Journal of Alzheimer's Disease - Volume 53, issue 3

Authors: Van Langenhove, Tim | Leyton, Cristian E. | Piguet, Olivier | Hodges, John R.

Article Type: Research Article

Abstract: Background: Differentiating between primary progressive aphasia (PPA) variants based on the profile of language deficits can be difficult in a proportion of patients. Further, little is presently know about the pattern of longitudinal changes in behavior in PPA variants. Objective: To determine the presence of behavioral changes in the main variants of PPA: semantic (sv-PPA), nonfluent/agrammatic (nfv-PPA), and logopenic (lv-PPA), and establish the course of these changes over time. Methods: We measured behavioral changes in 73 prospectively recruited PPA (30 sv-PPA, 22 nfv-PPA, and 21 lv-PPA), as well as 33 behavioral variant frontotemporal dementia (bv-FTD) …and 31 Alzheimer’s disease (AD) patients, at baseline and after 1 year, using the Cambridge Behavioural Inventory Revised. All included patients had mild dementia severity at baseline. Results: Both at baseline and follow-up, sv-PPA exhibited significantly more behavioral disturbances of the type characteristic of bv-FTD compared with other PPA variants. 74% of sv-PPA patients with mild dementia severity exhibited at least one behavior disturbance at baseline, which increased to 84% during follow-up. Behavioral symptoms did not differ between nfv-PPA and lv-PPA groups at baseline. At follow-up, however, empathy loss was significantly more pronounced in nfv-PPA. The prevalence and course of behavioral symptoms in lv-PPA was similar to that found in AD. Conclusions: sv-PPA show more prominent FTD-like behavioral disturbances compared with other PPA variants which typically emerge already early in the disease course. Empathy loss may be an important factor that helps differentiating nfv-PPA from lv-PPA. Our results may allow improved prediction of likely progression in behavioral symptoms across the PPA variants. Show more

Keywords: Behavioral symptoms, empathy, frontotemporal dementia, longitudinal studies, primary progressive aphasia

DOI: 10.3233/JAD-160010

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1033-1042, 2016

Authors: Callisaya, Michele L. | Ayers, Emmeline | Barzilai, Nir | Ferrucci, Luigi | Guralnik, Jack M. | Lipton, Richard B. | Otahal, Petr | Srikanth, Velandai K. | Verghese, Joe

Article Type: Research Article

Abstract: Background: The Motoric Cognitive Risk Syndrome (MCR) is characterized by slow gait speed and cognitive complaints. Objectives: The objective of this study was to determine if the presence of MCR increases the risk of falls in older people. Methods: Individual participant data (n  = 6,204) from five longitudinal studies from three countries were used for this analysis. MCR diagnosis was defined as both the presence of objectively measured slow gait speed and subjective cognitive complaints in those without dementia or mobility disability. Falls were prospectively ascertained using phone calls or questionnaires. Log binomial regression was performed …to determine if MCR increased the risk of falls separately in each cohort. Random effects meta-analysis was used to pool results from all cohorts. Results: The mean age of participants was 74.9 (SD 6.8) years and 44% (n  = 2728) were male. Overall 33.9% (n  = 2104) reported a fall over follow-up. Pooled relative risk of MCR with any falls was RR 1.44 95% CI 1.16, 1.79. The components of MCR, slow gait (RR 1.30 95% CI 1.14, 1.47) and cognitive complaint (RR 1.25, 95% CI 1.07, 1.46) were also associated with an increased risk of any falls. In sub-analyses MCR was associated with any fall independent of previous falls (RR 1.29 95% CI 1.09, 1.53) and with multiple falls (RR 1.77, 95% CI 1.25, 2.51). Conclusion: MCR is associated with an increased risk of falls. The increase in risk was higher than for its individual components. The simplicity of the MCR makes it an attractive falls risk screening tool for the clinic. Show more

Keywords: Cognition, dementia, falls, gait

DOI: 10.3233/JAD-160230

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1043-1052, 2016

Authors: Lin, Chih-Yun | Cheng, Yu-Sung | Liao, Tai-Yan | Lin, Chen | Chen, Zih-ten | Twu, Woan-Ing | Chang, Chi-Wei | Tan, David Tat-Wei | Liu, Ren-Shyan | Tu, Pang-hsien | Chen, Rita P.-Y.

Article Type: Research Article

Abstract: Amyloid-β (Aβ) aggregation in the brain plays a central and initiatory role in pathogenesis and/or progression of Alzheimer’s disease (AD). Inhibiting Aβ aggregation is a potential strategy in the prevention of AD. A scavenger peptide, V24P(10–40), designed to decrease Aβ accumulation in the brain, was conjugated to polyethylenimine (PEI) and tested as a preventive/therapeutic strategy for AD in this study. This PEI-conjugated V24P(10–40) peptide was delivered intranasally, as nasal drops, to four-month-old APP/PS1 double transgenic mice for four or eight months. Compared with control values, peptide treatment for four months significantly reduced the amount of GdnHCl-extracted Aβ40 and Aβ42 …in the mice’s hippocampus and cortex. After treatment for eight months, amyloid load, as quantified by Pittsburgh compound B microPET imaging, was significantly decreased in the mice’s hippocampus, cortex, amygdala, and olfactory bulb. Our data suggest that this intranasally delivered scavenger peptide is effective in decreasing Aβ accumulation in the brain of AD transgenic mice. Nasal application of peptide drops is easy to use and could be further developed to prevent and treat AD. Show more

Keywords: Aggregate, Alzheimer’s disease, amyloid, amyloid-β, D-proline, fibril, peptide inhibitor, scavenger peptide, therapy

DOI: 10.3233/JAD-151024

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1053-1067, 2016

Authors: Marseglia, Anna | Fratiglioni, Laura | Laukka, Erika J. | Santoni, Giola | Pedersen, Nancy L. | Bäckman, Lars | Xu, Weili

Article Type: Research Article

Abstract: Evidence links type 2 diabetes to dementia risk. However, our knowledge on the initial cognitive deficits in diabetic individuals and the factors that might promote such deficits is still limited. This study aimed to identify the cognitive domains initially impaired by diabetes and the factors that play a role in this first stage. Within the population-based Swedish National Study on Aging and Care–Kungsholmen, 2305 cognitively intact participants aged ≥60 y were identified. Attention/working memory, perceptual speed, category fluency, letter fluency, semantic memory, and episodic memory were assessed. Diabetes (controlled and uncontrolled) and prediabetes were ascertained by clinicians, who also collected information …on vascular disorders (hypertension, heart diseases, and stroke) and vascular risk factors (VRFs, including smoking and overweight/obesity). Data were analyzed with linear regression models. Overall, 196 participants (8.5%) had diabetes, of which 144 (73.5%) had elevated glycaemia (uncontrolled diabetes); 571 (24.8%) persons had prediabetes. In addition, diabetes, mainly uncontrolled, was related to lower performance in perceptual speed (β – 1.10 [95% CI – 1.98, – 0.23]), category fluency (β – 1.27 [95% CI – 2.52, – 0.03]), and digit span forward (β – 0.35 [95% CI – 0.54, – 0.17]). Critically, these associations were present only among APOE ɛ 4 non–carriers. The associations of diabetes with perceptual speed and category fluency were present only among participants with VRFs or vascular disorders. Diabetes, especially uncontrolled diabetes, is associated with poorer performance in perceptual speed, category fluency, and attention/primary memory. VRFs, vascular disorders, and APOE status play a role in these associations. Show more

Keywords: Apolipoprotein E4, cognition, type 2 diabetes mellitus, vascular disorders

DOI: 10.3233/JAD-160266

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1069-1078, 2016

Authors: Vermeiren, Yannick | Janssens, Jana | Aerts, Tony | Martin, Jean-Jacques | Sieben, Anne | Van Dam, Debby | De Deyn, Peter P.

Article Type: Research Article

Abstract: Routinely prescribed psychoactive drugs in behavioral variant frontotemporal dementia (FTD) for improvement of (non)cognitive symptoms are primarily based on monoamine replacement or augmentation strategies. These were, however, initially intended to symptomatically treat other degenerative, behavioral, or personality disorders, and thus lack disease specificity. Moreover, current knowledge on brain monoaminergic neurotransmitter deficiencies in this presenile disorder is scarce, particularly with reference to changes in Alzheimer’s disease (AD). The latter hence favors neurochemical comparison studies in order to elucidate the monoaminergic underpinnings of FTD compared to early-onset AD, which may contribute to better pharmacotherapy. Therefore, frozen brain samples, i.e., Brodmann area (BA) …6/8/9/10/11/12/22/24/46, amygdala, and hippocampus, of 10 neuropathologically confirmed FTD, AD, and control subjects were analyzed by means of reversed-phase high-performance liquid chromatography. Levels of serotonergic, dopaminergic, and noradrenergic compounds were measured. In nine brain areas, serotonin (5-HT) concentrations were significantly increased in FTD compared to AD patients, while 5-hydroxyindoleacetic acid/5-HT ratios were decreased in eight regions, also compared to controls. Furthermore, in all regions, noradrenaline (NA) levels were significantly higher, and 3-methoxy-4-hydroxyphenylglycol/NA ratios were significantly lower in FTD than in AD and controls. Contrarily, significantly higher dopamine (DA) levels and reduced homovanillic acid/DA ratios were only found in BA12 and BA46. Results indicate that FTD is defined by distinct serotonergic and noradrenergic deficiencies. Additional research regarding the interactions between both monoaminergic networks is required. Similarly, clinical trials investigating the effects of 5-HT1A receptor antagonists or NA-modulating agents, such as α 1/2 /β1 -blockers, seem to have a rationale and should be considered. Show more

Keywords: Alzheimer’s disease, brain tissue, frontotemporal dementia, monoamines, neurochemistry, neuropsychiatric symptoms, noradrenaline, prefrontal cortex, RP-HPLC-ECD, serotonin

DOI: 10.3233/JAD-160320

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1079-1096, 2016

Authors: Hsu, David C. | Mormino, Elizabeth C. | Schultz, Aaron P. | Amariglio, Rebecca E. | Donovan, Nancy J. | Rentz, Dorene M. | Johnson, Keith A. | Sperling, Reisa A. | Marshall, Gad A. | for the Harvard Aging Brain Study

Article Type: Research Article

Abstract: Background: Lower body-mass index (BMI) in late life has been associated with an increased risk of dementia, and weight loss has been associated with more rapid decline in Alzheimer’s disease (AD) dementia. Objective: To explore the association between BMI and cortical amyloid burden in clinically normal (CN) elderly at risk for AD dementia. Methods: Cross-sectional analyses were completed using baseline data from the Harvard Aging Brain Study, consisting of 280 community-dwelling CN older adults aged 62–90. Assessments included medical histories and physical exam, Pittsburgh compound B (PiB) positron emission tomography (PET) amyloid imaging, and apolipoprotein …E ɛ 4 (APOE4) genotyping. For the primary analysis, a general linear regression model was used to evaluate the association of BMI with PiB retention. Covariates included age, sex, years of education, and APOE4 carrier status. Secondary analyses were performed for BMI subdivisions (normal, overweight, obese), APOE4 carriers, and BMI×APOE4 interaction. Results: In the primary analysis, greater PiB retention was associated with lower BMI (β  =  –0.14, p  = 0.02). In the secondary analyses, APOE4 carrier status (β= –0.27, p  = 0.02) and normal BMI (β= –0.25, p  = 0.01), as opposed to overweight or obese BMI, were associated with greater PiB retention. The BMI×APOE4 interaction was also significant (β= –0.14, p  = 0.04). Conclusions: This finding offers new insight into the role of BMI at the preclinical stage of AD, wherein lower BMI late in life is associated with greater cortical amyloid burden. Future studies are needed to elucidate the mechanism behind this association, especially in those with lower BMI who are APOE4 carriers. Show more

Keywords: Alzheimer’s disease, amyloid, apolipoprotein E, body mass index, clinically normal elderly, Pittsburgh compound B, positron emission tomography

DOI: 10.3233/JAD-150987

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1097-1105, 2016

Authors: Feeney, Joanne | Savva, George M. | O’Regan, Claire | King-Kallimanis, Bellinda | Cronin, Hilary | Kenny, Rose Anne

Article Type: Research Article

Abstract: Background: Knowing the reliability of cognitive tests, particularly those commonly used in clinical practice, is important in order to interpret the clinical significance of a change in performance or a low score on a single test. Objective: To report the intra-class correlation (ICC), standard error of measurement (SEM) and minimum detectable change (MDC) for the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Color Trails Test (CTT) among community dwelling older adults. Methods: 130 participants aged 55 and older without severe cognitive impairment underwent two cognitive assessments between two and four months apart. Half …the group changed rater between assessments and half changed time of day. Results: Mean (standard deviation) MMSE was 28.1 (2.1) at baseline and 28.4 (2.1) at repeat. Mean (SD) MoCA increased from 24.8 (3.6) to 25.2 (3.6). There was a rater effect on CTT, but not on the MMSE or MoCA. The SEM of the MMSE was 1.0, leading to an MDC (based on a 95% confidence interval) of 3 points. The SEM of the MoCA was 1.5, implying an MDC95 of 4 points. MoCA (ICC = 0.81) was more reliable than MMSE (ICC = 0.75), but all tests examined showed substantial within-patient variation. Conclusion: An individual’s score would have to change by greater than or equal to 3 points on the MMSE and 4 points on the MoCA for the rater to be confident that the change was not due to measurement error. This has important implications for epidemiologists and clinicians in dementia screening and diagnosis. Show more

Keywords: Aging, cognition, measurement error, reliability

DOI: 10.3233/JAD-160248

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1107-1114, 2016

Authors: Lee, Chaeyoung

Article Type: Research Article

Abstract: Genetic factors of sporadic vascular dementia have been quite limitedly understood. Many underlying polygenes are suspected to contribute to susceptibility to sporadic vascular dementia as a typical complex disease although they have not been identified from genome-wide association studies. This study suggests a stochastic prediction of individual polygenetic susceptibility to sporadic vascular dementia using best linear unbiased prediction in a mixed model framework. The prediction shows a relative degree of individual genetic susceptibility to the disease that reflects its integrative polygenetic factors across the genome. The estimate should take into account heritability and the prevalence of sporadic vascular dementia to …cope with the disease. This offers a model for application of a genetic blueprint for a complex disease to personalized preventive medicine. Show more

Keywords: Complex trait, genetics, genome-wide association study, mixed model, vascular dementia

DOI: 10.3233/JAD-160391

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1115-1119, 2016

Authors: Vanderstichele, Hugo Marcel Johan | Janelidze, Shorena | Demeyer, Leentje | Coart, Els | Stoops, Erik | Herbst, Victor | Mauroo, Kimberley | Brix, Britta | Hansson, Oskar

Article Type: Research Article

Abstract: Background: Reduced cerebrospinal fluid (CSF) concentration of amyloid-β1-42 (Aβ1-42 ) reflects the presence of amyloidopathy in brains of subjects with Alzheimer’s disease (AD). Objective: To qualify the use of Aβ1-42 /Aβ1-40 for improvement of standard operating procedures (SOP) for measurement of CSF Aβ with a focus on CSF collection, storage, and analysis. Methods: Euroimmun ELISAs for CSF Aβ isoforms were used to set up a SOP with respect to recipient properties (low binding, polypropylene), volume of tubes, freeze/thaw cycles, addition of detergents (Triton X-100, Tween-20) in collection or storage tubes or during CSF …analysis. Data were analyzed with linear repeated measures and mixed effects models. Results: Optimization of CSF analysis included a pre-wash of recipients (e.g., tubes, 96-well plates) before sample analysis. Using the Aβ1-42 /Aβ1-40 ratio, in contrast to Aβ1-42 , eliminated effects of tube type, additional freeze/thaw cycles, or effect of CSF volumes for polypropylene storage tubes. ‘Low binding’ tubes reduced the loss of Aβ when aliquoting CSF or in function of additional freeze/thaw cycles. Addition of detergent in CSF collection tubes resulted in an almost complete absence of variation in function of collection procedures, but affected the concentration of Aβ isoforms in the immunoassay. Conclusion: The ratio of Aβ1-42 /Aβ1-40 is a more robust biomarker than Aβ1-42 toward (pre-) analytical interfering factors. Further, ‘low binding’ recipients and addition of detergent in collection tubes are able to remove effects of SOP-related confounding factors. Integration of the Aβ1-42 /Aβ1-40 ratio and ‘low-binding tubes’ into guidance criteria may speed up worldwide standardization of CSF biomarker analysis. Show more

Keywords: Amyloid, cerebrospinal fluid, ELISA, improvement, standard operating procedure

DOI: 10.3233/JAD-160286

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1121-1132, 2016

Authors: Perales, Jaime | Turró-Garriga, Oriol | Gascón-Bayarri, Jordi | Reñé-Ramírez, Ramón | Conde-Sala, Josep Lluís

Article Type: Research Article

Abstract: Background: According to cross-sectional studies, there is an association between anosognosia in people with dementia and caregiver’s burden and depression. Anosognosia in patients may be a cause of caregiver burden and depression. However, variability in caregiver anosognosia ratings may exist as caregivers with burden and depression may have a more pessimistic view of the patients’ health. Objective: To assess the variability of caregiver anosognosia ratings of patients with dementia using a widely used anosognosia scale and its longitudinal relationship with caregiver burden and depression. Methods: A convenience cohort of 221 consecutive dementia outpatient and caregiver …dyads was followed up at 12 and 24 months. The main instruments used were the Anosognosia Questionnaire-Dementia (AQ-D), Caregiver Burden Interview, and Geriatric Depression Scale. Linear mixed models were used including time as a factor in every model. Multivariate analyses controlled for caregiver’s socio-demographic and possible confounding factors. Results: Attrition at 12 and 24 months was 24.9% and 42.5% respectively. Patients at baseline were on average 77.8 years of age, 63.3% were women, and 63.3% had < 5 years of education. In the bivariate analyses, caregiver burden, depression, and gender were associated with caregiver ratings of total, cognitive, and personality AQ-D of the patient at different time points. Multivariate analyses revealed burden as the caregiver variable most consistently associated with total, cognitive, and personality caregiver AQ-D ratings of the patient. Conclusion: Some caregiver characteristics, especially burden, are associated with caregiver ratings of AQ-D with regard to the patient. Show more

Keywords: Anosognosia, bias, burden of illness, caregivers, dementia, depression, longitudinal studies

DOI: 10.3233/JAD-160065

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 1133-1143, 2016