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

Authors: Jansen, Willemijn J. | Handels, Ron L.H. | Visser, Pieter Jelle | Aalten, Pauline | Bouwman, Femke | Claassen, Jurgen | van Domburg, Peter | Hoff, Erik | Hoogmoed, Jan | Leentjens, Albert F.G. | Rikkert, Marcel Olde | Oleksik, Ania M. | Smid, Machiel | Scheltens, Philip | Wolfs, Claire | Verhey, Frans | Ramakers, Inez H.G.B.

Article Type: Research Article

Abstract: Background: Neuropsychological testing has long been embedded in daily clinical practice at memory clinics but the added value of a complete neuropsychological assessment (NPA) to standard clinical evaluation is unknown. Objective: To evaluate the added diagnostic and prognostic value of NPA to clinical evaluation only in memory clinic patients. Methods: In 221 memory clinic patients of a prospective cohort study, clinical experts diagnosed clinical syndrome (subjective cognitive impairment (SCI), mild cognitive impairment (MCI), or dementia) and etiology (Alzheimer’s disease (AD) or no AD), and provided a prognosis of disease course (decline or no decline) before …and after results of NPA were made available. The reference standard was a panel consensus based on all clinical information at baseline and up to 2 follow-up assessments. Results: With NPA data available, clinicians changed their initial syndromal diagnosis in 22% of patients, and the etiological diagnosis as well as the prognosis in 15%. This led to an increase in correctly classified cases of 18% for syndromal diagnosis, 5% for etiological diagnosis, and 1% for prognosis. NPA data resulted in the largest improvement in patients initially classified as SCI (syndrome: 93.3% (n  = 14) correctly reclassified, etiology: net reclassification improvement [NRI] = 0.61, prognosis: NRI = 0.13) or MCI (syndrome: 89.3% (n  = 23) correctly reclassified, etiology: NRI = 0.17, prognosis: NRI = 0.14), while there was no improvement in patients with dementia (syndrome: 100% (n  = 1) correctly reclassified, etiology: NRI = –0.05, prognosis: NRI = –0.06). Overall, inclusion of NPA in the diagnostic process increased confidence in all diagnoses with 6-7%. Conclusion: Administration of a complete NPA after standard clinical evaluation has added value for diagnosing cognitive syndrome and its underlying etiology in patients regarded as non-demented based on the first clinical impression. Show more

Keywords: Alzheimer’s disease, cognitive disorders, consensus, diagnosis, prognosis, mild cognitive impairment, neuropsychological tests, outpatient clinic, reclassification

DOI: 10.3233/JAD-160126

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 679-689, 2017

Authors: Wucherer, Diana | Eichler, Tilly | Hertel, Johannes | Kilimann, Ingo | Richter, Steffen | Michalowsky, Bernhard | Thyrian, Jochen René | Teipel, Stefan | Hoffmann, Wolfgang

Article Type: Research Article

Abstract: Background: Potentially inappropriate medication (PIM) in older people is a risk factor for adverse drug effects. This risk is even higher in older people with dementia (PWD). Objective: Our study aimed to determine (1) the prevalence of PIM among primary care patients who were screened positive for dementia and (2) the sociodemographic and clinical variables associated with the use of PIM. Methods: DelpHi-MV (Dementia: life- and person-centered help in Mecklenburg–Western Pomerania) is a general practitioner-based, cluster-randomized, controlled intervention study to implement and evaluate an innovative concept of collaborative dementia care management in Germany. The comprehensive …baseline assessment includes a home medication review. The present analyses are based on the data from 448 study participants (age 70+, DemTect <9). PIMs were identified using the list of Potentially Inappropriate Medications in the Elderly (Priscus). Results: (1) A total of 99 study participants (22%) received at least one PIM. The highest prevalence was found for antidepressants, benzodiazepines, and analgetics. The most frequently prescribed PIMs were amitriptyline, etoricoxib, and doxazosin. (2) Use of a PIM was significantly associated with a diagnosis of a mental or behavioral disorder. Conclusions: The prescription rate of PIMs for community-dwelling PWD was comparable with the rates found for the general population of older people in Germany (20–29%). Antidepressants with anticholinergic properties and long-acting benzodiazepines were the most prescribed PIMs, despite having an unfavorable benefit-risk ratio. This high prevalence of PIM prescriptions in a vulnerable population of PWD indicates that standard care for dementia should include careful medication review and management. Show more

Keywords: Dementia, PIM List, potentially inappropriate medications, primary health care

DOI: 10.3233/JAD-160581

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 691-701, 2017

Authors: Wawrziczny, Emilie | Berna, Guillaume | Ducharme, Francine | Kergoat, Marie-Jeanne | Pasquier, Florence | Antoine, Pascal

Article Type: Research Article

Abstract: Background: The progressive mobilization of spouse caregivers who take care of a person with dementia (PWD) can lead to situations of distress. Objective: The current study sought to investigate the influence of the characteristics of the caregiving context on spousal caregiver distress. Methods: 125 spousal caregivers participated in this study. The characteristics of the caregiving context were assessed using questionnaires. We examined a moderated-mediator model (Step 1) in which we hypothesized that PWD and caregiver characteristics and dyadic determinants contribute to spousal caregiver distress. This model was compared based on the age at onset of the …disease and the gender of the caregiver (Step 2). Results: The model revealed that poor self-rated health and a lack of family support accentuated spousal caregiver distress, whereas the feeling of being prepared and level of confidence decreased spousal caregiver distress. Moreover, the quality of couple adjustment affected spousal caregiver distress, and this effect was mediated by the severity of the PWD’s symptoms. Regarding the age at onset of the disease, the path between Couple Adjustment and the Care recipient’s impairments was more important for caregivers of person with early-onset dementia (PEOD). Female caregivers who reported poor self-rated health experienced greater distress. Conclusions: It would be interesting to create a support program that would incorporate these three areas of intervention regarding the progression of the disease: first, “preparedness modules”; second, “dyadic modules” (especially for caregivers of PEOD); and third, “family modules”. Specific attention should be given to female caregivers who report poor self-rated health. Show more

Keywords: Caregivers, dementia, early onset Alzheimer disease, late onset Alzheimer disease, psychological model, spouses

DOI: 10.3233/JAD-160558

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 703-716, 2017

Authors: Ulstein, Ingun | Bøhmer, Thomas

Article Type: Research Article

Abstract: Evidence supports an association between vitamin deficiencies and cognitive decline in Alzheimer’s disease (AD). If vitamin deficiencies are causative for AD development, they should be detectable during very early stages of AD. Here we investigated nutritional factors among home-living patients diagnosed with mild cognitive impairment (MCI) or mild dementia due to AD, compared to healthy controls. Our study included 73 patients with AD (25 with MCI, 48 with dementia) and 63 cognitively intact age-matched controls. All participants underwent cognitive testing, somatic examination, and measurements of vitamins A, B1, B6, folate, B12, C, D, and E, and F2-α-isoprostane. Results are given …as mean (SD). MMSE scores were 29.1 (1.0) for healthy controls, 27.4 (1.8) for patients with MCI, and 24.3 (3.2) for patients with dementia. Vitamin concentrations for the these groups, respectively, were as follows: B1 (nmol/l), 157 (29), 161 (35), and 161 (32); B6 (nmol/l), 57 (63), 71 (104), and 58 (44); folate (mmol/l), 23 (9), 26 (10), and 23 (11); B12 (pmol/l), 407 (159), 427 (116), and 397 (204); C (μmol/l), 63 (18), 61 (16), and 63 (29); A (μmol/l), 2.3 (0.6), 2.2 (0.5), and 2.3 (0.5); E (μmol/l), 36 (6.3), 36 (6.9), and 36 (8.2); 25-OH vitamin D (nmol/l), 65 (18), 61 (19), and 65 (20); and 8-iso-PGFα (pg/ml), 64 (27); 60 (19), and 66 (51). These concentrations did not significantly differ (p ≤0.05) between the three groups. Our results do not support the hypothesis that vitamin deficiencies play a causative role in the development of early cognitive impairment. Show more

Keywords: Alzheimer’s disease, mild cognitive impairment, vitamin deficiencies

DOI: 10.3233/JAD-160393

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 717-725, 2017

Authors: An, Hoyoung | Choi, Booyeol | Park, Kun-woo | Kim, Do-Hoon | Yang, Dong-Won | Hong, Chang Hyung | Kim, Seong Yoon | Han, Seol-Heui

Article Type: Research Article

Abstract: Background: Effective treatments to alleviate depression in Alzheimer’s disease (AD) have been scarce. Objective: To investigate the efficacy and tolerability of escitalopram in the treatment of depression in AD. Methods: In this 12-week randomized, double-blind, placebo-controlled trial with open-label, 12-week extension, AD subjects over 50 years of age, with depression defined by Olin’s provisional diagnostic criteria, were enrolled. The Cornell Scale for Depression in Dementia (CSDD), and other measures of depression and cognition were repeated. Results: 91 subjects were screened, and 84 were randomized into either the study group or placebo group (n … = 42 for both groups). Twenty-four subjects (29%) were unable to finish the study, yielding a per protocol population of 60 subjects (study group: n  = 27; placebo group: n  = 33). At week 12, differences in measures of depression and cognition between the two groups were not statistically significant. However, exploratory analysis suggested that further research on a subset of subjects with ‘definite major depression’ (baseline CSDD score ≥18) is needed. The number of treatment-related adverse-events (AE) did not differ between groups (p  = 0.83) and no serious treatment-related AE were observed. Conclusion: The use of escitalopram was well tolerated in depressive dementia patients. Future studies focusing on subjects with more severe levels of depression, and with more statistical power, will be needed. Show more

Keywords: Alzheimer’s disease, clinical trial, depression, escitalopram, placebo

DOI: 10.3233/JAD-160225

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 727-735, 2017

Authors: Coskun, Pinar | Helguera, Pablo | Nemati, Zahra | Bohannan, Ryan C. | Thomas, Jean | Samuel, Schriner E. | Argueta, Jocelyn | Doran, Eric | Wallace, Douglas C. | Lott, Ira T. | Busciglio, Jorge

Article Type: Research Article

Abstract: Background: Deficits in mitochondrial function and oxidative stress play pivotal roles in Down syndrome (DS) and Alzheimer’s disease (AD) and these alterations in mitochondria occur systemically in both conditions. Objective: We hypothesized that peripheral cells of elder subjects with DS exhibit disease-specific and dementia-specific metabolic features. To test this, we performed a comprehensive analysis of energy metabolism in lymphoblastic-cell-lines (LCLs) derived from subjects belonging to four groups: DS-with-dementia (DSAD), DS-without-dementia (DS), sporadic AD, and age-matched controls. Methods: LCLs were studied under regular or minimal feeding regimes with galactose or glucose as primary carbohydrate sources. We …assessed metabolism under glycolysis or oxidative phosphorylation by quantifying cell viability, oxidative stress, ATP levels, mitochondrial membrane potential (MMP), mitochondrial calcium uptake, and autophagy. Results: DS and DSAD LCLs showed slower growth rates under minimal feeding. DS LCLs mainly dependent on mitochondrial respiration exhibited significantly slower growth and higher levels of oxidative stress compared to other groups. While ATP levels (under mitochondrial inhibitors) and mitochondrial calcium uptake were significantly reduced in DSAD and AD cells, MMP was decreased in DS, DSAD, and AD LCLs. Finally, DS LCLs showed markedly reduced levels of the autophagy marker LC3-II, underscoring the close association between metabolic dysfunction and impaired autophagy in DS. Conclusion: There are significant mitochondrial functional changes in LCLs derived from DS, DSAD, and AD patients. Several parameters analyzed were consistently different between DS, DSAD, and AD lines suggesting that metabolic indicators between LCL groups may be utilized as biomarkers of disease progression and/or treatment outcomes. Show more

Keywords: Alzheimer’s disease, autophagy, dementia, Down syndrome, growth retardation, lymphoblastoid cell lines, metabolic alterations, mitochondrial dysfunction, oxidative stress

DOI: 10.3233/JAD-160278

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 737-748, 2017

Authors: Rueli, Rachel H.L.H. | Torres, Daniel J. | Dewing, Andrea S.T. | Kiyohara, Arlene C. | Barayuga, Stephanie M. | Bellinger, Miyoko T. | Uyehara-Lock, Jane H. | White, Lon R. | Moreira, Paula I. | Berry, Marla J. | Perry, George | Bellinger, Frederick P.

Article Type: Research Article

Abstract: Previous studies demonstrated that selenium in the form of sodium selenate reduces neurofibrillary tangle formation in Alzheimer’s disease models. Hyperphosphorylation of tau, which leads to formation of neurofibrillary tangles in Alzheimer’s disease, is increased by endoplasmic reticulum (ER) stress. Selenoprotein S (SelS) is part of an ER membrane complex that removes misfolded proteins from the ER as a means to reduce ER stress. Selenate, as with other forms of selenium, will increase selenoprotein expression. We therefore proposed that increased SelS expression by selenate would contribute to the beneficial actions of selenate in Alzheimer’s disease. SelS expression increased with ER stress and …decreased under conditions of elevated glucose concentrations in the SH-SY5Y neuronal cell line. Reducing expression of SelS with siRNA promoted cell death in response to ER stress. Selenate increased SelS expression, which significantly correlated with decreased tau phosphorylation. Restricting SelS expression during ER stress conditions increased tau phosphorylation, and also promoted aggregation of phosphorylated tau in neurites and soma. In human postmortem brain, SelS expression coincided with neurofibrillary tangles, but not with amyloid-β plaques. These results indicate that selenate can alter phosphorylation of tau by increasing expression of SelS in Alzheimer’s disease and potentially other neurodegenerative disorders. Show more

Keywords: Alzheimer’s disease, endoplasmic reticulum stress, neurofibrillary tangle, selenium, selenoprotein, tau

DOI: 10.3233/JAD-151208

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 749-762, 2017

Authors: Dekens, Doortje W. | Naudé, Petrus J.W. | Engelborghs, Sebastiaan | Vermeiren, Yannick | Van Dam, Debby | Oude Voshaar, Richard C. | Eisel, Ulrich L.M. | De Deyn, Peter P.

Article Type: Research Article

Abstract: Co-existing depression worsens Alzheimer’s disease (AD) pathology. Neutrophil gelatinase-associated lipocalin (NGAL) is a newly identified (neuro)inflammatory mediator in the pathophysiologies of both AD and depression. This study aimed to compare NGAL levels in healthy controls, AD without depression (AD–D), and AD with co-existing depression (AD+D) patients. Protein levels of NGAL and its receptors, 24p3R and megalin, were assessed in nine brain regions from healthy controls (n  = 19), AD–D (n  = 19), and AD+D (n  = 21) patients. NGAL levels in AD–D patients were significantly increased in brain regions commonly associated with AD. In the hippocampus, NGAL levels were even further increased in …AD+D subjects. Unexpectedly, NGAL levels in the prefrontal cortex of AD+D patients were comparable to those in controls. Megalin levels were increased in BA11 and amygdala of AD+D patients, while no changes in 24p3R were detected. These findings indicate significant differences in neuroimmunological regulation between AD patients with and without co-existing depression. Considering its known effects, elevated NGAL levels might actively promote neuropathological processes in AD with and without depression. Show more

Keywords: 24p3R, Alzheimer’s disease, depression, hippocampus, inflammation, lipocalin 2, megalin, NGAL

DOI: 10.3233/JAD-160330

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 763-776, 2017

Authors: Sun, Lin | Chen, Kathryn | Li, Xia | Xiao, Shifu

Article Type: Research Article

Abstract: Frontotemporal dementia includes a large spectrum of neurodegenerative disorders. Here, we report the case of a young patient with MAPT mutation G389R, who was 27 years old when he progressively developed severe behavioral disturbances. Initially, he presented with slowly progressive personality change. After 1 year, he exhibited moderate dementia with extrapyramidal and pyramidal symptoms. MRI showed frontotemporal atrophy. He rapidly progressed to severe dementia 3 years after onset. Genetic testing revealed a heterozygous guanine to cytosine mutation at the first base of codon 389 (c.1165G>A) of MAPT, the tau gene, resulting in a glycine to arginine substitution in the patient and two unaffected relatives. …We predicted the model of mutant tau protein through I-TASSER software, and speculated the structural change of tau protein caused by mutant site. We also detected the MAPT gene transcript and methylation of samples from peripheral blood leucocytes in an attempt to explain the possible mechanisms of incomplete penetrance, although there were not positive findings. This case is remarkable because of the early onset and rapid progression of the disease. Show more

Keywords: Early onset dementia, frontotemporal dementia, G389R mutation, MAPT, protein structure predicting

DOI: 10.3233/JAD-160802

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 777-785, 2017

Authors: Han, Ji Won | Lee, Hyeonggon | Hong, Jong Woo | Kim, Kayoung | Kim, Taehyun | Byun, Hye Jin | Ko, Ji Won | Youn, Jong Chul | Ryu, Seung-Ho | Lee, Nam-Jin | Pae, Chi-Un | Kim, Ki Woong

Article Type: Research Article

Abstract: We developed and evaluated the effect of Multimodal Cognitive Enhancement Therapy (MCET) consisting of cognitive training, cognitive stimulations, reality orientation, physical therapy, reminiscence therapy, and music therapy in combination in older people with mild cognitive impairment (MCI) or mild dementia. This study was a multi-center, double-blind, randomized, placebo-controlled, two-period cross-over study (two 8-week treatment phases separated by a 4-week wash-out period). Sixty-four participants with MCI or dementia whose Clinical Dementia Rating was 0.5 or 1 were randomized to the MCET group or the mock-therapy (placebo) group. Outcomes were measured at baseline, week 9, and week 21. Fifty-five patients completed the study. Mini-Mental …State Examination (effect size = 0.47, p  = 0.013) and Alzheimer’s Disease Assessment Scale-Cognitive Subscale (effect size = 0.35, p  = 0.045) scores were significantly improved in the MCET compared with mock-therapy group. Revised Memory and Behavior Problems Checklist frequency (effect size = 0.38, p  = 0.046) and self-rated Quality of Life – Alzheimer’s Disease (effect size = 0.39, p  = 0.047) scores were significantly improved in the MCET compared with mock-therapy. MCET improved cognition, behavior, and quality of life in people with MCI or mild dementia more effectively than conventional cognitive enhancing activities did. Show more

Keywords: Cognitive interventions, cognitive therapy, cognitive training, dementia, mild cognitive impairment, mild dementia, multimodal cognitive enhancement therapy, non-pharmacologic treatment, randomized controlled trials

DOI: 10.3233/JAD-160619

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 787-796, 2017

Authors: McClure, Richard | Ong, Henry | Janve, Vaibhab | Barton, Shawn | Zhu, Meiying | Li, Bo | Dawes, Mary | Jerome, W. Gray | Anderson, Adam | Massion, Pierre | Gore, John C. | Pham, Wellington

Article Type: Research Article

Abstract: We report a novel approach for the delivery of curcumin to the brain via inhalation of the aerosol for the potential treatment of Alzheimer’s disease. The percentage of plaque fraction in the subiculum and hippocampus reduced significantly when young 5XFAD mice were treated with inhalable curcumin over an extended period of time compared to age-matched nontreated counterparts. Further, treated animals demonstrated remarkably improved overall cognitive function, no registered systemic or pulmonary toxicity associated with inhalable curcumin observed during the course of this work.

Keywords: Aerosol, amyloid-β, curcumin, nebulization

DOI: 10.3233/JAD-160289

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 797-811, 2017

Authors: Lewczuk, Piotr | Matzen, Anja | Blennow, Kaj | Parnetti, Lucilla | Molinuevo, Jose Luis | Eusebi, Paolo | Kornhuber, Johannes | Morris, John C. | Fagan, Anne M.

Article Type: Research Article

Abstract: Background: Decreased concentrations of amyloid-β 1-42 (Aβ42 ) in cerebrospinal fluid (CSF) and increased retention of Aβ tracers in the brain on positron emission tomography (PET) are considered the earliest biomarkers of Alzheimer’s disease (AD). However, a proportion of cases show discrepancies between the results of the two biomarker modalities which may reflect inter-individual differences in Aβ metabolism. The CSF Aβ42/40 ratio seems to be a more accurate biomarker of clinical AD than CSF Aβ42 alone. Objective: We tested whether CSF Aβ42 alone or the Aβ42/40 ratio corresponds better with amyloid PET status …and analyzed the distribution of cases with discordant CSF-PET results. Methods: CSF obtained from a mixed cohort (n  = 200) of cognitively normal and abnormal research participants who had undergone amyloid PET within 12 months (n  = 150 PET-negative, n  = 50 PET-positive according to a previously published cut-off) was assayed for Aβ42 and Aβ40 using two recently developed immunoassays. Optimal CSF cut-offs for amyloid positivity were calculated, and concordance was tested by comparison of the areas under receiver operating characteristic (ROC) curves (AUC) and McNemar’s test for paired proportions. Results: CSF Aβ42/40 corresponded better than Aβ42 with PET results, with a larger proportion of concordant cases (89.4% versus 74.9%, respectively, p  < 0.0001) and a larger AUC (0.936 versus 0.814, respectively, p  < 0.0001) associated with the ratio. For both CSF biomarkers, the percentage of CSF-abnormal/PET-normal cases was larger than that of CSF-normal/PET-abnormal cases. Conclusion: The CSF Aβ42/40 ratio is superior to Aβ42 alone as a marker of amyloid-positivity by PET. We hypothesize that this increase in performance reflects the ratio compensating for general between-individual variations in CSF total Aβ. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarker, cerebrospinal fluid, positron emission tomography

DOI: 10.3233/JAD-160722

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 813-822, 2017

Authors: Peh, Chao Xu | Abdin, Edimansyah | Vaingankar, Janhavi A. | Verma, Swapna | Chua, Boon Yiang | Sagayadevan, Vathsala | Seow, Esmond | Zhang, YunJue | Shahwan, Shazana | Ng, Li Ling | Prince, Martin | Chong, Siow Ann | Subramaniam, Mythily

Article Type: Research Article

Abstract: Background: The latent variable δ has been proposed as a proxy for dementia. Previous validation studies have been conducted using convenience samples. It is currently unknown how δ performs in population-wide data. Objective: To validate δ in Singapore using population-wide epidemiological study data on persons aged 60 and above. Methods: δ was constructed using items from the Community Screening Instrument for Dementia (CSI’D) and World Health Organization Disability Assessment Schedule (WHODAS II). Confirmatory factor analysis (CFA) was conducted to examine δ model fit. Convergent validity was examined with the Clinical Dementia Rating scale (CDR) and GMS-AGECAT …dementia. Divergent validity was examined with GMS-AGECAT depression. Results: The δ model demonstrated fit to the data, χ2 (df ) = 249.71(55), p  < 0.001, CFI = 0.990, TLI = 0.997, RMSEA = 0.037. Latent variable δ was significantly associated with CDR and GMS-AGECAT dementia (range: β= 0.32 to 0.63), and was not associated with GMS-AGECAT depression. Compared to unadjusted models, δ model fit was poor when adjusted for age, gender, ethnicity, and education. Conclusion: The study found some support for δ as a proxy for dementia in Singapore based on population data. Both convergent and divergent validity were established. In addition, the δ model structure appeared to be influenced by age, gender, ethnicity, and education covariates. Show more

Keywords: Cognition, dementia, functional status, Singapore, validation studies

DOI: 10.3233/JAD-160575

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 823-833, 2017

Authors: Shen, Yijun | Xia, Yiling | Meng, Shiquan | Lim, Nastasia K.H. | Wang, Wenan | Huang, Fude

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is characterized by deficits in learning and memory abilities, as well as pathological changes of amyloid-β (Aβ) plaque and neurofibrillary tangle formation in the brain. Insulin has been identified as a modulator of the neuronal pathways involved in learning and memory, and is also implicated as a modulator of Aβ and tau metabolism. Disrupted insulin signaling pathways are evident in AD patients and it is understood that type 2 diabetes can increase the risk of developing AD, suggesting a possible link between metabolic disorders and neurodegeneration. SH2B1 is a key protein in the insulin signaling pathway involved …in regulating the activity of the insulin receptor. To further identify the role of the insulin signaling pathway in the pathology of AD, SH2B (dSH2B homologue in flies) in neurons was partially knocked out or overexpressed in an AD Drosophila model expressing Aβ42 . Partial knockout of neuronal SH2B in the Aβ42 -expressing Drosophila had a detrimental effect on mobility and neurotransmission, and increased levels and intraneuronal accumulation of Aβ42 , as assessed by ELISA and immunostaining. Alternatively, partial overexpression of neuronal SH2B in the Aβ42 -expressing Drosophila improved lifespan, mobility, and neurotransmission, as well as decreased levels and intraneuronal accumulation of Aβ42 . Thus, SH2B1 may be an upstream modulator of Aβ metabolism, acting to inhibit Aβ accumulation, and has a role in the pathogenesis of AD. SH2B1 may therefore have potential as a therapeutic target for this common form of dementia. Show more

Keywords: Alzheimer’s disease, amyloid-β accumulation, diabetes, SH2B1 protein

DOI: 10.3233/JAD-160233

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 835-847, 2017

Authors: de la Monte, Suzanne M. | Tong, Ming | Schiano, Irio | Didsbury, John

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is associated with progressive impairments in brain insulin, insulin-like growth factor (IGF), and insulin receptor substrate (IRS) signaling through Akt pathways that regulate neuronal growth, survival, metabolism, and plasticity. The intracerebral streptozotocin (i.c. STZ) model replicates the full range of abnormalities in sporadic AD. T3D-959, an orally active PPAR-delta/gamma agonist remediates neurocognitive deficits and AD neuropathology in the i.c. STZ model. Objective: This study characterizes the effects of T3D-959 on AD biomarkers, insulin/IGF/IRS signaling through Akt pathways, and neuroinflammation in an i.c. STZ model. Methods: Long Evans rats were treated with …i.c. STZ or saline, followed by daily oral doses of T3D-959 (1 mg/kg) or saline initiated 1 day (T3D-959-E) or 7 days (T3D-959-L) later through Experimental Day 28. Protein and phospho-protein expression and pro-inflammatory cytokine activation were measured in temporal lobe homogenates by duplex or multiplex bead-based ELISAs. Results: i.c. STZ treatments caused neurodegeneration with increased pTau, AβPP, Aβ42 , ubiquitin, and SNAP-25, and reduced levels of synaptophysin, IGF-1 receptor (R), IRS-1, Akt, p70S6K, mTOR, and S9 -GSK-3β. i.c. STZ also broadly increased neuroinflammation. T3D-959 abrogated or reduced most of the AD neuropathological and biomarker abnormalities, increased/normalized IGF-1R, IRS-1, Akt, p70S6K, and S9 -GSK-3β, and decreased expression of multiple pro-inflammatory cytokines. T3D-959-E or -L effectively restored insulin/IGF signaling, whereas T3D-959-L more broadly resolved neuroinflammation. Conclusion: AD remediating effects of T3D-959 are potentially due to enhanced expression of key insulin/IGF signaling proteins and inhibition of GSK-3β and neuroinflammation. These effects lead to reduced neurodegeneration, cognitive impairment, and AD biomarker levels in the brain. Show more

Keywords: Alzheimer’s disease, cytokines, insulin resistance, neurodegeneration, PPAR delta, rat model, T3D-959

DOI: 10.3233/JAD-160656

Citation: Journal of Alzheimer's Disease, vol. 55, no. 2, pp. 849-864, 2017