Town of Jay Annual Report Year Ending June 30, 2014

status: publishe

Integrated Care Models for Older Adults with Depression and Physical Comorbidity: A Scoping Review

Objective: Multimorbidity is a growing challenge in the care for older people with mental illness. To address both physical and mental illnesses, integrated care management is required. The purpose of this scoping review is to identify core components of integrated care models for older adults with depression and physical comorbidity, and map reported outcomes and implementation strategies. Methods: PubMed, EMBASE, CINAHL and Cochrane Library were searched independently by two reviewers for studies concerning integrated care interventions for older adults with depression and physical comorbidity. We used the SELFIE framework to map core components of integrated care models. Clinical and organisational outcomes were mapped. Results: Thirty-eight studies describing thirteen care models were included. In all care models, a multidisciplinary team was involved. The following core components were mainly described: continuity, person-centredness, tailored holistic assessment, pro-activeness, treatment interaction, individualized care planning, and coordination tailored to complexity of care needs. Twenty-seven different outcomes were evaluated, with more attention given to clinical than to organisational outcomes. Conclusion: The core components that comprise integrated care models are diverse. Future studies should focus more on implementation aspects of the intervention and describe financial parts, e.g., the cost of the intervention for the healthcare user, more transparently

What are the factors associated with physical activity (PA) participation in community dwelling adults with dementia? A systematic review of PA correlates

PA shows promise as a modifiable lifestyle intervention to benefit pathological symptoms of dementia. However, little is known about the factors associated with participation in PA in community dwelling adults with dementia. A systematic review was undertaken to identify PA correlates. Two independent reviewers searched major electronic databases and extracted data on studies reporting quantitative correlates of PA participation in community dwelling adults with dementia. PA correlates were analyzed using the summary code approach within the socio-ecological model. Out of a potential of 118 articles, 12 met the eligibility criteria encompassing 752 participants. We conducted secondary analysis on nine data sets. Increased energy intake, resting metabolic rate, fat free mass, gait speed, global motor function, overall health related quality of life (HRQOL), physical HRQOL, higher levels of social functioning and reduced apathy were positively associated with PA. Taking ≥four medications, dizziness, lower activities of daily living (ADL) function, a history of falls, less waking hours in the day, more autonomic problems and delirium were negatively associated with PA. Increasing age and lower global cognition were not consistently associated with PA participation. It is surprising that increasing age and lower global cognition do not appear to influence PA participation. All significant correlates should be confirmed in prospective studies with particular focus on the relationship of PA and gait speed, ADL function, falls history and dietary intake and the progression of frailty and nursing home admission as a priority

A 22-single nucleotide polymorphism Alzheimer's disease risk score correlates with family history, onset age, and cerebrospinal fluid Aβ42

Introduction: The ability to identify individuals at increased genetic risk for Alzheimer's disease (AD) may streamline biomarker and drug trials and aid clinical and personal decision making. Methods: We evaluated the discriminative ability of a genetic risk score (GRS) covering 22 published genetic risk loci forADin 1162 Flanders-BelgianADpatients and 1019 controls and assessed correlations with family history, onset age, and cerebrospinal fluid (CSF) biomarkers (A beta(1-42), T-Tau, P-Tau(181P)). Results: A GRS including all single nucleotide polymorphisms (SNPs) and age-specific APOE epsilon 4 weights reached area under the curve (AUC) 0.70, which increased to AUC 0.78 for patients with familial predisposition. Risk of AD increased with GRS (odds ratio, 2.32 (95% confidence interval 2.08-2.58 per unit; P < 1.0e(-15)). Onset age and CSF Ab1-42 decreased with increasing GRS (P-onset_age 5 9.0e(-11); P-A beta = 8.9e(-7)). Discussion: The discriminative ability of this 22-SNP GRS is still limited, but these data illustrate that incorporation of age-specific weights improves discriminative ability. GRS-phenotype correlations highlight the feasibility of identifying individuals at highest susceptibility. (C) 2015 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association

The efficacy of exergaming in people with major neurocognitive disorder residing in long-term care facilities: a pilot randomized controlled trial

Background: It is currently unknown whether exergaming is efficacious in people with major neurocognitive disorder (MNCD) residing in long-term care facilities. This pilot randomized controlled trial (RCT) explored the efficacy of a stepping exergame program on gait speed, balance, mobility, reaction time, cognitive and neuropsychiatric outcomes, quality of life, and daily life functioning in people with MNCD residing in long-term care facilities. Methods: Participants were randomly assigned to 8 weeks, three times weekly, 15 min of exergaming versus watching preferred music videos. The exergame device consisted of a pressure-sensitive step training platform on which participants performed stepping movements to play the games. The device automatically adapted the training level to the participants’ capabilities. The Short Physical Performance Battery (SPPB), step reaction time test (SRTT), Montréal Cognitive Assessment (MoCA), Neuropsychiatric Inventory (NPI), Cornell Scale for Depression in Dementia (CSDD), Dementia Quality of Life (DQoL), and Katz Activities of Daily Living (Katz ADL) were assessed at baseline and post-intervention. A Quade’s non-parametric ANCOVA controlling for baseline values with post hoc Bonferroni correction (p < 0.00625) was used to analyze pre- and post-differences between the groups. Partial eta-squared (η2p) effect sizes were calculated. Results: Forty-five of 55 randomized inpatients with mild to moderate MNCD (Mini-Mental State Examination score = 17.2 ± 4.5; aged 70–91; 35 women) completed the study. The exergame group (n = 23) demonstrated improvements in gait speed (p < 0.001, η2p = 0.41), total SPPB (p < 0.001, η2p = 0.64), SRTT (p<0.001, η2p = 0.51), MoCA (p<0.001, η2p = 0.38), and reductions in CSDD (p<0.001, η2p = 0.43) compared to the control group (n = 22). There were no differences in NPI (p = 0.165, η2p = 0.05), DQoL (p = 0.012, η2p = 0.16), and ADL (p = 0.008, η2p = 0.16) post-intervention scores between the experimental and control group, albeit DQol and ADL measures showed large effect sizes in the exergame group. The mean attendance rate was 82.9% in the exergame group and 73.7% in the music control group. There were no study-related adverse events reported by the participants, nor observed by the research team. Conclusions: The findings of this pilot RCT suggest that an individually adapted exergame training improves lower extremity functioning, cognitive functioning and step reaction time and symptoms of depression in inpatients with MNCD residing in long-term care facilities

A 22-single nucleotide polymorphism Alzheimer's disease risk score correlates with family history, onset age, and cerebrospinal fluid A beta(42)

Introduction: The ability to identify individuals at increased genetic risk for Alzheimer's disease (AD) may streamline biomarker and drug trials and aid clinical and personal decision making. Methods: We evaluated the discriminative ability of a genetic risk score (GRS) covering 22 published genetic risk loci forADin 1162 Flanders-BelgianADpatients and 1019 controls and assessed correlations with family history, onset age, and cerebrospinal fluid (CSF) biomarkers (A beta(1-42), T-Tau, P-Tau(181P)). Results: A GRS including all single nucleotide polymorphisms (SNPs) and age-specific APOE epsilon 4 weights reached area under the curve (AUC) 0.70, which increased to AUC 0.78 for patients with familial predisposition. Risk of AD increased with GRS (odds ratio, 2.32 (95% confidence interval 2.08-2.58 per unit; P <1.0e(-15)). Onset age and CSF Ab1-42 decreased with increasing GRS (P-onset_age 5 9.0e(-11); P-A beta = 8.9e(-7)). Discussion: The discriminative ability of this 22-SNP GRS is still limited, but these data illustrate that incorporation of age-specific weights improves discriminative ability. GRS-phenotype correlations highlight the feasibility of identifying individuals at highest susceptibility. (C) 2015 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association. This is an open access article under the CC BY-NC-ND licens

LATE-NC aggravates GVD-mediated necroptosis in Alzheimer's disease

It has become evident that Alzheimer's Disease (AD) is not only linked to its hallmark lesions-amyloid plaques and neurofibrillary tangles (NFTs)-but also to other co-occurring pathologies. This may lead to synergistic effects of the respective cellular and molecular players, resulting in neuronal death. One of these co-pathologies is the accumulation of phosphorylated transactive-response DNA binding protein 43 (pTDP-43) as neuronal cytoplasmic inclusions, currently considered to represent limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), in up to 70% of symptomatic AD cases. Granulovacuolar degeneration (GVD) is another AD co-pathology, which also contains TDP-43 and other AD-related proteins. Recently, we found that all proteins required for necroptosis execution, a previously defined programmed form of neuronal cell death, are present in GVD, such as the phosphorylated necroptosis executioner mixed-lineage kinase domain-like protein (pMLKL). Accordingly, this protein is a reliable marker for GVD lesions, similar to other known GVD proteins. Importantly, it is not yet known whether the presence of LATE-NC in symptomatic AD cases is associated with necroptosis pathway activation, presumably contributing to neuron loss by cell death execution. In this study, we investigated the impact of LATE-NC on the severity of necroptosis-associated GVD lesions, phosphorylated tau (pTau) pathology and neuronal density. First, we used 230 human post-mortem cases, including 82 controls without AD neuropathological changes (non-ADNC), 81 non-demented cases with ADNC, i.e.: pathologically-defined preclinical AD (p-preAD) and 67 demented cases with ADNC. We found that Braak NFT stage and LATE-NC stage were good predictors for GVD expansion and neuronal loss in the hippocampal CA1 region. Further, we compared the impact of TDP-43 accumulation on hippocampal expression of pMLKL-positive GVD, pTau as well as on neuronal density in a subset of nine non-ADNC controls, ten symptomatic AD cases with (ADTDP+) and eight without LATE-NC (ADTDP-). Here, we observed increased levels of pMLKL-positive, GVD-exhibiting neurons in ADTDP+ cases, compared to ADTDP- and controls, which was accompanied by augmented pTau pathology. Neuronal loss in the CA1 region was increased in ADTDP+ compared to ADTDP- cases. These data suggest that co-morbid LATE-NC in AD impacts not only pTau pathology but also GVD-mediated necroptosis pathway activation, which results in an accelerated neuronal demise. This further highlights the cumulative and synergistic effects of comorbid pathologies leading to neuronal loss in AD. Accordingly, protection against necroptotic neuronal death appears to be a promising therapeutic option for AD and LATE

Characterization of gray matter volume changes from one week to 6 months after termination of electroconvulsive therapy in depressed patients

Background: Increased gray matter volume (GMV) following electroconvulsive therapy (ECT) has been well-documented, with limited studies reporting a subsequent decrease in GMV afterwards. Objective: This study characterized the reversion pattern of GMV after ECT and its association with clinical depression outcome, using multi-site triple time-point data from the Global ECT-MRI Research Collaboration (GEMRIC). Methods: 86 subjects from the GEMRIC database were included, and GMV in 84 regions-of-interest (ROI) was obtained from automatic segmentation of T1 MRI images at three timepoints: pre-ECT (T0), within one-week post-ECT (T1), and one to six months post-ECT (T2). RM-ANOVAs were used to assess longitudinal changes and LMM analyses explored associations between GMV changes and demographical and clinical characteristics. Results: 63 of the 84 ROIs showed a significant increase-and-decrease pattern (RM-ANOVA, Bonferroni corrected p &lt; 0.00059). Post hoc tests indicated a consistent pattern in each of these 63 ROIs: significant increase from T0 to T1inGMV, followed by significant decrease from T1 to T2 and no difference between T0 and T2, except for both amygdalae, right hippocampus and pars triangularis, which showed the same increase and decrease but GMV at T2 remained higher compared to T0. No consistent relationship was found between GMV change pattern and clinical status. Conclusion: The GEMRIC cohort confirmed a rapid increase of GMV after ECT followed by reversion of GMV one to six months thereafter. The lack of association between the GMV change pattern and depression outcome scores implies a transient neurobiological effect of ECT unrelated to clinical improvement.</p

Effective resting-state connectivity in severe unipolar depression before and after electroconvulsive therapy

Background Electroconvulsive therapy (ECT) is one of the most effective treatments for severe depressive disorders. A recent multi-center study found no consistent changes in correlation-based (undirected) resting-state connectivity after ECT. Effective (directed) connectivity may provide more insight into the working mechanism of ECT. Objective We investigated whether there are consistent changes in effective resting-state connectivity. Methods This multi-center study included data from 189 patients suffering from severe unipolar depression and 59 healthy control participants. Longitudinal data were available for 81 patients and 24 healthy controls. We used dynamic causal modeling for resting-state functional magnetic resonance imaging to determine effective connectivity in the default mode, salience and central executive networks before and after a course of ECT. Bayesian general linear models were used to examine differences in baseline and longitudinal effective connectivity effects associated with ECT and its effectiveness. Results Compared to controls, depressed patients showed many differences in effective connectivity at baseline, which varied according to the presence of psychotic features and later treatment outcome. Additionally, effective connectivity changed after ECT, which was related to ECT effectiveness. Notably, treatment effectiveness was associated with decreasing and increasing effective connectivity from the posterior default mode network to the left and right insula, respectively. No effects were found using correlation-based (undirected) connectivity. Conclusions A beneficial response to ECT may depend on how brain regions influence each other in networks important for emotion and cognition. These findings further elucidate the working mechanisms of ECT and may provide directions for future non-invasive brain stimulation research.publishedVersio

Reduced secreted clusterin as a mechanism for Alzheimer-associated CLU mutations

Background: The clusterin (CLU) gene has been identified as an important risk locus for Alzheimer's disease (AD). Although the actual risk-increasing polymorphisms at this locus remain to be identified, we previously observed an increased frequency of rare non-synonymous mutations and small insertion-deletions of CLU in AD patients, which specifically clustered in the beta-chain domain of CLU. Nonetheless the pathogenic nature of these variants remained unclear. Here we report a novel non-synonymous CLU mutation (p.I360N) in a Belgian Alzheimer patient and have explored the pathogenic nature of this and 10 additional CLU mutations on protein localization and secretion in vitro using immunocytochemistry, immunodetection and ELISAs. Results: Three patient-specific CLU mutations in the beta-chain (p.I303NfsX13, p.R338W and p.I360N) caused an alteration of the subcellular CLU localization and diminished CLU transport through the secretory pathway, indicative of possible degradation mechanisms. For these mutations, significantly reduced CLU intensity was observed in the Golgi while almost all CLU protein was exclusively present in the endoplasmic reticulum. This was further confirmed by diminished CLU secretion in HEK293T and HEK293 FLp-In cell lines. Conclusions: Our data lend further support to the contribution of rare coding CLU mutations in the pathogenesis of neurodegenerative diseases. Functional analyses suggest reduced secretion of the CLU protein as the mode of action for three of the examined CLU mutations. One of those is a frameshift mutation leading to a loss of secreted protein, and the other two mutations are amino acid substitutions in the disulfide bridge region, possibly interfering with heterodimerization of the alpha- and beta-chain of CLU