Journal of Alzheimer's Disease - Volume 55, issue 2

Authors: Savica, Rodolfo | Wennberg, Alexandra M.V. | Hagen, Clinton | Edwards, Kelly | Roberts, Rosebud O. | Hollman, John H. | Knopman, David S. | Boeve, Bradley F. | Machulda, Mary M. | Petersen, Ronald C. | Mielke, Michelle M.

Article Type: Research Article

Abstract: Background: Previous studies reported that slower gait speed might predict cognitive impairment and dementing illnesses, supporting the role of gait speed as a possible subclinical marker of cognitive impairment. However, the predictive value of other gait parameters for cognitive decline is unclear. Objective: To investigate and compare the association with, and prediction of, specific gait parameters for cognition in a population-based sample. Methods: The analysis included 3,426 cognitively normal participants enrolled in the Mayo Clinic Study of Aging. At baseline and every 15 months (mean follow-up = 1.93 years), participants had a study coordinator evaluation, neurological examination, …and a neuropsychological assessment using nine tests that covered four domains. Gait parameters were assessed with the GAITRite® instrument. General linear mixed effects models were used to compute the annualized rate of change in cognitive domain z-scores, controlling for age, sex, education, depression, comorbidities, body mass index, APOE ɛ 4 allele, and visit number, and excluding individuals with a history of stroke, alcoholism, Parkinson’s disease, subdural hematoma, and normal pressure hydrocephalus. Results: Spatial (stride length), temporal (ambulatory time, gait speed, step count, cadence, double support time), and spatiotemporal (cadence) gait parameters, and greater intraindividual variability in stride length, swing time, and stance time were associated with a significant decline in global cognition and in specific domains including memory, executive function, visuospatial, and language. Conclusions: Spatial, temporal, and spatiotemporal measures of gait and greater variability of gait parameters were associated with and predictive of both global- and domain-specific cognitive decline. Show more

Keywords: Cognition, epidemiology, gait variability, GAITRite® instrument

DOI: 10.3233/JAD-160697

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 559-567, 2017

Authors: Petersen, Sandra | Houston, Susan | Qin, Huanying | Tague, Corey | Studley, Jill

Article Type: Research Article

Abstract: Background: Behavioral problems may affect individuals with dementia, increasing the cost and burden of care. Pet therapy has been known to be emotionally beneficial for many years. Robotic pets have been shown to have similar positive effects without the negative aspects of traditional pets. Robotic pet therapy offers an alternative to traditional pet therapy. Objective: The study rigorously assesses the effectiveness of the PARO robotic pet, an FDA approved biofeedback device, in treating dementia-related symptoms. Methods: A randomized block design with repeated measurements guided the study. Before and after measures included reliable, valid tools such …as: RAID, CSDD, GDS, pulse rate, pulse oximetry, and GSR. Participants interacted with the PARO robotic pet, and the control group received standard activity programs. Five urban secure dementia units comprised the setting. Results: 61 patients, with 77% females, average 83.4 years in age, were randomized into control and treatment groups. Compared to the control group, RAID, CSDD, GSR, and pulse oximetry were increased in the treatment group, while pulse rate, pain medication, and psychoactive medication use were decreased. The changes in GSR, pulse oximetry, and pulse rate over time were plotted for both groups. The difference between groups was consistent throughout the 12-week study for pulse oximetry and pulse rate, while GSR had several weeks when changes were similar between groups. Conclusions: Treatment with the PARO robot decreased stress and anxiety in the treatment group and resulted in reductions in the use of psychoactive medications and pain medications in elderly clients with dementia. Show more

Keywords: Animal assisted therapy, biofeedback, dementia, psychology, robotics

DOI: 10.3233/JAD-160703

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 569-574, 2017

Authors: Okamoto, Nozomi | Morikawa, Masayuki | Amano, Nobuko | Yanagi, Motokazu | Takasawa, Shin | Kurumatani, Norio

Article Type: Research Article

Abstract: Background: Several studies have suggested that periodontal disease can exacerbate the pro-inflammatory status of the brain. Tooth loss is one of the alternative evaluation indices of periodontal disease. There are few data on the relationship between tooth loss and memory impairment, depending on the apolipoprotein E (APOE ) ɛ 4 genotype. Objective: To determine if tooth loss is associated with mild memory impairment (MMI) and if this association is modified by the presence of the APOE ɛ 4 allele. Methods: A nested case-control study was conducted from 2007 to 2012 in Japan. Five …hundred and thirty-seven Japanese subjects aged 65 years and over who were cognitively intact at baseline were analyzed. MMI at follow-up was evaluated. Results: The median number of teeth at baseline was significantly lower in MMI participants (n  = 179) than in controls (n  = 358) (MMI: median 21.0, interquartile range 10.0–25.0 versus controls: 24.0, 14.0–27.0). After adjustment for demographics, vascular risk factors, and APOE ɛ 4 allele, the multivariate adjusted odds ratio (OR) of ≤8 teeth was 1.97 (95% confidence interval [CI], 1.13–3.44) compared to 25–32 teeth. Participants with both the presence of at least 1 APOE ɛ 4 allele and ≤8 teeth had a higher risk of MMI compared with those with neither (OR, 2.82; 95% CI, 1.15–6.91). Those with either risk factor alone did not have a higher risk of MMI. Conclusions: A lower number of teeth is related to risk of MMI. This may be primarily true for those individuals with an APOE ɛ 4 allele. Show more

Keywords: APOE ɛ4 allele, community-based, memory decline, nested case-control study, tooth loss

DOI: 10.3233/JAD-160638

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 575-583, 2017

Authors: Kuiperij, H. Bea | Versleijen, Alexandra A.M. | Beenes, Marijke | Verwey, Nicolaas A. | Benussi, Luisa | Paterlini, Anna | Binetti, Giuliano | Teunissen, Charlotte E. | Raaphorst, Joost | Schelhaas, Helenius J. | Küsters, Benno | Pijnenburg, Yolande A.L. | Ghidoni, Roberta | Verbeek, Marcel M.

Article Type: Research Article

Abstract: Background: Frontotemporal dementia (FTD) is a heterogeneous disease both at the clinical, genetic, and pathobiological level. The underlying pathological spectrum (termed FTLD, frontotemporal lobar degeneration) is in most cases defined by accumulation of either tau (FTLD-tau) or TDP-43 proteins (FTLD-TDP). Biomarkers to differentiate these subtypes are not yet available, whereas these are essential requirements to study the natural course of disease and for homogeneous inclusion of patients in clinical studies. Objective: To study if a combination of total (t-) and phosphorylated (p-)tau, and t-TDP-43 and p-TDP-43 proteins in cerebrospinal fluid (CSF) is suitable to discriminate FTLD-tau and …FTLD-TDP subtypes. Methods: We developed immunoassays for the quantification of t-TDP-43 and p-TDP-43 proteins and used commercially available assays for the quantification of t-tau and p-tau proteins. We quantified these proteins in ventricular CSF samples from neuropathologically defined FTLD-tau and FTLD-TDP cases to study the reflection of underlying brain pathology in CSF composition, and in lumbar CSF samples from FTLD-tau and FTLD-TDP patients to study the diagnostic potential of CSF biomarkers. Results: In ventricular CSF, t-TDP-43 and t-tau levels, when combined into one model, were significantly different between neuropathologically-defined FTLD-tau and FTLD-TDP cases. In a pilot study using lumbar CSF, the p-tau/t-tau ratio, but not t-TDP-43 levels, were significantly different between FTLD-TDP and FTLD-tau patients. Conclusion: We conclude that with current available methods, CSF tau, rather than TDP-43 proteins, may have diagnostic value in the differentiation of FTLD patients with either tau or TDP-43 pathology. Show more

Keywords: Biomarkers, cerebrospinal fluid, frontotemporal lobar degeneration, TAR DNA-binding protein 43, tau proteins

DOI: 10.3233/JAD-160386

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 585-595, 2017

Authors: Ibrahim, Nor Faeizah | Yanagisawa, Daijiro | Durani, Lina Wati | Hamezah, Hamizah Shahirah | Damanhuri, Hanafi Ahmad | Wan Ngah, Wan Zurinah | Tsuji, Mayumi | Kiuchi, Yuji | Ono, Kenjiro | Tooyama, Ikuo

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common cause of dementia. The cardinal neuropathological characteristic of AD is the accumulation of amyloid-β (Aβ) into extracellular plaques that ultimately disrupt neuronal function and lead to neurodegeneration. One possible therapeutic strategy therefore is to prevent Aβ aggregation. Previous studies have suggested that vitamin E analogs slow AD progression in humans. In the present study, we investigated the effects of the tocotrienol-rich fraction (TRF), a mixture of vitamin E analogs from palm oil, on amyloid pathology in vitro and in vivo . TRF treatment dose-dependently inhibited the formation of Aβ fibrils and Aβ …oligomers in vitro . Moreover, daily TRF supplementation to AβPPswe/PS1dE9 double transgenic mice for 10 months attenuated Aβ immunoreactive depositions and thioflavin-S-positive fibrillar type plaques in the brain, and eventually improved cognitive function in the novel object recognition test compared with control AβPPswe/PS1dE9 mice. The present result indicates that TRF reduced amyloid pathology and improved cognitive functions, and suggests that TRF is a potential therapeutic agent for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, AβPP/PS1 mice, tocotrienol-rich fraction, vitamin E

DOI: 10.3233/JAD-160685

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 597-612, 2017

Authors: Hamasaki, Hideomi | Honda, Hiroyuki | Okamoto, Tsuyoshi | Koyama, Sachiko | Suzuki, Satoshi O. | Ohara, Tomoyuki | Ninomiya, Toshiharu | Kiyohara, Yutaka | Iwaki, Toru

Article Type: Research Article

Abstract: Background: The Hisayama study is a prospective cohort study of lifestyle-related diseases that commenced in 1961. Through it, a significant increasing trend in the prevalence of Alzheimer’s disease has been observed over the past 18 years. Objectives: We sought to investigate the increases in brain pathology related to Alzheimer’s disease using automated MATLAB morphometric analyses for quantifying tau pathology. Methods: We examined a series of autopsied cases from Hisayama residents obtained between 1998 and 2003 (group A: 203 cases), and between 2009 and 2014 (group B: 232 cases). We developed custom software in MATLAB to …analyze abnormal tau deposits quantitatively. Specimens were immunostained with both anti-amyloid-β-protein and anti-phosphorylated tau antibodies. Results: Both the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) criteria for senile plaques and Braak stage for NFT were higher in group B. Morphometric analyses of the hippocampi also revealed a trend toward increased tau pathology in both men and women over 80 years of age in group B. The increases were also significant when the subjects were examined independently according to high or low CERAD scores and in all levels of AD neuropathologic change according to the National Institute on Aging-Alzheimer’s Association guidelines (2012). Conclusion: We revealed a recent trend of increased tauopathy in the older people, which is partly independent of amyloid-β pathology. Show more

Keywords: Alzheimer’s disease, image analysis, neurofibrillary tangles, tauopathy

DOI: 10.3233/JAD-160521

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 613-624, 2017

Authors: Rivero-Santana, Amado | Ferreira, Daniel | Perestelo-Pérez, Lilisbeth | Westman, Eric | Wahlund, Lars-Olof | Sarría, Antonio | Serrano-Aguilar, Pedro

Article Type: Research Article

Abstract: Background: Differential diagnosis in dementia is at present one of the main challenges both in clinical practice and research. Cerebrospinal fluid (CSF) biomarkers are included in the current diagnostic criteria of Alzheimer’s disease (AD) but their clinical utility is still unclear. Objective: We performed a systematic review of studies analyzing the diagnostic performance of CSF Aβ42 , total tau (t-tau), and phosphorylated tau (p-tau) in the discrimination between AD and frontotemporal lobar degeneration (FTLD) dementias. Methods: The following electronic databases were consulted until May 2016: Medline and PreMedline, EMBASE, PsycInfo, CINAHL, Cochrane Library, and CRD. …For the first-time in the field, a Hierarchical Summary Receiver Operating Characteristic (HRSOC) model was applied, which avoids methodological problems of meta-analyses based on summary points of sensitivity and specificity values. We also investigated relevant confounders of CSF biomarkers’ diagnostic performance such as age, disease duration, and global cognitive impairment. Results: The p-tau/Aβ42 ratio showed the best diagnostic performance. No statistically significant effects of the confounders were observed. Nonetheless, the p-tau/Aβ42 ratio may be especially indicated for younger patients. P-tau may be preferable for less cognitively impaired patients (high MMSE scores) and the t-tau/Aβ42 ratio for more cognitively impaired patients (low MMSE scores). Conclusion: The p-tau/Aβ42 ratio has potential for being implemented in the clinical routine for the differential diagnosis between AD and FTLD. It is of utmost importance that future studies report information on confounders such as age, disease duration, and cognitive impairment, which should also stimulate understanding of the role of these factors in disease mechanisms and pathophysiology. Show more

Keywords: Age, Alzheimer’s disease, cerebrospinal fluid markers, confounding factor, disease duration, frontotemporal lobar degeneration, HSROC analysis, Mini-Mental State Examination, systematic review

DOI: 10.3233/JAD-160366

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 625-644, 2017

Authors: Håkansson, Krister | Ledreux, Aurélie | Daffner, Kirk | Terjestam, Yvonne | Bergman, Patrick | Carlsson, Roger | Kivipelto, Miia | Winblad, Bengt | Granholm, Ann-Charlotte | Mohammed, Abdul Kadir H.

Article Type: Research Article

Abstract: Brain-derived neurotrophic factor (BDNF) has a central role in brain plasticity by mediating changes in cortical thickness and synaptic density in response to physical activity and environmental enrichment. Previous studies suggest that physical exercise can augment BDNF levels, both in serum and the brain, but no other study has examined how different types of activities compare with physical exercise in their ability to affect BDNF levels. By using a balanced cross over experimental design, we exposed nineteen healthy older adults to 35-minute sessions of physical exercise, cognitive training, and mindfulness practice, and compared the resulting changes in mature BDNF levels between the …three activities. We show that a single bout of physical exercise has significantly larger impact on serum BDNF levels than either cognitive training or mindfulness practice in the same persons. This is the first study on immediate BDNF effects of physical activity in older healthy humans and also the first study to demonstrate an association between serum BDNF responsivity to acute physical exercise and working memory function. We conclude that the BDNF increase we found after physical exercise more probably has a peripheral than a central origin, but that the association between post-intervention BDNF levels and cognitive function could have implications for BDNF responsivity in serum as a potential marker of cognitive health. Show more

Keywords: Aging, brain-derived neurotrophic factor, cognitive function, cognitive training, crossover design, exercise, geriatrics, intervention study, mindfulness, neuroplasticity

DOI: 10.3233/JAD-160593

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 645-657, 2017

Authors: Varma, Vijay R. | Watts, Amber

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disease that results in severe disability. Very few studies have explored changes in daily physical activity patterns during early stages of AD when components of physical function and mobility may be preserved. Objective: Our study explored differences in daily physical activity profiles, independent of the effects of non-cognitive factors including physical function and age, among individuals with mild AD compared to controls. Methods: Patients with mild AD and controls (n  = 92) recruited from the University of Kansas Alzheimer’s Disease Center Registry, wore the Actigraph GT3X+ for seven days, …and provided objective physical function (VO2 max) and mobility data. Using multivariate linear regression, we explored whether individuals with mild AD had different daily average and diurnal physical activity patterns compared to controls independent of non-cognitive factors that may affect physical activity, including physical function and mobility. Results: We found that mild AD was associated with less moderate-intensity physical activity (p  < 0.05), lower peak activity (p  < 0.01), and lower physical activity complexity (p  < 0.05) particularly during the morning. Mild AD was not associated with greater sedentary activity or less lower-intensity physical activity across the day after adjusting for non-cognitive covariates. Conclusions: These findings suggest that factors independent of physical capacity and mobility may drive declines in moderate-intensity physical activity, and not lower-intensity or sedentary activity, during the early stage of AD. This underscores the importance of a better mechanistic understanding of how cognitive decline and AD pathology impact physical activity. Findings emphasize the potential value of designing and testing time-of-day specific physical activity interventions targeting individuals in the early stages of AD, prior to significant declines in mobility and physical function. Show more

Keywords: Alzheimer’s disease, motor activity, physical conditioning, physical exertion, physical fitness

DOI: 10.3233/JAD-160582

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 659-667, 2017

Authors: Lin, Feng | Ren, Ping | Lo, Raymond Y. | Chapman, Benjamin P. | Jacobs, Alanna | Baran, Timothy M. | Porsteinsson, Anton P. | Foxe, John J. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Apolipoprotein E (APOE) ɛ 4 carriers and patients with amnestic mild cognitive impairment (MCI) have high risk of developing Alzheimer’s disease (AD). The Scaffolding Theory of Aging and Cognition proposes that recruitment of additional frontal brain regions can protect cognition against aging. This thesis has yet to be fully tested in older adults at high risk for AD. In the present study, 75 older participants (mean age: 74 years) were included. Applying a voxel-wise approach, fractional amplitude of low-frequency fluctuations (fALFF) in resting-state functional neuroimaging data were analyzed as a function of APOEɛ 4 status (carrier versus noncarrier) and clinical …status (healthy control [HC] versus MCI) using a 2×2 analysis of covariance (ANCOVA). Measures of cognition and cerebrospinal fluid levels of amyloid- β were also obtained. Three frontal regions were identified with significant interaction effects using ANCOVA (corrected p  < 0.01): left-insula, left-inferior frontal gyrus (IFG), and right-precentral gyrus. The HC/APOEɛ 4 carrier group had significantly higher fALFF in all three regions than other groups. In the entire sample, for two regions (left insula and left IFG), a significant positive relationship between amyloid-β and memory was only observed among individuals with low fALFF. Our results suggest higher activity in frontal regions may explain being cognitively normal among a subgroup of APOEɛ 4 carriers and protect against the negative impact of AD-associated pathology on memory. This is an observation with potential implications for AD therapeutics. Show more

Keywords: Amyloid-β, apolipoprotein E ɛ4, frontal cortex, memory, mild cognitive impairment, resting state functional MRI

DOI: 10.3233/JAD-160715

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 669-678, 2017