Journal of Alzheimer's Disease - Volume 56, issue 1

Authors: Amen, Daniel G. | Darmal, Borhan | Raji, Cyrus A. | Bao, Weining | Jorandby, Lantie | Meysami, Somayeh | Raghavendra, Cauligi S.

Article Type: Research Article

Abstract: Background: Few studies have evaluated the impact of marijuana use on regional cerebral blood flow. Objective: To determine whether perfusion in specific brain regions on functional neuroimaging, including those affected by Alzheimer’s disease pathology, are abnormal in marijuana users compared to controls. Method: Persons with a diagnosis of cannabis use disorder by DSM-IV and DSM-V criteria (n  = 982) were compared to controls (n  = 92) with perfusion neuroimaging with SPECT at rest and at a concentration task. Perfusion estimates were quantified using a standard atlas. Cerebral perfusion differences were calculated using one-way ANOVA. Diagnostic separation was …determined with discriminant analysis of all subjects. Feature selection with a minimum redundancy maximum relevancy (mRMR) identified predictive regions in a subset of marijuana users (n  = 436) with reduced psychiatric co-morbidities. Results: Marijuana users showed lower cerebral perfusion on average (p  < 0.05). Discriminant analysis distinguished marijuana users from controls with correct classification of 96% and leave one out cross-validation of 92%. With concentration SPECT regions, there was correct classification of 95% with a leave-one-out cross validation of 90%. AUC analysis for concentration SPECT regions showed 95% accuracy, 90% sensitivity, and 83% specificity. The mRMR analysis showed right hippocampal hypoperfusion on concentration SPECT imaging was the most predictive in separating marijuana subjects from controls. Conclusion: Multiple brain regions show low perfusion on SPECT in marijuana users. The most predictive region distinguishing marijuana users from healthy controls, the hippocampus, is a key target of Alzheimer’s disease pathology. This study raises the possibility of deleterious brain effects of marijuana use. Show more

Keywords: Hippocampus, imaging, marijuana, SPECT

DOI: 10.3233/JAD-160833

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 261-273, 2017

Authors: Last, Nicole | Tufts, Emily | Auger, Leslie E.

Article Type: Research Article

Abstract: The present systematic review is based on the premise that a variety of neurodegenerative diseases are accompanied by grey matter atrophy in the brain and meditation may impact this. Given that age is a major risk factor for many of these progressive and neurodegenerative diseases and that the percentage of the population over the age of 65 is quickly increasing, there is an obvious need for prompt treatment and prevention advances in research. As there is currently no cure for Alzheimer’s disease and other neurodegenerative diseases, many are seeking non-pharmacological treatment options in attempts to offset the disease-related cognitive and functional declines. …On the basis of a growing body of research suggesting that meditation is effective in increasing grey matter volume in healthy participants, this paper systematically reviewed the literature regarding the effects of meditation on restoring grey matter volume in healthy individuals and those affected by neurodegeneration. This review searched PubMed, CINAHL, and APA PsycNET to identify original studies that included MRI imaging to measure grey matter volume in meditators and post-mindfulness-based intervention participants compared to controls. Thirteen studies were considered eligible for review and involved a wide variety of meditation techniques and included participants with and without cognitive impairment. All studies reported significant increases in grey matter volume in the meditators/intervention group, albeit in assorted regions of the brain. Limited research exists on the mechanisms through which meditation affects disease-related neurodegeneration, but preliminary evidence suggests that it may offset grey matter atrophy. Show more

Keywords: Alzheimer’s disease, dementia, grey matter, meditation, mindfulness, neurodegenerative diseases, neuroprotection, Parkinson’s disease

DOI: 10.3233/JAD-160899

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 275-286, 2017

Authors: Glozman, Tanya | Solomon, Justin | Pestilli, Franco | Guibas, Leonidas | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: We describe a fully automatic framework for classification of two types of dementia based on the differences in the shape of brain structures. We consider Alzheimer’s disease (AD), mild cognitive impairment of individuals who converted to AD within 18 months (MCIc), and normal controls (NC). Our approach uses statistical learning and a feature space consisting of projection-based shape descriptors, allowing for canonical representation of brain regions. Our framework automatically identifies the structures most affected by the disease. We evaluate our results by comparing to other methods using a standardized data set of 375 adults available from the Alzheimer’s Disease Neuroimaging …Initiative (ADNI). Our framework is sensitive to identifying the onset of Alzheimer’s disease, achieving up to 88.13% accuracy in classifying MCIc versus NC, outperforming previous methods. Show more

Keywords: Alzheimer’s disease, classification, mild cognitive impairment, shape descriptors, support vector machine

DOI: 10.3233/JAD-160900

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 287-295, 2017

Authors: Fenesi, Barbara | Fang, Hanna | Kovacevic, Ana | Oremus, Mark | Raina, Parminder | Heisz, Jennifer J.

Article Type: Research Article

Abstract: Genetics and lifestyle independently determine dementia risk, but the interaction is unclear. We assessed the interactive relationship of apolipoprotein E (APOE) genotype and physical exercise on dementia risk over a 5-year period in 1,646 older adults from the Canadian Study of Health and Aging who were dementia-free at baseline. Physical exercise moderated the relationship between genotype and dementia (p  < 0.01). Specifically, for APOE ɛ4 non-carriers, the odds of developing dementia were higher in non-exercisers than exercisers (OR = 1.98, 95% CI = 1.44, 2.71, p  < 0.001), whereas, for APOE ɛ4 carriers, the odds of developing dementia were not significantly different between non-exercisers and exercisers …(OR = 0.71, 95% CI = 0.46, 1.31, p  = 0.34). Given that most individuals are not at genetic risk, physical exercise may be an effective strategy for preventing dementia. Show more

Keywords: Alzheimer’s disease, apolipoprotein E4, dementia, exercise, physical activity, prevention

DOI: 10.3233/JAD-160424

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 297-303, 2017

Authors: Ho, Lap | Legere, Marc | Li, Tongbin | Levine, Samara | Hao, Ke | Valcarcel, Breanna | Pasinetti, Giulio M.

Article Type: Research Article

Abstract: Autonomic dysfunction is very common in patients with dementia, and its presence might also help in differential diagnosis among dementia subtypes. Various central nervous system structures affected in Alzheimer’s disease (AD) are also implicated in the central autonomic nervous system (ANS) regulation. For example, deficits in central cholinergic function in AD could likely lead to autonomic dysfunction. We recently developed a simple, readily applicable evaluation for monitoring ANS disturbances in response to traumatic brain injury (TBI). This ability to monitor TBI allows for the possible detection and targeted prevention of long-term, detrimental brain responses caused by TBI that lead to …neurodegenerative diseases such as AD. We randomly selected and extracted de-identified medical record information from subjects who have been assessed using the ANS evaluation protocol. Using machine learning strategies in the analysis of information from individual as well as a combination of ANS evaluation protocol components, we identified a novel prediction model that is effective in correctly segregating between cases with or without a documented history of TBI exposure. Results from our study support the hypothesis that trauma-induced ANS dysfunctions may contribute to clinical TBI features. Because autonomic dysfunction is very common in AD patients it is possible that TBI may also contribute to AD and/or other forms of dementia through these novel mechanisms. This study provides a novel prediction model to physiologically assess the likelihood of subjects with prior history of TBI to develop clinical TBI complications, such as AD. Show more

Keywords: Alzheimer’s disease, autonomic nervous system, biomarker, neurodegenerative disorders, risk factor, traumatic brain injury

DOI: 10.3233/JAD-160948

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 305-315, 2017

Authors: Jurjević, Ivana | Miyajima, Masakazu | Ogino, Ikuko | Akiba, Chihiro | Nakajima, Madoka | Kondo, Akihide | Kikkawa, Mika | Kanai, Mitsuyasu | Hattori, Nobutaka | Arai, Hajime

Article Type: Research Article

Abstract: Background: Patients presenting with the classical idiopathic normal pressure hydrocephalus (iNPH) triad often show additional parkinsonian spectrum signs. Accurate differential diagnosis strongly influences the long-term outcome of cerebrospinal fluid (CSF) shunting. Objective: The aim of this study was to find potential CSF microRNA (miRNA) biomarkers for NPH mimics with parkinsonian syndromes that can reliably distinguish them from iNPH patients. Methods: Two cohorts of 81 patients (cohort 1, n  = 55; cohort 2, n  = 26) with possible iNPH who were treated in two centers between January 2011 and May 2014 were studied. In both cohorts, CSF samples …were obtained from patients clinically diagnosed with iNPH (n  = 21 and n  = 10, respectively), possible iNPH with parkinsonian spectrum (PS) (n  = 18, n  = 10, respectively), possible iNPH with Alzheimer’s disease (AD) (n  = 16), and non-affected elderly individuals (NC) (n  = 6). A three-step qRT-PCR analysis of the CSF samples was performed to detect miRNAs that were differentially expressed in the groups. Results: The expression of hsa-miR-4274 in CSF was decreased in both cohorts of PS group patients (cohort 1: p  < 0.0001, cohort 2: p  < 0.0001), and was able to distinguish PS from iNPH with high accuracy (area under the curve = 0.908). The CSF concentration of hsa-miR-4274 also correlated with the specific binding ratio of ioflupane (123 I) dopamine transporter scan (r  = –0.494, p  = 0.044). By contrast, the level of hsa-miR-4274 was significantly increased in the PS group after CSF diversion. Conclusion: Levels of CSF hsa-miR-4274 can differentiate PS from patients with iNPH, AD, and NC. This may be clinically useful for diagnostic purposes and predicting shunt treatment responses. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, idiopathic normal pressure hydrocephalus, microRNAs, parkinsonian syndrome

DOI: 10.3233/JAD-160848

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 317-325, 2017

Authors: Li, Xiaozhen | Westman, Eric | Thordardottir, Steinunn | Ståhlbom, Anne Kinhult | Almkvist, Ove | Blennow, Kaj | Wahlund, Lars-Olof | Graff, Caroline

Article Type: Research Article

Abstract: Familial Alzheimer’s disease (FAD) mutations have very high penetrance but age at onset and rate of disease progression differ. Neuroimaging and cerebrospinal fluid (CSF) examinations in mutation carriers (MCs) may provide an opportunity to identify early biomarkers that can be used to track disease progression from presymptomatic to the dementia stages of disease. The default mode network (DMN) is a resting state neuronal network composed of regions known to associate with amyloid deposition in AD. We hypothesized that functional connectivity in the DMN might change at pre-clinical stages in FAD MCs and correlate with changes in CSF biomarkers as a …consequence of AD brain pathology. To test the hypothesis, we compared the functional connectivity in DMN between pre-MCs/MCs and non-carriers (NCs). No significant differences between pre-MCs and NCs were observed. When comparing all MCs with NCs, significant decreased functional connectivity in the right inferior parietal lobule, right precuneus, and left posterior cingulate cortex were found. We also found statistically significant correlations between CSF amyloid-β 42 and tau protein levels and average Z-score, a resting-state functional MRI measurement reflecting the degree of the correlation between a given voxel’s time courses and the time courses corresponding to DMN, from the region with statistical difference. The observed disruption of DMN and pathological levels of AD CSF-biomarkers in FAD MCs are similar to the changes described in sporadic AD, which give further support that amyloid and tau pathology impairs neuronal and synaptic function. Show more

Keywords: Cerebrospinal fluid biomarkers, default mode network, familial Alzheimer’s disease, mutation carrier, resting-state functional MRI, synaptic function

DOI: 10.3233/JAD-160730

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 327-334, 2017

Authors: Shukla, Varsha | Seo, Jinsoo | Binukumar, B.K. | Amin, Niranjana D. | Reddy, Preethi | Grant, Philip | Kuntz, Susan | Kesavapany, Sashi | Steiner, Joseph | Mishra, Santosh K. | Tsai, Li-Huei | Pant, Harish C.

Article Type: Research Article

Abstract: It has been reported that cyclin-dependent kinase 5 (cdk5), a critical neuronal kinase, is hyperactivated in Alzheimer’s disease (AD) and may be, in part, responsible for the hallmark pathology of amyloid plaques and neurofibrillary tangles (NFTs). It has been proposed by several laboratories that hyperactive cdk5 results from the overexpression of p25 (a truncated fragment of p35, the normal cdk5 regulator), which, when complexed to cdk5, induces hyperactivity, hyperphosphorylated tau/NFTs, amyloid-β plaques, and neuronal death. It has previously been shown that intraperitoneal (i.p.) injections of a modified truncated 24-aa peptide (TFP5), derived from the cdk5 activator p35, penetrated the blood-brain …barrier and significantly rescued AD-like pathology in 5XFAD model mice. The principal pathology in the 5XFAD mutant, however, is extensive amyloid plaques; hence, as a proof of concept, we believe it is essential to demonstrate the peptide’s efficacy in a mouse model expressing high levels of p25, such as the inducible CK-p25Tg model mouse that overexpresses p25 in CamKII positive neurons. Using a modified TFP5 treatment, here we show that peptide i.p. injections in these mice decrease cdk5 hyperactivity, tau, neurofilament-M/H hyperphosphorylation, and restore synaptic function and behavior (i.e., spatial working memory, motor deficit using Rota-rod). It is noteworthy that TFP5 does not inhibit endogenous cdk5/p35 activity, nor other cdks in vivo suggesting it might have no toxic side effects, and may serve as an excellent therapeutic candidate for neurodegenerative disorders expressing abnormally high brain levels of p25 and hyperactive cdk5. Show more

Keywords: Alzheimer’s disease, cyclin-dependent kinase 5, hyperphosphorylation, synaptic function, TFP5

DOI: 10.3233/JAD-160916

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 335-349, 2017

Authors: Law, Lena L. | Schultz, Stephanie A. | Boots, Elizabeth A. | Einerson, Jean A. | Dougherty, Ryan J. | Oh, Jennifer M. | Korcarz, Claudia E. | Edwards, Dorothy F. | Koscik, Rebecca L. | Dowling, N. Maritza | Gallagher, Catherine L. | Bendlin, Barbara B. | Carlsson, Cynthia M. | Asthana, Sanjay | Hermann, Bruce P. | Sager, Mark A. | Johnson, Sterling C. | Cook, Dane B. | Stein, James H. | Okonkwo, Ozioma C.

Article Type: Research Article

Abstract: The objective of this study was to examine the association of chronotropic response (CR) and heart rate (HR) recovery— two indices of cardiovascular function within the context of a graded exercise test— with cognitive performance in a cognitively healthy, late-middle-aged cohort at risk for Alzheimer’s disease (AD). Ninety participants (age = 63.52±5.86 years; 65.6% female) from the Wisconsin Registry for Alzheimer’s Prevention participated in this study. They underwent graded exercise testing and a comprehensive neuropsychological assessment that assessed the following four cognitive domains: Immediate Memory, Verbal & Learning Memory, Working Memory, and Speed & Flexibility. Regression analyses, adjusted for age, sex, and …education, were used to examine the association between CR, HR recovery, and cognition. We found significant associations between CR and cognitive performance in the domains of Immediate Memory, Verbal Learning & Memory, and Speed & Flexibility. In contrast, HR recovery was not significantly associated with cognitive function. The association between CR and cognition persisted even after controlling for HR recovery. Together, these findings indicatethat, in a cognitively normal, late-middle-aged cohort, CR is a stronger correlate of cognitive performance than HR recovery. Overall, this study reinforces the idea that cardiovascular health plays an important role in cognitive function, specifically in a cohort at risk for AD; and that interventions that promote vascular health may be a viable pathway to preventing or slowing cognitive decline due to AD. Show more

Keywords: Alzheimer disease, cardiopulmonary exercise test, cardiovascular health, cognition, heart rate

DOI: 10.3233/JAD-160642

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 351-359, 2017

Authors: Shen, Liming | Liao, Liping | Chen, Cheng | Guo, Yi | Song, Dalin | Wang, Yong | Chen, Youjiao | Zhang, Kaoyuan | Ying, Ming | Li, Shuiming | Liu, Qiong | Ni, Jiazuan

Article Type: Research Article

Abstract: Alzheimer’ disease (AD) is the most common form of dementia affecting up to 6% of the population over the age of 65. In order to discover differentially expressed proteins that might serve as potential biomarkers, the serums from AD patients and healthy controls were compared and analyzed using the proteomics approach of isobaric tagging for relative and absolute quantitation (iTRAQ). For the first time, AD biomarkers in serums are investigated in the Han Chinese population using iTRAQ labeled proteomics strategy. Twenty-two differentially expressed proteins were identified and out of which nine proteins were further validated with more sample test. Another …three proteins that have been reported in the literature to be potentially associated with AD were also investigated for alteration in expression level. Functions of those proteins were mainly related to the following processes: amyloid-β (Aβ) metabolism, cholesterol transport, complement and coagulation cascades, immune response, inflammation, hemostasis, hyaluronan metabolism, and oxidative stress. These results support current views on the molecular mechanism of AD. For the first time, differential expression of zinc-alpha-2-glycoprotein (AZGP1), fibulin-1 (FBLN1), platelet basic protein (PPBP), thrombospondin-1 (THBS1), S100 calcium-binding protein A8 (S100A8), and S100 calcium-binding protein A9 (S100A9) were detected in the serums of AD patients compared with healthy controls. These proteins might play a role in AD pathophysiology and serve as potential biomarkers for AD diagnosis. Specifically, our results strengthened the crucial role of Aβ metabolism and blood coagulation in AD pathogenesis and proteins related to these two processes may be used as peripheral blood biomarkers for AD. Show more

Keywords: Alzheimer’ disease, biomarker, iTRAQ, proteomics, serum

DOI: 10.3233/JAD-160913

Citation: Journal of Alzheimer's Disease, vol. 56, no. 1, pp. 361-378, 2017