Journal of Alzheimer's Disease - Volume 42, issue 2

Authors: Hogervorst, Eef

Article Type: Article Commentary

DOI: 10.3233/JAD-140909

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 583-586, 2014

Authors: Kawahara, Kohichi | Suenobu, Michita | Ohtsuka, Hideyuki | Kuniyasu, Akihiko | Sugimoto, Yukihiko | Nakagomi, Madoka | Fukasawa, Hiroshi | Shudo, Koichi | Nakayama, Hitoshi

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a neurodegenerative process involving amyloid-β (Aβ) peptide deposition, neuroinflammation, and progressive memory loss. Here, we evaluated whether oral administration of retinoic acid receptor (RAR)α,β agonist Am80 (tamibarotene) or specific retinoid X receptor (RXR) pan agonist HX630 or their combination could improve deficits in an AD model, 8.5-month-old amyloid-β protein precursor 23 (AβPP23) mice. Co-administration of Am80 (0.5 mg/kg) and HX630 (5 mg/kg) for 17 days significantly improved memory deficits (Morris water maze) in AβPP23 mice, whereas administration of either agent alone produced no effect. Only co-administration significantly reduced the level of insoluble Aβ peptide in the …brain. These results thus indicate that effective memory improvement via reduction of insoluble Aβ peptide in 8.5-month-old AβPP23 mice requires co-activation of RARα,β and RXRs. RARα-positive microglia accumulated Aβ plaques in the AβPP23 mice. Rat primary microglia co-treated with Am80/HX630 showed increased degradation activity towards 125 I-labeled oligomeric Aβ1-42 peptide in an insulin-degrading enzyme (IDE)-dependent manner. The co-administration increased mRNA for IDE and membrane-associated IDE protein in vivo, suggesting that IDE contributes to Aβ clearance in Am80/HX630-treated AβPP23 mice. Am80/HX630 also increased IL-4Rα expression in microglial MG5 cells. The improvement in memory of Am80/HX630-treated AβPP23 mice was correlated with the levels and signaling of hippocampal interleukin-4 (IL-4). Therefore, Am80/HX630 may promote differentiation of IL-4-responsive M2-like microglia and increase their activity for clearance of oligomeric Aβ peptides by restoring impaired IL-4 signaling in AβPP23 mice. Combination treatment with RAR and RXR agonists may be an effective approach for AD therapy. Show more

Keywords: Alzheimer's disease, Am80, amyloid-β peptides, HX630, interleukin-4, memory improvement

DOI: 10.3233/JAD-132720

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 587-605, 2014

Authors: Hawkins, Kara M. | Sergio, Lauren E.

Article Type: Research Article

Abstract: Background and Objective: Recent evidence suggests that visuomotor behaviors may be disrupted in the very early stages of Alzheimer’s disease (AD). Here we propose that using kinematic measures under conditions that place demands on visual-spatial and cognitive-motor processing may provide an effective behavioral means to detect subtle changes associated with AD risk. Methods: To this end, we have tested 22 young adults (mean age = 26.4 ± 4.1) and 22 older adults (mean age = 64.3 ± 10.1) at low AD, and 22 older adults (mean age = 67.7 ± 11.3) at high AD risk (i.e., strong family …history or diagnosis of mild cognitive impairment). Kinematic measures were acquired on four visuomotor transformation tasks (standard, feedback reversal, plane dissociated, and plane dissociated + feedback reversal) using a dual-touchscreen tablet. Results: Comparing participants at increased AD risk with both young and old healthy control groups revealed significant performance disruptions in at-risk individuals as task demands increased. Furthermore, we were able to discriminate between individuals at high and low AD risk with a classification accuracy of 86.4% (sensitivity: 81.8%, specificity: 90.9%). Conclusion: We suggest that the impairments observed in individuals at increased AD risk may reflect inherent brain alteration and/or early neuropathology disrupting the reciprocal communication between hippocampal, parietal, and frontal brain regions required to successfully prepare and update complex reaching movements. Such impairment has the potential to affect activities of daily living, and may serve as a sensitive measure of functional ability in at-risk adults. Show more

Keywords: Aging, Alzheimer's disease, geriatric assessment, motor skills, movement, neurodegenerative disorder

DOI: 10.3233/JAD-140051

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 607-621, 2014

Authors: Conde-Sala, Josep L. | Turró-Garriga, Oriol | Calvó-Perxas, Laia | Vilalta-Franch, Joan | Lopez-Pousa, Secundino | Garre-Olmo, Josep

Article Type: Research Article

Abstract: Although numerous studies have examined caregiver burden in the context of Alzheimer's disease, discrepancies remain regarding the influence of certain factors. This study aimed to identify trajectories of caregiver burden in the context of Alzheimer's disease, as well as the factors associated with them. A cohort of patients and caregivers (n = 330) was followed up over three years. Growth mixture models were fitted to identify trajectories of caregiver burden according to scores on the Zarit Burden Interview (ZBI). A multilevel multinomial regression analysis was then conducted with the resulting groups and the patient and caregiver factors. In the sample …as a whole, burden increased during follow-up (F = 4.4, p = 0.004). Three groups were identified: G1 (initially high but decreasing burden), G2 (moderate but increasing burden), and G3 (low burden that increased slightly). Patients in G1 and G2 presented more neuropsychiatric symptoms and poorer functional status than did those in G3. Caregivers in G1 and G2 had poorer mental health. Spouses and, especially, adult children who lived with their parent (the patient) were more likely to belong to G2 (odds ratio [OR] 6.24; 95% CI 2.89–13.47), as were sole caregivers (OR 3.51; 95% CI 1.98–6.21). The patient factors associated with increased burden are neuropsychiatric symptoms and functional status, while among caregivers, being the sole carer, poor mental health, and living with the patient are of relevance. Show more

Keywords: Burden, family caregivers, longitudinal studies, mental health, neurobehavioral manifestations

DOI: 10.3233/JAD-140360

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 623-633, 2014

Authors: Edwards, Melissa | Balldin, Valerie Hobson | Hall, James | O'Bryant, Sid

Article Type: Research Article

Abstract: Background: Current work has sought to establish a rapid and cost effective means of screening for Alzheimer’s disease (AD) with the most recent findings showing utility of integrating blood-based biomarkers with cognitive measures. Objective: The current project sought to create a combined biomarker-cognitive profile to detect mild AD. Methods: Data was analyzed from 266 participants (129 AD cases [Early AD n = 93; Very Early AD n = 36]; 137 controls) enrolled in the Texas Alzheimer’s Research and Care Consortium (TARCC). Non-fasting serum samples were collected from each participant and assayed via a multi-plex biomarker assay …platform using electrochemiluminescence. Logistic Regression was utilized to detect early AD using two serum biomarkers (TNFα and IL7), demographic information (age), and one neuropsychological measure (Clock 4-point) as predictor variable. Disease severity was determined via Clinical Dementia Rating (CDR) scale global scores. Results: In the total sample (all levels of CDR scores), the combination of biomarkers, cognitive test score, and demographics yielded the obtained sensitivity (SN) of 0.94, specificity (SP) of 0.90, and an overall accuracy of 0.92. When examining early AD cases (i.e.m CDR = 0.5–1), the biomarker-cognitive profile yielded SN of 0.94, SP of 0.85, and an overall accuracy of 0.91. When restricted to very early AD cases (i.e., CDR = 0.5), the biomarker-cognitive profile yielded SN of 0.97 and SP of 0.72, with an overall accuracy of 0.91. Conclusions: The combination of demographics, two biomarkers, and one cognitive test created a biomarker-cognitive profile that was highly accurate in detecting the presence of AD, even in the very early stages. Show more

Keywords: Alzheimer's disease, biomarkers, molecular, neuropsychology

DOI: 10.3233/JAD-140852

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 635-640, 2014

Authors: Keage, Hannah A.D. | Hunter, Sally | Matthews, Fiona E. | Ince, Paul G. | Hodges, John | Hokkanen, Suvi R.K. | Highley, J. Robin | Dening, Tom | Brayne, Carol | On behalf of the Cambridge City over 75s Cohort

Article Type: Research Article

Abstract: Background: The significance of TDP-43 pathology in relation to aging and dementia in the population is unclear. Objective: We aimed to determine the prevalence of transactive response DNA-binding protein of 43 kDA (TDP-43) neuronal inclusions in a population-based sample, and associations with age group at death (≤90 and >90 years) and clinical dementia status prior to death. Further, we investigate associations between TDP-43 inclusions and other key dementia-related neuropathologies (plaques, tangles, and neuronal loss) within the hippocampus and entorhinal and temporal cortices. Methods: All brain donors within the Cambridge City over-75 s Cohort (CC75C), which is …population-based and longitudinally tracked (n = 228), were included. Age at death ranged from 78 to 106 years. TDP-43 neuronal inclusions were assessed in the hippocampus, entorhinal cortex, and temporal cortex. These data were combined with existing clinical and neuropathological data. Results: TDP-43 neuronal inclusions were present in 27% of the sample, 36% of those with clinical dementia and 18% without dementia. Individuals who died later (>90 years) or with clinical dementia were more likely to show TDP-43 inclusions. Hippocampal and entorhinal TDP-43 inclusions were significantly associated with dementia severity and increasing age, taking into account other neuropathologies. TDP-43 neuronal inclusions appeared to be co-localize with severe neuronal loss. Conclusion: Findings indicate that hippocampal and entorhinal TDP-43 inclusions are important substrates of late onset dementia which appear to co-localize with severe neuronal loss, but not with Alzheimer’s disease markers of amyloid and tau. This broadens the accepted view of TDP-43 pathology in dementias. Show more

Keywords: Aging, Alzheimer's disease, aging, dementia, population, TDP-43

DOI: 10.3233/JAD-132351

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 641-650, 2014

Authors: Peter, Jessica | Abdulkadir, Ahmed | Kaller, Christoph | Kümmerer, Dorothee | Hüll, Michael | Vach, Werner | Klöppel, Stefan | for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Although episodic memory impairment is usually the earliest sign of Alzheimer's disease (AD), there are up to 15% of patients presenting with early impairment in non-memory cognitive functions (i.e., atypical AD). Stratifying patients with AD may aid clinical trials. Previous studies divided patients by cognitive profile, focusing on cross-sectional analyses without testing stability of clusters over time. We used principal component analysis followed by cluster analyses in 127 patients with AD based on 24 cognitive scores at 0, 6, 12, and 24 months follow-up. We investigated the definition of clusters and their stability over time as well as interactions of …cluster assignment and disease severity. At each time point, six distinct factors and four distinct clusters were extracted that did not differ substantially between time points. Clusters were defined by cognitive profile rather than disease severity. 85% of patients fell into the same cluster twice, 42% three times, and 17% four times. Subjects with focal semantic impairment progressed significantly faster than the other cluster. Longitudinally, focal deficits increased relatively rather than tending toward average disease severity. The observed similar cluster definitions at each time point indicate the validity of the approach. Cluster-specific longitudinal increases of focal impairments and significant between-cluster differences in disease progression make this approach useful for stratified inclusion into clinical trials. Show more

Keywords: Alzheimer's disease, atypical AD, cluster analysis, clustering, subgroups, subtypes, typical AD

DOI: 10.3233/JAD-140261

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 651-661, 2014

Authors: Wang, Chong | Yu, Jin-Tai | Wang, Hui-Fu | Tan, Chen-Chen | Meng, Xiang-Fei | Tan, Lan

Article Type: Research Article

Abstract: Background: Non-pharmacological interventions, including cognition-based intervention and physical exercise, are available for mild cognitive impairment (MCI), but their efficacy remains uncertain. Objective: To evaluate efficacy of cognition-based intervention and physical exercise on cognitive domains in patients with MCI. Methods: We searched MEDLINE, EMBASE, the Cochrane library, and BIOSIS previews to identify randomized controlled trials (RCTs) that involved cognition-based intervention and physical exercise for persons who were diagnosed with MCI. The pooled weight mean difference or standard mean difference (SMD) were calculated using a random-effect model. Results: We found significant effects of cognition-based intervention on …global cognitive function (SMD 0.37 [0.07, 0.68] p = 0.02). Besides, cognition-based intervention produced significant effects on executive function reported with TMT-B (SMD 0.8 [0.09, 1.5] p = 0.03) and delayed memory (SMD 0.31 [0.01, 0.61] p = 0.05). A beneficial improvement in global cognitive function was also seen in the exercise group compared to the control group (SMD 0.25 [0.08, 0.41] p = 0.003). Conclusions: Both of cognition-based intervention and physical exercise had the potential to improve global cognitive function. Weak evidence of improvements was also observed for the domains of executive function and delayed memory following cognition-based intervention. Nevertheless, future standard RCTs are still needed to identify the clinical value of our results. Show more

Keywords: Cognition-based intervention, cognitive function, exercise, meta-analysis, mild cognitive impairment, non-pharmacological interventions

DOI: 10.3233/JAD-140660

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 663-678, 2014

Authors: Tao, Yunlong | Wang, Yu | Rogers, Jack T. | Wang, Fudi

Article Type: Research Article

Abstract: Background: The homeostasis and physiological role of iron in Alzheimer’s disease (AD) has been debated for decades. Overall, it has been difficult to reach a consensus to prove marked disease-associated changes in the iron content of the AD brain, blood, or cerebrospinal fluid (CSF). Objectives: We sought to contribute to resolve this issue by quantifying the iron content in serum, CSF, and sub-regions of the AD brain. Methods: We conducted a comprehensive systematic meta-analysis and review of multiple observational studies till October 2013 that investigated the iron content in AD serum, CSF, or brain tissue. …Results: 2,556 publications were screened. Forty-three eligible studies with 1,813 AD patients and 2,401 healthy controls were identified. Twenty-one studies investigated the serum iron in AD while seven and nineteen studies investigated the CSF iron and various brain regions iron respectively. Our meta-analysis showed that serum iron was significant lower in AD than healthy controls. CSF iron appeared not to be affected by AD although more studies are required due to the relative small number of CSF studies reported to date. We critically analyzed iron content in twelve selective brain regions by separated meta-analyses using cross-referenced statistical methods. We found that eight specific brain regions had higher iron concentrations that correlated with the clinical diagnosis of AD in a statistically validated manner. Conclusions: These data provided rigorous statistical support for the model that iron homeostasis was changed in AD patients, including the finding of lower iron in their serum and evidence for iron overload in several specific brain regions. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, iron, iron overload, meta-analysis, serum iron, systematic review

DOI: 10.3233/JAD-140396

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 679-690, 2014

Authors: Guo, Hui | Song, Xiaowei | Schmidt, Matthias H. | Vandorpe, Robert | Yang, Zhan | LeBlanc, Emily | Zhang, Jing | Beyea, Steven | Zhang, Yunting | Rockwood, Kenneth | for the Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The Brain Atrophy and Lesion Index (BALI), a semi-quantitative rating scale, has been developed to evaluate whole brain structural changes in aging and Alzheimer’s disease (AD). Objective: This study describes a standard procedure to score the BALI and train new raters for reliable BALI evaluation following this procedure. Methods: Structural MRI of subjects in the Alzheimer’s Disease Neuroimaging Initiative dataset who had 3.0T, T1, and T2 weighted MRI scans at baseline and at 6, 12, and 24 month follow-ups were retrieved (n = 122, including 24 AD, 51 mild cognitive impairment patients, and 47 healthy …control subjects). Images were evaluated by four raters following training with a step-by-step BALI process. Seven domains of structural brain changes were evaluated, and a total score was calculated as the sum of the sub-scores. Results: New raters achieved >90% accuracy after two weeks of training. Reliability was shown in both intra-rater correlation coefficients (ICC ≥ 0.92, p < 0.001) and inter-rater correlation coefficients (ICC ≥0.88, p < 0.001). Mean BALI total scores differed by diagnosis (F ≥ 2.69, p ≤ 0.049) and increased consistently over two years. Conclusion: The BALI can be introduced using a standard procedure that allows new users to achieve highly reliable evaluation of structural brain changes. This can advance its potential as a robust method for assessing global brain health in aging, AD, and mild cognitive impairment. Show more

Keywords: Aging, Alzheimer's disease, brain, Brain Atrophy and Lesion Index (BALI), cognition, structural MRI

DOI: 10.3233/JAD-140333

Citation: Journal of Alzheimer's Disease, vol. 42, no. 2, pp. 691-703, 2014