was found in prion-affected …brain tissues and hippocampal neuronal cells. Scrapie infection-induced Cx43 formed aggregated plaques within the cytoplasmic compartments at the cell-cell interfaces. The ethidium bromide (EtBr) uptake assay and scrape-loading dye transfer assay demonstrated that increased Cx43 has functional consequences for the activity of Cx43 hemichannels. Interestingly, blockade of PrPSc accumulation reduced Cx43 expression through the inhibition of JNK signaling, indicating that PrPSc accumulation may be directly involved in JNK activation-mediated Cx43 upregulation. Overall, our findings describe a scrapie infection-mediated novel regulatory signaling pathway of Cx43 expression and may suggest a role for Cx43 in the pathogenesis of prion diseases. Show more

Keywords: Connexin 43, gap junction, JNK, prion protein, scrapie

DOI: 10.3233/JAD-150283

Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 1005-1019, 2016

Authors: Arroyo-Anlló, Eva Mª | Bouston, Adèle Turpin | Fargeau, Marie-Noëlle | Orgaz Baz, Begõna | Gil, Roger

Article Type: Research Article

Abstract: Self-consciousness (SC) is multifaceted and considered to be the consciousness of one’s own mental states. The medial prefrontal cortex may play a critical role in SC. The main aim of this paper was to examine SC in patients with behavioral variant frontotemporal dementia, who are characterized more by changes in personal, social, and emotional conduct and loss of insight than by cognitive disturbances. Control and patient groups of 21 subjects each, matched by age, educational level, gender, and nationality were assessed using a SC questionnaire. It measures several aspects: Personal identity, Anosognosia, Affective state, Body representation, Prospective memory, Introspection, and …Moral judgments. The most disturbed ones in patients were Anosognosia, Affective state, and Moral judgments, and the least disturbed aspects were awareness of identity and of body representation. No significant correlations were found between the SC score and any clinical or demographical characteristics. The core deficiency of SC in patients was related to behavioral SC aspects, which are more dependent on orbito-frontal functioning. Show more

Keywords: Awareness, behavioral, executive functions, prefrontal

DOI: 10.3233/JAD-150821

Citation: Journal of Alzheimer's Disease, vol. 49, no. 4, pp. 1021-1029, 2016