Journal of Alzheimer's Disease - Volume 52, issue 2

Authors: Clements-Cortes, Amy | Ahonen, Heidi | Evans, Michael | Freedman, Morris | Bartel, Lee

Article Type: Research Article

Abstract: This study assessed the effect of stimulating the somatosensory system of Alzheimer’s disease (AD) patients at three stages of their illness with 40 Hz sound. In this AB cross-over study design, 18 participants (6 mild, 6 moderate, 6 severe) each participated in 13 sessions: one intake and 12 treatment. Treatment A consisted of 40 Hz sound stimulation and Treatment B consisted of visual stimulation using DVDs, each provided twice a week over 6 weeks for a total of 6 times per treatment. Outcome measures included: St. Louis University Mental Status Test (SLUMS), Observed Emotion Rating Scale, and behavioral observation by the researcher. …Data were submitted to regression analysis for the series of 6 SLUMS scores in treatment A and 6 scores in B with comparison by group. The slopes for the full sample and subgroups in the 40 Hz treatment were all significant beyond alpha = 0.05, while those for the DVD were not. A thematic analysis of qualitative observations supported the statistical findings. 40 Hz treatment appeared to have the strongest impact on persons with mild and moderate AD. Results are promising in terms of a potential new treatment for persons with AD, and further research is needed. Show more

Keywords: Alzheimer’s disease, auditory stimulation, cognition, vibration

DOI: 10.3233/JAD-160081

Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 651-660, 2016

Authors: Gardener, Samantha L. | Sohrabi, Hamid R. | Shen, Kai-kai | Rainey-Smith, Stephanie R. | Weinborn, Michael | Bates, Kristyn A. | Shah, Tejal | Foster, Jonathan K. | Lenzo, Nat | Salvado, Olivier | Laske, Christoph | Laws, Simon M. | Taddei, Kevin | Verdile, Giuseppe | Martins, Ralph N.

Article Type: Research Article

Abstract: Increasing evidence suggests that Alzheimer’s disease (AD) sufferers show region-specific reductions in cerebral glucose metabolism, as measured by [18 F]-fluoro-2-deoxyglucose positron emission tomography (18 F-FDG PET). We investigated preclinical disease stage by cross-sectionally examining the association between global cognition, verbal and visual memory, and 18 F-FDG PET standardized uptake value ratio (SUVR) in 43 healthy control individuals, subsequently focusing on differences between subjective memory complainers and non-memory complainers. The 18 F-FDG PET regions of interest investigated include the hippocampus, amygdala, posterior cingulate, superior parietal, entorhinal cortices, frontal cortex, temporal cortex, and inferior parietal region. In the cohort as a whole, …verbal logical memory immediate recall was positively associated with 18 F-FDG PET SUVR in both the left hippocampus and right amygdala. There were no associations observed between global cognition, delayed recall in logical memory, or visual reproduction and 18 F-FDG PET SUVR. Following stratification of the cohort into subjective memory complainers and non-complainers, verbal logical memory immediate recall was positively associated with 18 F-FDG PET SUVR in the right amygdala in those with subjective memory complaints. There were no significant associations observed in non-memory complainers between 18 F-FDG PET SUVR in regions of interest and cognitive performance. We observed subjective memory complaint-specific associations between 18 F-FDG PET SUVR and immediate verbal memory performance in our cohort, however found no associations between delayed recall of verbal memory performance or visual memory performance. It is here argued that the neural mechanisms underlying verbal and visual memory performance may in fact differ in their pathways, and the characteristic reduction of 18 F-FDG PET SUVR observed in this and previous studies likely reflects the pathophysiological changes in specific brain regions that occur in preclinical AD. Show more

Keywords: Brain glucose metabolism, cognition, 18F-FDG PET, subjective memory complaints, verbal memory, visual memory

DOI: 10.3233/JAD-151084

Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 661-672, 2016

Authors: Eyre, Harris A. | Acevedo, Bianca | Yang, Hongyu | Siddarth, Prabha | Van Dyk, Kathleen | Ercoli, Linda | Leaver, Amber M. | Cyr, Natalie St. | Narr, Katherine | Baune, Bernhard T. | Khalsa, Dharma S. | Lavretsky, Helen

Article Type: Research Article

Abstract: Background: No study has explored the effect of yoga on cognitive decline and resting-state functional connectivity. Objectives: This study explored the relationship between performance on memory tests and resting-state functional connectivity before and after a yoga intervention versus active control for subjects with mild cognitive impairment (MCI). Methods: Participants ( ≥ 55 y) with MCI were randomized to receive a yoga intervention or active “gold-standard” control (i.e., memory enhancement training (MET)) for 12 weeks. Resting-state functional magnetic resonance imaging was used to map correlations between brain networks and memory performance changes over time. Default mode …networks (DMN), language and superior parietal networks were chosen as networks of interest to analyze the association with changes in verbal and visuospatial memory performance. Results: Fourteen yoga and 11 MET participants completed the study. The yoga group demonstrated a statistically significant improvement in depression and visuospatial memory. We observed improved verbal memory performance correlated with increased connectivity between the DMN and frontal medial cortex, pregenual anterior cingulate cortex, right middle frontal cortex, posterior cingulate cortex, and left lateral occipital cortex. Improved verbal memory performance positively correlated with increased connectivity between the language processing network and the left inferior frontal gyrus. Improved visuospatial memory performance correlated inversely with connectivity between the superior parietal network and the medial parietal cortex. Conclusion: Yoga may be as effective as MET in improving functional connectivity in relation to verbal memory performance. These findings should be confirmed in larger prospective studies. Show more

Keywords: Aging, cognitive decline, memory training, mild cognitive impairment, mind-body, older adults, subjective memory complaints, yoga

DOI: 10.3233/JAD-150653

Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 673-684, 2016

Authors: Edmonds, Emily C. | Delano-Wood, Lisa | Jak, Amy J. | Galasko, Douglas R. | Salmon, David P. | Bondi, Mark W. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Mild cognitive impairment (MCI) is typically diagnosed using subjective complaints, screening measures, clinical judgment, and a single memory score. Our prior work has shown that this method is highly susceptible to false-positive diagnostic errors. We examined whether the criteria also lead to “false-negative” errors by diagnostically reclassifying 520 participants using novel actuarial neuropsychological criteria. Results revealed a false-negative error rate of 7.1%. Participants’ neuropsychological performance, cerebrospinal fluid biomarkers, and rate of decline provided evidence that an MCI diagnosis is warranted. The impact of “missed” cases of MCI has direct relevance to clinical practice, research studies, and clinical trials of prodromal …Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, mild cognitive impairment, misclassification, misdiagnosis, neuropsychology

DOI: 10.3233/JAD-150986

Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 685-691, 2016

Authors: Zhao, Qing-Fei | Wan, Yu | Wang, Hui-Fu | Sun, Fu-Rong | Hao, Xiao-Ke | Tan, Meng-Shan | Tan, Chen-Chen | Zhang, Dao-Qiang | Tan, Lan | Yu, Jin-Tai | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: ABCA7 gene has been identified as a strong genetic locus for Alzheimer’s disease (AD) susceptibility in genome wide association studies (GWAS). However, the possible roles of ABCA7 variants in AD pathology were not specifically assessed. Using tagger methods, we extracted 15 targeted ABCA7 loci to investigate their associations with cerebrospinal fluid (CSF) and neuroimaging markers in Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. Finally, although we did not detect any significant associations of previously published GWAS SNPs (rs3764650 and rs78117248) with all the CSF (Aβ1 - 42 , T-tau, and P-tau) and neuroimaging markers, three other variants (rs3752242, rs3752240, and …rs4147912) at ABCA7 loci were detected to show significant associations with amyloid deposition on AV-45 PET in brain. Moreover, haplotype and subgroup analysis confirmed these significant findings. Furthermore, there were no remarkable correlations between ABCA7 variants and neuronal degeneration biomarkers (elevated CSF tau, brain structure atrophy, and hypometabolism on imaging) in this study. Thus, our study suggested that ABCA7 genotypes contribute to the AD risk through involvement in amyloid-β deposition on in vivo imaging, but not in tau pathology, brain atrophy, or decreased glucose metabolism. Show more

Keywords: ABCA7, Aβ pathogenesis, Alzheimer’s disease, Alzheimer’s disease neuroimaging initiative

DOI: 10.3233/JAD-151005

Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 693-703, 2016

Authors: Min, Jin-young | Min, Kyoung-bok

Article Type: Research Article

Abstract: Abnormal hemoglobin levels are a risk factor for Alzheimer’s disease (AD). Although the mechanism underlying these associations is elusive, inadequate micronutrients, particularly folate and vitamin B12, may increase the risk for anemia, cognitive impairment, and AD. In this study, we investigated whether the nutritional status of folate and vitamin B12 is involved in the association between low hemoglobin levels and the risk of AD mortality. Data were obtained from the 1999–2006 National Health and Nutrition Examination Survey (NHANES) and the NHANES (1999–2006) Linked Mortality File. A total of 4,688 participants aged ≥60 years with available baseline data were included in …this study. We categorized three groups based on the quartiles of folate and vitamin B12 as follows: Group I (low folate and vitamin B12); Group II (high folate and low vitamin B12 or low folate and high vitamin B12); and Group III (high folate and vitamin B12). Of 4,688 participants, 49 subjects died due to AD. After adjusting for age, sex, ethnicity, education, smoking history, body mass index, the presence of diabetes or hypertension, and dietary intake of iron, significant increases in the AD mortality were observed in Quartile1 for hemoglobin (HR: 8.4, 95% CI: 1.4–50.8), and the overall risk of AD mortality was significantly reduced with increases in the quartile of hemoglobin (p for trend = 0.0200), in subjects with low levels of both folate and vitamin B12 at baseline. This association did not exist in subjects with at least one high level of folate and vitamin B12. Our finding shows the relationship between folate and vitamin B12 levels with respect to the association between hemoglobin levels and AD mortality. Show more

Keywords: Anemia, cohort, dementia, folate, mortality, vitamin B

DOI: 10.3233/JAD-151095

Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 705-712, 2016

Authors: Silbert, Lisa C. | Dodge, Hiroko H. | Lahna, David | Promjunyakul, Nutta-on | Austin, Daniel | Mattek, Nora | Erten-Lyons, Deniz | Kaye, Jeffrey A.

Article Type: Research Article

Abstract: Background: Computer use is becoming a common activity in the daily life of older individuals and declines over time in those with mild cognitive impairment (MCI). The relationship between daily computer use (DCU) and imaging markers of neurodegeneration is unknown. Objective: The objective of this study was to examine the relationship between average DCU and volumetric markers of neurodegeneration on brain MRI. Methods: Cognitively intact volunteers enrolled in the Intelligent Systems for Assessing Aging Change study underwent MRI. Total in-home computer use per day was calculated using mouse movement detection and averaged over a one-month period …surrounding the MRI. Spearman’s rank order correlation (univariate analysis) and linear regression models (multivariate analysis) examined hippocampal, gray matter (GM), white matter hyperintensity (WMH), and ventricular cerebral spinal fluid (vCSF) volumes in relation to DCU. A voxel-based morphometry analysis identified relationships between regional GM density and DCU. Results: Twenty-seven cognitively intact participants used their computer for 51.3 minutes per day on average. Less DCU was associated with smaller hippocampal volumes (r  = 0.48, p  = 0.01), but not total GM, WMH, or vCSF volumes. After adjusting for age, education, and gender, less DCU remained associated with smaller hippocampal volume (p  = 0.01). Voxel-wise analysis demonstrated that less daily computer use was associated with decreased GM density in the bilateral hippocampi and temporal lobes. Conclusions: Less daily computer use is associated with smaller brain volume in regions that are integral to memory function and known to be involved early with Alzheimer’s pathology and conversion to dementia. Continuous monitoring of daily computer use may detect signs of preclinical neurodegeneration in older individuals at risk for dementia. Show more

Keywords: Alzheimer’s disease, assessment of cognitive disorders/dementia, cognitive aging, MRI, volumetric MRI

DOI: 10.3233/JAD-160079

Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 713-717, 2016

Authors: Raji, Cyrus A. | Merrill, David A. | Eyre, Harris | Mallam, Sravya | Torosyan, Nare | Erickson, Kirk I. | Lopez, Oscar L. | Becker, James T. | Carmichael, Owen T. | Gach, H. Michael | Thompson, Paul M. | Longstreth Jr., W.T. | Kuller, Lewis H.

Article Type: Research Article

Abstract: Background: Physical activity (PA) can be neuroprotective and reduce the risk for Alzheimer’s disease (AD). In assessing physical activity, caloric expenditure is a proxy marker reflecting the sum total of multiple physical activity types conducted by an individual. Objective: To assess caloric expenditure, as a proxy marker of PA, as a predictive measure of gray matter (GM) volumes in the normal and cognitively impaired elderly persons. Methods: All subjects in this study were recruited from the Institutional Review Board approved Cardiovascular Health Study (CHS), a multisite population-based longitudinal study in persons aged 65 and older. We …analyzed a sub-sample of CHS participants 876 subjects (mean age 78.3, 57.5% F, 42.5% M) who had i) energy output assessed as kilocalories (kcal) per week using the standardized Minnesota Leisure-Time Activities questionnaire, ii) cognitive assessments for clinical classification of normal cognition, mild cognitive impairment (MCI), and AD, and iii) volumetric MR imaging of the brain. Voxel-based morphometry modeled the relationship between kcal/week and GM volumes while accounting for standard covariates including head size, age, sex, white matter hyperintensity lesions, MCI or AD status, and site. Multiple comparisons were controlled using a False Discovery Rate of 5 percent. Results: Higher energy output, from a variety of physical activity types, was associated with larger GM volumes in frontal, temporal, and parietal lobes, as well as hippocampus, thalamus, and basal ganglia. High levels of caloric expenditure moderated neurodegeneration-associated volume loss in the precuneus, posterior cingulate, and cerebellar vermis. Conclusion: Increasing energy output from a variety of physical activities is related to larger gray matter volumes in the elderly, regardless of cognitive status. Show more

Keywords: Aging, dementia risk, energy expenditure, neuroimaging, neuroprotection, physical activity

DOI: 10.3233/JAD-160057

Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 719-729, 2016

Authors: Tanifum, Eric A. | Ghaghada, Ketan | Vollert, Craig | Head, Elizabeth | Eriksen, Jason L. | Annapragada, Ananth

Article Type: Research Article

Abstract: Amyloid binding molecules with greater hydrophilicity than existing ligands were synthesized. The lead candidate ET6-21 bound amyloid fibrils, and amyloid deposits in dog brain and human brain tissue ex vivo . The ligand was used to prepare novel amyloid-targeted liposomal nanoparticles. The preparation was tested in the Tg2576 and TetO/APP mouse models of amyloid deposition. Gd chelates and Indocyanine green were included in the particles for visualization by MRI and near-infrared microscopy. Upon intravenous injection, the particles successfully traversed the blood-brain barrier in these mice, and bound to the plaques. Magnetic resonance imaging (T1-MRI) conducted 4 days after injection demonstrated …elevated signal in the brains of mice with amyloid plaques present. No signal was observed in amyloid-negative mice, or in amyloid-positive mice injected with an untargeted version of the same agent. The MRI results were confirmed by immunohistochemical and fluorescent microscopic examination of mouse brain sections, showing colocalization of the fluorescent tags and amyloid deposits. Show more

Keywords: Alzheimer’s disease, amyloid angiopathy, amyloid plaque, gadolinium, imaging, liposome, magnetic resonance imaging, molecular imaging, nanoparticle

DOI: 10.3233/JAD-151124

Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 731-745, 2016

Authors: Hu, Qingting | Teng, Wenhui | Li, Jiajia | Hao, Fangfang | Wang, Naidong

Article Type: Research Article

Abstract: Background/Objective: The relationship between plasma homocysteine (Hcy) levels and Alzheimer’s disease (AD) has been studied for many years, but remains controversial. While a recent meta-analysis of epidemiological studies, which included observational studies, indicated that homocysteine may be a risk factor for AD, there remains a need to further demonstrate this link due to the large degree of heterogeneity between studies. Epidemiological studies have certain limitations, as their results can be affected by confounding factors and reverse causation. In this study, we evaluated the relationship between plasma homocysteine and AD by using a Mendelian randomization method to avoid problems of …confounding bias and reverse causality. Methods: We searched the PubMed and EMBASE databases for reports regarding the MTHFR C677T polymorphism (rs1801133) from the time of their inception to September 2015. These reports were combined with related observational studies, and used to evaluate the effect of MTHFR C677T (rs1801133) on the risk for AD. A recent meta-analysis of genome-wide association studies had previously suggested a relationship between homocysteine and MTHFR C677T (rs 1801133). Results: Our met-analysis included 34 studies with 9397 subjects, and demonstrated a significant relationship between plasma total homocysteine levels and the risk for AD (OR = 3.37; 95% CI = 1.90–5.95; p  = 2.9×10–5 ). Conclusion: Our meta-analysis demonstrated a causal link between plasma total homocysteine and the risk for AD, and provides a new insight into the etiology and prevention of AD. Show more

Keywords: Alzheimer’s disease, homocysteine, Mendelian randomization analysis, meta-analysis, MTHFR C677T, polymorphism

DOI: 10.3233/JAD-150977

Citation: Journal of Alzheimer's Disease, vol. 52, no. 2, pp. 747-756, 2016