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Objective: Ongoing research has evidenced the importance of muscle measurement in predicting adverse outcomes. Measurement of other muscles is promising in current research. This study aimed to determine the correlation between temporal muscle thickness (TMT) and appendicular lean soft tissue (ALSTI) in older adults., Design: Cross-sectional study., Settings and Participants: Single cohort gathered in Gothenburg, Sweden, consisting of individuals born in 1944 (n = 1203)., Methods: We studied 657 magnetic resonance images to measure TMT. Comparisons of TMT with dual-energy X-ray absorptiometry ALSTI (kg/m 2 ) as a reference standard were performed. Finally, TMT associations with cognition evaluated using the Mini-Mental State Examination (MMSE), gait speed, and handgrip strength were explored with linear regressions., Results: The correlation between TMT and ALSTI was weak yet significant (r = 0.277, P < .001). TMT exhibited significant associations with MMSE (estimate = 0.168, P = .002), gait speed (estimate = 1.795, P < .001), and ALSTI (estimate = 0.508, P < .001). These associations varied when analyzed by sex. In women, TMT was significantly associated with gait speed (estimate = 1.857, P = .005) and MMSE (estimate = 0.223, P = .003). In men, TMT scores were significantly correlated with ALSTI scores (estimate = 0.571, P < .001)., Conclusion and Implications: Repurposing head images can be an accessible alternative to detect muscle mass and ultimately detect sarcopenia. These studies have the potential to trigger interventions or further evaluation to improve the muscle and overall health of individuals. However, additional research is warranted before translating these findings into clinical practice., Competing Interests: Disclosure S.K. has served on scientific advisory boards and/or as a consultant for Geras Solutions and Biogen. The other authors declare no conflicts of interest., (Copyright © 2024 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Mild Cognitive Impairment (MCI) is common in Parkinson's Disease (PD). Few studies have compared the Health-Related Quality of Life (HRQoL) in patients with and without MCI due to PD (PD-MCI), and its correlation to patients' subjective cognitive and communicative difficulties has not been explored., Objective: We aimed to compare HRQoL in PD-MCI and PD without MCI (PD-nMCI), and explore its possible relationship to subjective cognitive and communicative complaints., Methods: We included 29 PD-nMCI and 11 PD-MCI patients. The HRQoL was assessed with the Parkinson's Disease Questionnaire-39 (PDQ-39): its Cognition dimension was used as a measure of subjective cognitive complaints, its Communication dimension for subjective communicative complaints, and the summary index (PDQ-39 SI) as an indicator of HRQoL. Non-parametric partial correlations between the Cognition and Communication dimensions, and the adjusted PDQ-39 SI were conducted., Results: PD-MCI patients had greater subjective cognitive and communicative complaints and worse HRQoL than PD-nMCI patients. In the PD-MCI group, both subjective cognitive and communicative complaints exhibited significant direct correlations with the adjusted HRQoL scores., Conclusions: HRQoL seems to be affected in PD-MCI, and it might be influenced by greater subjective cognitive and communicative complaints. Including patient-reported outcome measures of HRQoL, and providing cognitive and speech rehabilitation, as well as psychotherapeutic strategies to face these deficits can enhance the patient-centred approach in PD., (Copyright © 2021 Asociación Colombiana de Psiquiatría. Published by Elsevier España, S.L.U. All rights reserved.)

Objective: This study aims 1) To analyse differences in resting-state electroencephalogram (rs-EEG) spectral features of Parkinson's Disease (PD) and healthy subjects (non-PD) using Functional Data Analysis (FDA) and 2) To explore, in four independent cohorts, the external validity and reproducibility of the findings using both epoch-to-epoch FDA and averaged-epochs approach., Methods: We included 169 subjects (85 non-PD; 84 PD) from four centres. Rs-EEG signals were preprocessed with a combination of automated pipelines. Sensor-level relative power spectral density (PSD), dominant frequency (DF), and DF variability (DFV) features were extracted. Differences in each feature were compared between PD and non-PD on averaged epochs and using FDA to model the epoch-to-epoch change of each feature., Results: For averaged epochs, significantly higher theta relative PSD in PD was found across all datasets. Also, higher pre-alpha relative PSD was observed in three of four datasets in PD patients. For FDA, similar findings were achieved in theta, but all datasets showed consistently significant posterior pre-alpha differences across multiple epochs., Conclusions: Increased generalised theta, with posterior pre-alpha relative PSD, was the most reproducible finding in PD., Significance: Rs-EEG theta and pre-alpha findings are generalisable in PD. FDA constitutes a reliable and powerful tool to analyse epoch-to-epoch the rs-EEG., (Copyright © 2023 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Importance: Identifying nutritional compounds which can reduce cognitive decline in older people is a hugely important topic., Objective: To study the safety and effect of anthocyanins in maintaining cognitive functioning in people at increased risk for dementia., Design, Setting, and Participants: Participants (206 individuals, aged 60-80 years) diagnosed with either mild cognitive impairment (MCI) or two or more cardiometabolic disorders (i.e., diabetes, hypertension, obesity) were enrolled at three different centres in Norway., Intervention: Participants were randomly assigned to four capsules with a total of 320 mg/d of naturally purified anthocyanins or placebo 1:1 for 24 weeks., Main Outcomes and Measures: The primary outcome was the Quality of Episodic Memory composite measure (0-100) from an online cognitive test battery CogTrack, which was administered at baseline and monthly for the next 24 weeks. Secondary outcomes included other cognitive scores from the CogTrack battery. We applied mixed effects models with a baseline test score, group, time and their interaction as fixed effects, as well as other predefined baseline covariates. The primary comparison was the group difference at week 24 based on a modified intention-to-treat principle., Results: The primary analysis did not show a significant group difference at 24 weeks (78.2 versus 76.8; adjusted mean difference 1.4 (95% confidence interval -0.9-3.7); effect size 0.15; p = 0.23). However, there was a significant difference in slopes during weeks 8-24 (p = 0.007); the anthocyanin group improved while the placebo group worsened. No differences were found for the secondary cognitive outcomes. Anthocyanin capsules were well-tolerated and safe to use., Conclusion: Anthocyanin supplementation for 24 weeks was safe and well tolerated in people with MCI or cardiometabolic disorders. We found no significant group difference in episodic memory at the end of the study but statistically significant differences in slopes. Further studies are warranted to explore whether anthocyanins supplementation can reduce cognitive decline in people at increased risk of dementia., Trial Registration: ClinicalTrials.gov, (Identifier NCT03419039). http://www., Clinicaltrials: gov/, NCT03419039., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Please modify the Abstract as follows:Here we tested if the reactivity of posterior resting-state electroencephalographic (rsEEG) alpha rhythms from the eye-closed to the eyes-open condition may differ in patients with dementia due to Lewy Bodies (DLB) and Alzheimer's disease (ADD) as a functional probe of the dominant neural synchronization mechanisms regulating the vigilance in posterior visual systems.We used clinical, demographical, and rsEEG datasets in 28 older adults (Healthy), 42 DLB, and 48 ADD participants. The eLORETA freeware was used to estimate cortical rsEEG sources.Results showed a substantial (> -10%) reduction in the posterior alpha activities during the eyes-open condition in 24 Healthy, 26 ADD, and 22 DLB subjects. There were lower reductions in the posterior alpha activities in the ADD and DLB groups than in the Healthy group. That reduction in the occipital region was lower in the DLB than in the ADD group.These results suggest that DLB patients may suffer from a greater alteration in the neural synchronization mechanisms regulating vigilance in occipital cortical systems compared to ADD patients., Competing Interests: Disclosure statement None of the authors have potential conflicts of interest to be disclosed., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Biomarkers for the early detection of dementia risk hold promise for better disease monitoring and targeted interventions. However, most biomarker studies, particularly in neuroimaging, have analysed artificially 'clean' research groups, free from comorbidities, erroneous referrals, contraindications and from a narrow sociodemographic pool. Such biases mean that neuroimaging samples are often unrepresentative of the target population for dementia risk (e.g., people referred to a memory clinic), limiting the generalisation of these studies to real-world clinical settings. To facilitate better translation from research to the clinic, datasets that are more representative of dementia patient groups are warranted., Methods: We analysed T1-weighted MRI scans from a real-world setting of patients referred to UK memory clinic services (n = 1140; 60.2 % female and mean [SD] age of 70.0[10.8] years) to derive 'brain-age'. Brain-age is an index of age-related brain health based on quantitative analysis of structural neuroimaging, largely reflecting brain atrophy. Brain-predicted age difference (brain-PAD) was calculated as brain-age minus chronological age. We determined which patients went on to develop dementia between three months and 7.8 years after neuroimaging assessment (n = 476) using linkage to electronic health records., Results: Survival analysis, using Cox regression, indicated a 3 % increased risk of dementia per brain-PAD year (hazard ratio [95 % CI] = 1.03 [1.02,1.04], p < 0.0001), adjusted for baseline age, age 2 , sex, Mini Mental State Examination (MMSE) score and normalised brain volume. In sensitivity analyses, brain-PAD remained significant when time-to-dementia was at least 3 years (hazard ratio [95 % CI] = 1.06 [1.02, 1.09], p = 0.0006), or when baseline MMSE score ≥ 27 (hazard ratio [95 % CI] = 1.03 [1.01, 1.05], p = 0.0006)., Conclusions: Memory clinic patients with older-appearing brains are more likely to receive a subsequent dementia diagnosis. Potentially, brain-age could aid decision-making during initial memory clinic assessment to improve early detection of dementia. Even when neuroimaging assessment was more than 3 years prior to diagnosis and when cognitive functioning was not clearly impaired, brain-age still proved informative. These real-world results support the use of quantitative neuroimaging biomarkers like brain-age in memory clinics., Competing Interests: Declaration of Competing Interest JHC is a scientific advisor to and shareholder in Brain Key and Claritas HealthTech, both medical image analysis companies. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Plasma phosphorylated tau at threonine-181 (P-tau181) demonstrates promise as an accessible blood-based biomarker specific to Alzheimer's Disease (AD), with levels recently demonstrating high predictive accuracy for AD-relevant pathology. The genetic underpinnings of P-tau181 levels, however, remain elusive. This study presents the first genome-wide association study of plasma P-tau181 in a total sample of 1153 participants from 2 independent cohorts. No loci, other than those within the APOE genomic region (lead variant = rs429358, beta = 0.32, p =8.44 × 10 -25 ) demonstrated association with P-tau181 at genome-wide significance (p < 5 × 10 -08 ), though rs60872856 on chromosome 2 came close (beta = -0.28, p = 3.23 × 10 -07 , nearest gene=CYTIP). As the APOE ε4 allele is already a well-established genetic variant associated with AD, this study found no evidence of novel genetic associations relevant to plasma P-tau181, though presents rs60872856 on chromosome 2 as a candidate locus to be further evaluated in future larger size GWAS., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Mild Cognitive Impairment (MCI) is common in Parkinson's Disease (PD). Few studies have compared the Health-Related Quality of Life (HRQoL) in patients with and without MCI due to PD (PD-MCI), and its correlation to patients' subjective cognitive and communicative difficulties has not been explored., Objective: We aimed to compare HRQoL in PD-MCI and PD without MCI (PD-nMCI), and explore its possible relationship to subjective cognitive and communicative complaints., Methods: We included 29 PD-nMCI and 11 PD-MCI patients. The HRQoL was assessed with the Parkinson's Disease Questionnaire-39 (PDQ-39): its Cognition dimension was used as a measure of subjective cognitive complaints, its Communication dimension for subjective communicative complaints, and the summary index (PDQ-39 SI) as an indicator of HRQoL. Non-parametric partial correlations between the Cognition and Communication dimensions, and the adjusted PDQ-39 SI were conducted., Results: PD-MCI patients had greater subjective cognitive and communicative complaints and worse HRQoL than PD-nMCI patients. In the PD-MCI group, both subjective cognitive and communicative complaints exhibited significant direct correlations with the adjusted HRQoL scores., Conclusions: HRQoL seems to be affected in PD-MCI, and it might be influenced by greater subjective cognitive and communicative complaints. Including patient-reported outcome measures of HRQoL, and providing cognitive and speech rehabilitation, as well as psychotherapeutic strategies to face these deficits can enhance the patient-centred approach in PD., (Copyright © 2021 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España, S.L.U. All rights reserved.)

We investigated whether cerebrovascular disease contributes to neurodegeneration and clinical phenotype in dementia with Lewy bodies (DLB). Regional cortical thickness and subcortical gray matter volumes were estimated from structural magnetic resonance imaging (MRI) in 165 DLB patients. Cortical and subcortical infarcts were recorded and white matter hyperintensities (WMHs) were assessed. Subcortical only infarcts were more frequent (13.3%) than cortical only infarcts (3.1%) or both subcortical and cortical infarcts (2.4%). Infarcts, irrespective of type, were associated with WMHs. A higher WMH volume was associated with thinner orbitofrontal, retrosplenial, and posterior cingulate cortices, smaller thalamus and pallidum, and larger caudate volume. A higher WMH volume was associated with the presence of visual hallucinations and lower global cognitive performance, and tended to be associated with the absence of probable rapid eye movement sleep behavior disorder. Presence of infarcts was associated with the absence of parkinsonism. We conclude that cerebrovascular disease is associated with gray matter neurodegeneration in patients with probable DLB, which may have implications for the multifactorial treatment of probable DLB., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: To compare online cognitive-behavioral therapy (CBT) with and without telephone support respectively to online psychoeducation in a randomized controlled trial (RCT) in caregivers of people with dementia with mild anxiety or depression., Design: Three-arm parallel-group RCT comparing online CBT with and without telephone support respectively to online psychoeducation., Setting and Participants: Online study with caregivers of people with dementia., Measures: The primary outcome measure was mental health measured by General Health Questionnaire-12 (GHQ-12) at 26 weeks. Secondary outcomes included the Hospital Anxiety and Depression Scale (HADS); the Relative Stress Scale (RSS) and the Short Sense of Competency Questionnaire. The primary analysis focused on people completing GHQ-12 at both baseline and 26 weeks, evaluated using analysis of covariance., Results: 638 people were randomized to the 3 treatment arms, of whom 208 were included in the analysis population. There were significant improvements in GHQ-12 in all treatment arms compared to baseline (P < .001 for all interventions), but neither CBT with nor without telephone support conferred any significant advantage compared to psychoeducation. For the secondary outcomes, there were no significant differences between CBT with telephone support and psychoeducation, but CBT without telephone support was less effective than psychoeducation with respect to HADS depression subscale [mean difference 1.86, 95% confidence interval (CI) 0.61, 3.11; P = .004] and caregiver stress (RSS mean difference 3.11, 95% CI 0.13, 6.09; P = .04). Good safety was achieved in all 3 treatment arms, with no deaths or serious adverse events., Conclusions and Implications: Online CBT with telephone support and psychoeducation both achieved significant benefits over 26 weeks compared with baseline in mental health and mood, but there were no advantages for CBT compared with the psychoeducation intervention. CBT without telephone support was less effective with respect to mood outcomes than psychoeducation and should not be recommended based on current evidence., (Copyright © 2020 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: There is an urgent clinical need for identifying blood-based diagnostic biomarkers for Dementia with Lewy Bodies (DLB). Transcriptomic studies have reported unique RNA changes in postmortem DLB brains. Small extracellular vesicles (SEV) that transport RNA between brain and peripheral circulation enable identifying molecular changes in living human brain. Hence, we aimed to identify differentially expressed RNA in serum SEVs from people with DLB., Methods: We investigated serum SEV total RNA profiles in people with DLB (n = 10) and age and gender matched comparisons (n = 10) using next-generation RNA-sequencing. SEVs were separated by ultracentrifugation with density gradient and were characterized by nanoparticle analysis and western blotting. We verified the differential expression levels of identified differentially expressed genes (DEG) using high-throughput qPCR. Functional implications of identified DEG were evaluated using Ingenuity pathway analyses., Results: We identified 846 nominally significant DEG including 30 miRNAs in DLB serum SEVs. We identified significant downregulation of proinflammatory genes, IL1B, CXCL8, and IKBKB. Previously reported postmortem DLB brain DEGs were significantly enriched (χ 2 =4.99; df=1; p = 0.03) among the identified DEGs, and the differential expression of 40 postmortem DLB brain DEGs could be detected in serum SEVs of people living with DLB. Functional pathway and network analyses highlighted the importance of immunosenescence, ubiquitin proteasome system (UPS) dysfunction, DNA repair, and RNA post-transcriptional modification deficits in DLB pathology., Conclusion: Identified DEGs, especially reduced expression levels of inflammation, and UPS-associated RNA, may aid diagnosing DLB, and their biomarker potential warrants further investigation in larger clinical cohorts. Our findings corroborate the absence of chronic neuroinflammation in DLB., (Copyright © 2020 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: To determine possible associations of hemispheric-regional alpha/theta ratio (α/θ) with neuropsychological test performance in Parkinson's Disease (PD) non-demented patients., Methods: 36 PD were matched to 36 Healthy Controls (HC). The α/θ in eight hemispheric regions was computed from the relative power spectral density of the resting-state quantitative electroencephalogram (qEEG). Correlations between α/θ and performance in several neuropsychological tests were conducted, significant findings were included in a moderation analysis., Results: The α/θ in all regions was lower in PD than in HC, with larger effect sizes in the posterior regions. Right parietal, and right and left occipital α/θ had significant positive correlations with performance in Judgement of Line Orientation Test (JLOT) in PD. Adjusted moderation analysis indicated that right, but not left, occipital α/θ influenced the JLOT performance related to PD., Conclusions: Reduction of the occipital α/θ, in particular on the right side, was associated with visuospatial performance impairment in PD., Significance: Visuospatial impairment in PD, which is highly correlated with the subsequent development of dementia, is reflected in α/θ in the right posterior regions. The right occipital α/θ may represent a useful qEEG marker for evaluating the presence of early signs of cognitive decline in PD and the subsequent risk of dementia., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Deep learning (DL) methods have in recent years yielded impressive results in medical imaging, with the potential to function as clinical aid to radiologists. However, DL models in medical imaging are often trained on public research cohorts with images acquired with a single scanner or with strict protocol harmonization, which is not representative of a clinical setting. The aim of this study was to investigate how well a DL model performs in unseen clinical datasets-collected with different scanners, protocols and disease populations-and whether more heterogeneous training data improves generalization. In total, 3117 MRI scans of brains from multiple dementia research cohorts and memory clinics, that had been visually rated by a neuroradiologist according to Scheltens' scale of medial temporal atrophy (MTA), were included in this study. By training multiple versions of a convolutional neural network on different subsets of this data to predict MTA ratings, we assessed the impact of including images from a wider distribution during training had on performance in external memory clinic data. Our results showed that our model generalized well to datasets acquired with similar protocols as the training data, but substantially worse in clinical cohorts with visibly different tissue contrasts in the images. This implies that future DL studies investigating performance in out-of-distribution (OOD) MRI data need to assess multiple external cohorts for reliable results. Further, by including data from a wider range of scanners and protocols the performance improved in OOD data, which suggests that more heterogeneous training data makes the model generalize better. To conclude, this is the most comprehensive study to date investigating the domain shift in deep learning on MRI data, and we advocate rigorous evaluation of DL models on clinical data prior to being certified for deployment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: Here we tested if cortical sources of resting state electroencephalographic (rsEEG) rhythms may differ in sub-groups of patients with prodromal and overt dementia with Lewy bodies (DLB) as a function of relevant clinical symptoms., Methods: We extracted clinical, demographic and rsEEG datasets in matched DLB patients (N = 60) and control Alzheimer's disease (AD, N = 60) and healthy elderly (Nold, N = 60) seniors from our international database. The eLORETA freeware was used to estimate cortical rsEEG sources., Results: As compared to the Nold group, the DLB and AD groups generally exhibited greater spatially distributed delta source activities (DLB > AD) and lower alpha source activities posteriorly (AD > DLB). As compared to the DLB "controls", the DLB patients with (1) rapid eye movement (REM) sleep behavior disorders showed lower central alpha source activities (p < 0.005); (2) greater cognitive deficits exhibited higher parietal and central theta source activities as well as higher central, parietal, and occipital alpha source activities (p < 0.01); (3) visual hallucinations pointed to greater parietal delta source activities (p < 0.005)., Conclusions: Relevant clinical features were associated with abnormalities in spatial and frequency features of rsEEG source activities in DLB patients., Significance: Those features may be used as neurophysiological surrogate endpoints of clinical symptoms in DLB patients in future cross-validation prospective studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

A growing number of epigenome-wide association studies have demonstrated a role for DNA methylation in the brain in Alzheimer's disease. With the aim of exploring peripheral biomarker potential, we have examined DNA methylation patterns in whole blood collected from 284 individuals in the AddNeuroMed study, which included 89 nondemented controls, 86 patients with Alzheimer's disease, and 109 individuals with mild cognitive impairment, including 38 individuals who progressed to Alzheimer's disease within 1 year. We identified significant differentially methylated regions, including 12 adjacent hypermethylated probes in the HOXB6 gene in Alzheimer's disease, which we validated using pyrosequencing. Using weighted gene correlation network analysis, we identified comethylated modules of genes that were associated with key variables such as APOE genotype and diagnosis. In summary, this study represents the first large-scale epigenome-wide association study of Alzheimer's disease and mild cognitive impairment using blood. We highlight the differences in various loci and pathways in early disease, suggesting that these patterns relate to cognitive decline at an early stage., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To examine the bidirectional temporal relationship between depressive symptoms and cognition in relation to risk, reaction, and prodrome., Design: Cross-lag analysis of longitudinal data collected online at baseline and 12-month follow-up., Setting and Participants: A United Kingdom population cohort of 11,855 participants aged 50 years and over., Measures: Patient Health Questionnaire-9 (depressive symptoms), cognitive measures: Paired Associate Learning, Verbal Reasoning, Spatial Working Memory, and Digit Span., Results: Depressive symptoms predicted a decline in paired associates learning [β = -.020, P = .013, (95% confidence interval [CI], ‒.036, -.004)] and verbal reasoning [β = -.014, P = .016, (95% CI ‒.025, -.003)] but not vice versa. Depressive symptoms predicted [β = -.043, P < .001, (95% CI ‒.060, -.026); β = -.029, P < .001, (95% CI ‒.043, -.015)] and were predicted by [β = -.030, P = < .001, (95% CI ‒.047, -.014); β = -.025, P = .003, (95% CI ‒.041, -.009)], a decline in spatial working memory and verbal digit span, respectively., Conclusions and Implications: Depressive symptoms may be either a risk factor or prodrome for cognitive decline. In addition, a decline in attention predicts depressive symptoms. Clinical implications and implications for further research are discussed., (Copyright © 2020 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Compared with Alzheimer's disease (AD), Parkinson's disease (PD) shows peculiar clinical manifestations related to vigilance (i.e., executive cognitive deficits and visual hallucinations) that may be reflected in resting-state electroencephalographic rhythms. To test this hypothesis, clinical and resting-state electroencephalographic rhythms in age-, sex-, and education-matched PD patients (N = 136) and Alzheimer's disease patients (AD, N = 85), and healthy older participants (Nold, N = 65), were available from an international archive. Electroencephalographic sources were estimated by eLORETA software. The results are as follows: (1) compared to the Nold participants, the AD and PD patients showed higher widespread delta source activities (PD > AD) and lower posterior alpha source activities (AD > PD); (2) the PD patients with the most pronounced motor deficits exhibited very low alpha source activities in widespread cortical regions; (3) the PD patients with the strongest cognitive deficits showed higher alpha source activities in widespread cortical regions; and (4) compared to the PD patients without visual hallucinations, those with visual hallucinations were characterized by higher posterior alpha sources activities. These results suggest that in PD patients resting in quiet wakefulness, abnormalities in cortical neural synchronization at alpha frequencies are differently related to cognitive, motor, and visual hallucinations. Interestingly, parallel PD neuropathological processes may have opposite effects on cortical neural synchronization mechanisms generating cortical alpha rhythms in quiet wakefulness., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: Prevalence of Lewy body dementias (LBD) is second only to Alzheimer's disease (AD) among people with neurodegenerative dementia. LBD cause earlier mortality, more intense neuropsychiatric symptoms, more caregivers' burden, and higher costs than AD. The molecular mechanisms underlying LBD are largely unknown. As advancing molecular level mechanistic understanding is essential for identifying reliable peripheral biomarkers and novel therapeutic targets for LBD, the authors aimed to identify differentially expressed genes (DEG), and dysfunctional molecular networks in postmortem LBD brains., Methods: The authors investigated the transcriptomics of postmortem anterior cingulate and dorsolateral prefrontal cortices of people with pathology-verified LBD using next-generation RNA-sequencing. The authors verified the identified DEG using high-throughput quantitative polymerase chain reactions. Functional implications of identified DEG and the consequent metabolic reprogramming were evaluated by Ingenuity pathway analyses, genome-scale metabolic modeling, reporter metabolite analyses, and in silico gene silencing., Results: The authors identified and verified 12 novel DEGs (MPO, SELE, CTSG, ALPI, ABCA13, GALNT6, SST, RBM3, CSF3, SLC4A1, OXTR, and RAB44) in LBD brains with genome-wide statistical significance. The authors documented statistically significant down-regulation of several cytokine genes. Identified dysfunctional molecular networks highlighted the contributions of mitochondrial dysfunction, oxidative stress, and immunosenescence toward neurodegeneration in LBD., Conclusion: Our findings support that chronic microglial activation and neuroinflammation, well-documented in AD, are notably absent in LBD. The lack of neuroinflammation in LBD brains was corroborated by statistically significant down-regulation of several inflammatory markers. Identified DEGs, especially down-regulated inflammatory markers, may aid distinguishing LBD from AD, and their biomarker potential warrant further investigation., (Copyright © 2019 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Alzheimer's disease (AD)-related pathology is frequently found in patients with dementia with Lewy bodies (DLB). However, it is unknown how amyloid-β and tau-related pathologies influence neurodegeneration in DLB. Understanding the mechanisms underlying brain atrophy in DLB can improve our knowledge about disease progression, differential diagnosis, drug development and testing of anti-amyloid and anti-tau therapies in DLB., Objectives: We aimed at investigating the combined effect of CSF amyloid-β42, phosphorylated tau and total tau on regional brain atrophy in DLB in the European DLB (E-DLB) cohort., Methods: 86 probable DLB patients from the E-DLB cohort with CSF and MRI data were included. Random forest was used to analyze the association of CSF biomarkers (predictors) with visual rating scales for medial temporal lobe atrophy (MTA), posterior atrophy (PA) and global cortical atrophy scale-frontal subscale (GCA-F) (outcomes), including age, sex, education and disease duration as extra predictors., Results: DLB patients with abnormal MTA scores had abnormal CSF Aβ42, shorter disease duration and older age. DLB patients with abnormal PA scores had abnormal levels of CSF Aβ42 and p-tau, older age, lower education and shorter disease duration. Abnormal GCA-F scores were associated with lower education, male sex, and older age, but not with any AD-related CSF biomarker., Conclusions: This study shows preliminary data on the potential combined effect of amyloid-β and tau-related pathologies on the integrity of posterior brain cortices in DLB patients, whereas only amyloid-β seems to be related to MTA. Future availability of α-synuclein biomarkers will help us to understand the effect of α-synuclein and AD-related pathologies on brain integrity in DLB., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Mild behavioral impairment (MBI) is a neurobehavioral syndrome characterized by later life emergent neuropsychiatric symptoms (NPS) that represent an at-risk state for incident cognitive decline and dementia in people with mild cognitive impairment (MCI). We undertook a study to determine whether MBI was associated with progressive changes in neuropsychological performance in people without significant cognitive impairment., Methods: A total of 9,931 older adults enrolled in the PROTECT study who did not have MCI or dementia undertook a comprehensive neuropsychological battery measuring attention, reasoning, executive function, and working memory at baseline and 1 year. MBI was ascertained using self-administration of the Mild Behavioral Impairment Checklist at 1 year, and participants were grouped according to MBI status: No Symptoms, Intermediate NPS and MBI. All assessments were completed online, and data analyzed using mixed-effects model repeated measures analysis of covariance., Results: A total of 949 (10%) people had MBI. These individuals had significantly worse cognitive performance at baseline and significantly greater decline over 1 year in the four composite cognitive scores measuring attentional intensity (F [2,8578] = 3.97; p = 0.019), sustained attention (F [2,8578] = 18.63; p <0.0001), attentional fluctuation (F [2,8578] = 10.13; p <0.0001) and working memory (F [2,9895] = 13.1; p <0.0001)., Conclusion: Our novel findings show that MBI is associated with faster decline in attention and working memory in this cognitively normal sample. MBI may be an earlier marker of neurodegenerative disease than MCI, captured at the stage of subjective cognitive decline or before, raising the possibility that MBI represents a novel target for dementia clinical trials or prevention strategies., (Copyright © 2019 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objectives: To describe the incidence of delirium recording before and after a diagnosis of dementia is established in patients with dementia with Lewy bodies (DLB) and compare findings to a matched cohort of patients with Alzheimer's disease (AD)., Design: Retrospective cohort study., Setting and Participants: A cohort of patients with dementia from a large mental health and dementia care database in South London, linked to hospitalization and mortality data. We identified 194 patients with DLB and 1:4 matched these with 776 patients diagnosed with AD on age, gender, and cognitive status., Measures: We identified delirium episodes recorded in mental health and hospital records from 1 year before to 1 year after dementia diagnosis. Using dementia diagnosis as an index date we additionally followed patients until first episode of delirium, death or a censoring point without restricting the observation period., Results: Patients with DLB had significantly more episodes of delirium recorded in the year before dementia diagnosis than patients with AD (incidence rate 17.6 vs 3.2 per 100 person-years; P < .001). Whereas the incidence of recording of delirium episodes reduced substantially in patients with DLB after dementia diagnosis, it remained significantly higher than in patients with AD (incidence rate 6.2 vs 2.3 per 100 person-years; P = .032). Cox regression models indicate that patients with DLB remain at a higher risk of delirium than patients with AD after a dementia diagnosis., Conclusions/relevance: Establishing a diagnosis of dementia reduces episodes classified as delirium in patients with DLB and might lead to fewer potentially harmful interventions such as hospitalization or use of antipsychotic medication., (Copyright © 2018 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Previous evidence has shown different resting-state eyes-closed electroencephalographic delta (<4 Hz) and alpha (8-10.5 Hz) source connectivity in subjects with dementia due to Alzheimer's (ADD) and Lewy body (DLB) diseases. The present study tested if the same differences may be observed in the prodromal stages of mild cognitive impairment (MCI). Here, clinical and resting-state eyes-closed electroencephalographic data in age-, gender-, and education-matched 30 ADMCI, 23 DLBMCI, and 30 healthy elderly (Nold) subjects were available in our international archive. Mini-Mental State Evaluation (MMSE) score was matched in the ADMCI and DLBMCI groups. The eLORETA freeware estimated delta and alpha source connectivity by the tool called lagged linear connectivity (LLC). Area under receiver operating characteristic curve (AUROCC) indexed the classification accuracy among individuals. Results showed that widespread interhemispheric and intrahemispheric LLC solutions in alpha sources were abnormally lower in both MCI groups compared with the Nold group, but with no differences were found between the 2 MCI groups. AUROCCs of LLC solutions in alpha sources exhibited significant accuracies (0.72-0.75) in the discrimination of Nold versus ADMCI-DLBMCI individuals, but not between the 2 MCI groups. These findings disclose similar abnormalities in ADMCI and DLBMCI patients as revealed by alpha source connectivity. It can be speculated that source connectivity mostly reflects common cholinergic impairment in prodromal state of both AD and DLB, before a substantial dopaminergic derangement in the dementia stage of DLB., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: To investigate if the multicomponent intervention of the COSMOS trial, combining communication, systematic pain management, medication review, and activities, improved quality of life (QoL) in nursing home patients with complex needs., Design: Multicenter, cluster-randomized, single-blinded, controlled trial., Setting: Thirty-three nursing homes with 67 units (clusters) from 8 Norwegian municipalities., Participants: Seven hundred twenty-three patients with and without dementia (≥65 years) were cluster randomized to usual care or intervention in which health care staff received standardized education and on-site training for 4 months with follow-up at month 9., Measurements: Primary outcome was change in QoL as measured by QUALIDEM (QoL dementia scale); QUALID (QoL late-stage dementia scale), and EQ-VAS (European QoL-visual analog scale) from baseline to month 4. Secondary outcomes were activities of daily living (ADL), total medication, staff distress, and clinical global impressions of change (CGIC)., Results: During the active intervention, all 3 QoL measures worsened, 2 significantly (QUALID P = .04; QUALIDEM P = .002). However, follow-up analysis from month 4 to 9 showed an intervention effect for EQ-VAS (P = .003) and QUALIDEM total score (P = .01; care relationship P = .02; positive affect P = .04, social relations P = .01). The secondary outcomes of ADL function, reduction of medication (including psychotropics) and staff distress, improved significantly from baseline to month 4. Intervention effects were also demonstrated for CGIC at month 4 (P = .023) and 9 (P = .009), mainly because of deterioration in the control group., Conclusion and Implications: Temporarily, the QoL decreased in the intervention group, leading to our hypothesis that health care staff may be overwhelmed by the work-intensive COSMOS intervention period. However, the decrease reversed significantly during follow-up, indicating a potential learning effect. Further, the intervention group improved in ADL function and received less medication, and staff reported less distress and judged COSMOS as able to bring about clinically relevant change. This suggests that nonpharmacologic multicomponent interventions require long follow-up to ensure uptake and beneficial effects., (Copyright © 2018 AMDA – The Society for Post-Acute and Long-Term Care Medicine. All rights reserved.)

Introduction: Tryptophan, its downstream metabolites in the kynurenine pathway and neopterin have been associated with inflammation and dementia. We aimed to study the associations between plasma levels of these metabolites and cognitive function in community-dwelling, older adults., Methods: This cross-sectional study included 2174 participants aged 70-72 years of the community-based Hordaland Health Study. Tryptophan, kynurenine, neopterin and eight downstream kynurenines were measured in plasma. Kendrick Object Learning Test (KOLT), Digit Symbol Test (DST) and the Controlled Oral Word Association Test (COWAT) were all outcomes in standardized Zellner's regression. The Wald test of a composite linear hypothesis of an association with each metabolite was adjusted by the Bonferroni method. Age, body mass index, C-reactive protein, depressive symptoms, diabetes, education, glomerular filtration rate, hypertension, previous myocardial infarction, prior stroke, pyridoxal 5'phosphate, sex and smoking were considered as potential confounders., Results: Higher levels of the kynurenine-to-tryptophan ratio (KTR) and neopterin were significantly associated with poorer, overall cognitive performance (p < 0.002). Specifically, KTR was negatively associated with KOLT (β -0.08, p = 0.001) and COWAT (β -0.08, p = 0.001), but not with DST (β -0.03, p = 0.160). This pattern was also seen for neopterin (KOLT: β -0.07; p = 0.001; COWAT: β -0.06, p = 0.010; DST: β -0.01, p = 0.800). The associations were not confounded by the examined variables. No significant associations were found between the eight downstream kynurenines and cognition., Conclusion: Higher KTR and neopterin levels, biomarkers of cellular immune activation, were associated with reduced cognitive performance, implying an association between the innate immune system, memory, and language., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Previous evidence showed abnormal posterior sources of resting-state delta (<4 Hz) and alpha (8-12 Hz) rhythms in patients with Alzheimer's disease with dementia (ADD), Parkinson's disease with dementia (PDD), and Lewy body dementia (DLB), as cortical neural synchronization markers in quiet wakefulness. Here, we tested the hypothesis of additional abnormalities in functional cortical connectivity computed in those sources, in ADD, considered as a "disconnection cortical syndrome", in comparison with PDD and DLB. Resting-state eyes-closed electroencephalographic (rsEEG) rhythms had been collected in 42 ADD, 42 PDD, 34 DLB, and 40 normal healthy older (Nold) participants. Exact low-resolution brain electromagnetic tomography (eLORETA) freeware estimated the functional lagged linear connectivity (LLC) from rsEEG cortical sources in delta, theta, alpha, beta, and gamma bands. The area under receiver operating characteristic (AUROC) curve indexed the classification accuracy between Nold and diseased individuals (only values >0.7 were considered). Interhemispheric and intrahemispheric LLCs in widespread delta sources were abnormally higher in the ADD group and, unexpectedly, normal in DLB and PDD groups. Intrahemispheric LLC was reduced in widespread alpha sources dramatically in ADD, markedly in DLB, and moderately in PDD group. Furthermore, the interhemispheric LLC in widespread alpha sources showed lower values in ADD and DLB than PDD groups. At the individual level, AUROC curves of LLC in alpha sources exhibited better classification accuracies for the discrimination of ADD versus Nold individuals (0.84) than for DLB versus Nold participants (0.78) and PDD versus Nold participants (0.75). Functional cortical connectivity markers in delta and alpha sources suggest a more compromised neurophysiological reserve in ADD than DLB, at both group and individual levels., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The aim of this retrospective exploratory study was that resting state eyes-closed electroencephalographic (rsEEG) rhythms might reflect brain arousal in patients with dementia due to Alzheimer's disease dementia (ADD), Parkinson's disease dementia (PDD), and dementia with Lewy body (DLB). Clinical and rsEEG data of 42 ADD, 42 PDD, 34 DLB, and 40 healthy elderly (Nold) subjects were available in an international archive. Demography, education, and Mini-Mental State Evaluation score were not different between the patient groups. Individual alpha frequency peak (IAF) determined the delta, theta, alpha 1, alpha 2, and alpha 3 frequency bands. Fixed beta 1, beta 2, and gamma bands were also considered. rsEEG cortical sources were estimated by means of the exact low-resolution brain electromagnetic source tomography and were then classified across individuals, on the basis of the receiver operating characteristic curves. Compared to Nold, IAF showed marked slowing in PDD and DLB and moderate slowing in ADD. Furthermore, all patient groups showed lower posterior alpha 2 source activities. This effect was dramatic in ADD, marked in DLB, and moderate in PDD. These groups also showed higher occipital delta source activities, but this effect was dramatic in PDD, marked in DLB, and moderate in ADD. The posterior delta and alpha sources allowed good classification accuracy (approximately 0.85-0.90) between the Nold subjects and patients, and between ADD and PDD patients. In quiet wakefulness, delta and alpha sources unveiled different spatial and frequency features of the cortical neural synchronization underpinning brain arousal in ADD, PDD, and DLB patients. Future prospective cross-validation studies should test these rsEEG markers for clinical applications and drug discovery., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: To investigate whether it is possible to determine signs of imminent dying and change in pain and symptom intensity during pharmacological treatment in nursing home patients, from day perceived as dying and to day of death., Design: Prospective, longitudinal trajectory trial., Setting: Forty-seven nursing homes within 35 municipalities of Norway., Participants: A total of 691 nursing home patients were followed during the first year after admission and 152 were assessed carefully in their last days of life., Measurements: Time between admission and day of death, and symptom severity by Edmonton symptom assessment system (ESAS), pain (mobilization-observation-behavior-intensity-dementia-2), level of dementia (clinical dementia rating scale), physical function (Karnofsky performance scale), and activities of daily living (physical self-maintenance scale)., Results: Twenty-five percent died during the first year after admission. Increased fatigue (logistic regression, odds ratio [OR] 1.8, P = .009) and poor appetite (OR 1.2, P = .005) were significantly associated with being able to identify the day a person was imminently dying, which was possible in 61% of the dying (n = 82). On that day, the administration of opioids, midazolam, and anticholinergics increased significantly (P < .001), and was associated with amelioration of symptoms, such as pain (mixed-models linear regression, 60% vs 46%, P < .001), anxiety (44% vs 31%, P < .001), and depression (33% vs 15%, P < .001). However, most symptoms were still prevalent at day of death, and moderate to severe dyspnea and death rattle increased from 44% to 53% (P = .040) and 8% to 19% (P < .001), respectively. Respiratory symptoms were not associated with opioids or anticholinergics., Conclusion: Pharmacological treatment ameliorated distressing symptoms in dying nursing home patients; however, most symptoms, including pain and dyspnea, were still common at day of death. Results emphasize critical needs for better implementation of guidelines and staff education., Trial Registration: ClinicalTrials.govNCT01920100., (Copyright © 2016 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

The aim of this study was to explore cross-sectional associations between Cardiovascular Risk Factors, Aging and Dementia Study (CAIDE) Dementia Risk Score and dementia-related cerebrospinal fluid and neuroimaging biomarkers in 724 patients without dementia from the Memory Clinic at Karolinska University Hospital, Huddinge, Sweden. We additionally evaluated the score's capacity to predict dementia. Two risk score versions were calculated: one including age, gender, obesity, hyperlipidemia, and hypertension; and one additionally including apolipoprotein E (APOE) ε4 carrier status. Cerebrospinal fluid was analyzed for amyloid β (Aβ), total tau, and phosphorylated tau. Visual assessments of medial temporal lobe atrophy (MTA), global cortical atrophy-frontal subscale, and Fazekas scale for white matter changes (WMC) were performed. Higher CAIDE Dementia Risk Score (version without APOE) was significantly associated with higher total tau, more severe MTA, WMC, and global cortical atrophy-frontal subscale. Higher CAIDE Dementia Risk Score (version with APOE) was associated with reduced Aβ, more severe MTA, and WMC. CAIDE Dementia Risk Score version with APOE seemed to predict dementia better in this memory clinic population with short follow-up than the version without APOE., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: To assess the long-term mortality risk associated with antipsychotic drug (AP) use in nursing homes., Design: A longitudinal study with 5 assessments over a 75-month follow-up period., Setting: A representative sample of nursing home patients in 4 Norwegian counties., Participants: At baseline, 1163 patients were included. At the last follow-up, 98 patients were still alive., Measurements: Prevalent drug use at each assessment was registered. Level of dementia, neuropsychiatric symptoms, level of functioning, medical health, and use of restraints were recorded at each assessment. A Cox regression model with time-dependent psychotropic drug use as the main predictor was estimated and adjusted for confounders., Results: In unadjusted Cox regression, a lower mortality risk was associated with the use of other psychotropic drugs, but not APs, compared with nonusers. In the adjusted analysis, neither use of APs nor other psychiatric drugs was associated with increased mortality risk. Higher age, male gender, not being married, medical disease burden, lower level of functioning, more severe degree of dementia, and a higher number of drugs were all associated with increased mortality risk., Conclusion: In this long-term study of nursing home patients, AP drug use was not associated with increased risk of mortality. This is in line with results from earlier studies of clinical samples, but contrasts with results from randomized controlled trials and registry-based studies. The findings should be interpreted with caution. Taking into account the modest benefit and high risk of adverse effects of AP drug use, nonpharmacological treatment remains the first-line treatment approach., (Copyright © 2016 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

We compared cortical thickness between patients with late-life depression (LLD) and healthy controls and between patients with early-onset (EOD) and late-onset (LOD) depression. We also tested age effects on cortical thickness in LLD and controls and if cortical thickness and hippocampal volumes were associated with cognitive performance in LLD. Three-dimensional T1-weighted magnetic resonance images were obtained in 49 LLD and 49 matched hospital controls and processed using FreeSurfer. General linear model analysis was used as a statistical approach. LLD group had thinning in the left parahippocampal, fusiform, and inferior-parietal cortex compared with controls. Age correlated with cortical thinning in controls but not in LLD. Women in the LOD groups had extensive cortical thinning in the lateral prefrontal cortex bilaterally compared with EOD women. Absence of statistically significant changes observed in men should however be treated with caution because of the low number of men in the study. Mini-Mental Status Examination score correlated with lateral prefrontal cortical thickness bilaterally and hippocampal volume in the total group of LLD and in LOD but not EOD. LLD is associated with cortical thinning, which is associated with age at depression onset, gender, and level of cognitive functioning., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The broad importance of dementia is undisputed, with Alzheimer's disease justifiably getting the most attention. However, dementia with Lewy bodies and Parkinson's disease dementia, now called Lewy body dementias, are the second most common type of degenerative dementia in patients older than 65 years. Despite this, Lewy body dementias receive little attention and patients are often misdiagnosed, leading to less than ideal management. Over the past 10 years, considerable effort has gone into improving diagnostic accuracy by refining diagnostic criteria and using imaging and other biomarkers. Dementia with Lewy bodies and Parkinson's disease dementia share the same pathophysiology, and effective treatments will depend not only on successful treatment of symptoms but also on targeting the pathological mechanisms of disease, ideally before symptoms and clinical signs develop. We summarise the most pertinent progress from the past 10 years, outlining some of the challenges for the future, which will require refinement of diagnosis and clarification of the pathogenesis, leading to disease-modifying treatments., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Neuropsychiatric symptoms in Alzheimer disease (AD) cause significant distress and present a complex clinical challenge for treatment. Pharmacological treatment options are limited to antipsychotics, which carry extensive safety issues. There is emerging evidence to support the potential benefits of memantine, currently licensed for moderate to severe AD, in the prophylaxis of neuropsychiatric symptoms., Methods: The MAIN-AD study is a double-blind randomized placebo-controlled withdrawal trial comparing memantine with antipsychotics for the treatment of neuropsychiatric symptoms over 24 weeks. A total of 199 people with probable AD living in care homes already receiving an antipsychotic were randomized to receive either memantine or to continue an antipsychotic. The primary outcomes were function (Bristol Activities of Daily Living Scale [BADLS]) and agitation (Cohen-Mansfield Agitation Inventory [CMAI]). Secondary outcomes were Neuropsychiatric Inventory (NPI), Mini-Mental State Examination (MMSE), and mortality., Results: There was no significant difference between groups on the BADLS or CMAI. At 24 weeks, there was a nonsignificant adjusted difference in favor of memantine on the BADLS of 0.23 (95% CI -1.80-2.27; P = .82) and in favor of antipsychotic on the CMAI of 0.09 (95% CI -0.35-8.53; P = .07). Although there were no significant differences in total NPI, there were 5.01 (95% CI -1.68-11.70; P = .05) and 3.63 (95% CI -1.40-8.67; P = .16) point advantages favoring antipsychotics at weeks 12 and 24, respectively. In addition, in an exploratory analysis, individuals allocated to antipsychotics were significantly less likely to experience relapse of neuropsychiatric symptoms at all time points. The group receiving memantine had a nonsignificant 1.3-point advantage on the MMSE at 24 weeks., Discussion: This study indicates no benefits for memantine in the long-term treatment and prophylaxis of clinically significant neuropsychiatric symptoms. The results did indicate some benefits for antipsychotic medications in reducing the relapse of neuropsychiatric symptoms, but this must be balanced against increased mortality risk., (Copyright © 2015 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: Depression is a common symptom in dementia with Lewy bodies (DLB), Parkinson disease dementia (PDD), and Alzheimer disease (AD), yet its molecular basis remains unclear and current antidepressants do not appear to be effective. Cerebral zinc has been implicated in depression and synaptic dysfunction. We investigated the relationship between synaptic zinc regulation (for which zinc transporter 3 [ZnT3] is responsible) and depression in a large clinicopathologic study., Methods: We examined brains from people with PDD (N = 29), DLB (N = 27), and AD (N = 15) and comparison subjects without depression or dementia (N = 24). Individuals were categorized according to the presence and severity of depression (on a scale of 0-3) based on standardized assessments during life (principally Neuropsychiatric Inventory). Western blotting was used to determine ZnT3 levels in Brodmann area 9 (BA9), and regression analysis was used to determine the relationship between ZnT3 and depression., Results: Reductions in ZnT3 in BA9 were significantly associated with elevated depression scores in the study cohort (β = -0.351, df = 93, t = -3.318 p = 0.0004). This association remained when only individuals with DLB, PDD, and no dementia or depression were examined (β = -0.347, df = 78, t = -3.271, p = 0.002) or only individuals with AD and no dementia or depression were examined (β = -0.433, df = 37, t = -2.924, p = 0.006)., Conclusion: Although decreased zinc levels have been implicated in the genesis of depression in animal models and in major depressive disorder in humans, this study provides the first evidence of a role for zinc in depression in people with dementia and highlights zinc metabolism as a therapeutic target., (Copyright © 2015 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

The loss of zinc transporter 3 (ZnT3) has been implicated in age-related cognitive decline in mice, and the protein has been associated with plaques. We investigated the levels of ZnT3 and postsynaptic density protein 95 (PSD95), a marker of the postsynaptic terminal, in people with Parkinson's disease dementia (PDD, n = 31), dementia with Lewy bodies (DLB, n = 44), Alzheimer's disease (AD, n = 16), and controls (n = 24), using semiquantitative western blotting and immunohistochemistry in 3 cortical regions. Standardized cognitive assessments during life and semiquantitative scoring of amyloid β (Aβ), tau, and α-synuclein at postmortem were used to investigate the relationship between ZnT3 and PSD95, cognition and pathology. Associations were observed between ZnT3 and PSD95 levels in prefrontal cortex and cognitive impairment (p = 0.001 and p = 0.002, respectively) and between ZnT3 levels in the parietal cortex and cognitive impairment (p = 0.036). Associations were also seen between ZnT3 levels in cingulate cortex and severity of Aβ (p = 0.003) and tau (p = 0.011) pathologies. DLB and PDD were characterized by significant reductions of PSD95 (p < 0.05) and ZnT3 (p < 0.001) in prefrontal cortex compared with controls and AD. PSD95 levels in the parietal cortex were found to be decreased in AD cases compared with controls (p = 0.02) and PDD (p = 0.005). This study has identified Zn(2+) modulation as a possible novel target for the treatment of cognitive impairment in DLB and PDD and the potential for synaptic proteins to be used as a biomarker for the differentiation of DLB and PDD from AD., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Computer-aided diagnosis of Alzheimer's disease (AD) is a rapidly developing field of neuroimaging with strong potential to be used in practice. In this context, assessment of models' robustness to noise and imaging protocol differences together with post-processing and tuning strategies are key tasks to be addressed in order to move towards successful clinical applications. In this study, we investigated the efficacy of Random Forest classifiers trained using different structural MRI measures, with and without neuroanatomical constraints in the detection and prediction of AD in terms of accuracy and between-cohort robustness. From The ADNI database, 185 AD, and 225 healthy controls (HC) were randomly split into training and testing datasets. 165 subjects with mild cognitive impairment (MCI) were distributed according to the month of conversion to dementia (4-year follow-up). Structural 1.5-T MRI-scans were processed using Freesurfer segmentation and cortical reconstruction. Using the resulting output, AD/HC classifiers were trained. Training included model tuning and performance assessment using out-of-bag estimation. Subsequently the classifiers were validated on the AD/HC test set and for the ability to predict MCI-to-AD conversion. Models' between-cohort robustness was additionally assessed using the AddNeuroMed dataset acquired with harmonized clinical and imaging protocols. In the ADNI set, the best AD/HC sensitivity/specificity (88.6%/92.0% - test set) was achieved by combining cortical thickness and volumetric measures. The Random Forest model resulted in significantly higher accuracy compared to the reference classifier (linear Support Vector Machine). The models trained using parcelled and high-dimensional (HD) input demonstrated equivalent performance, but the former was more effective in terms of computation/memory and time costs. The sensitivity/specificity for detecting MCI-to-AD conversion (but not AD/HC classification performance) was further improved from 79.5%/75%-83.3%/81.3% by a combination of morphometric measurements with ApoE-genotype and demographics (age, sex, education). When applied to the independent AddNeuroMed cohort, the best ADNI models produced equivalent performance without substantial accuracy drop, suggesting good robustness sufficient for future clinical implementation.

Objectives: Behavioral disturbances and pain are common in nursing home (NH) patients with dementia. An association between pain and increased agitation has been suggested, and recently a significant reduction of agitation has been demonstrated by pain treatment in patients with moderate to severe dementia. We now examined which specific agitated behaviors respond to individualized pain treatment., Design: Cluster randomized clinical trial., Setting: 60 clusters (i.e., clusters defined as single independent NH units) in 18 NHs within five municipalities of Western Norway., Participants: 352 patients with moderate to severe dementia and clinically significant behavioral disturbances., Intervention: The control group received usual treatment and care. According to a predefined scheme for 8 weeks, all patients in the intervention group received individual daily pain treatment with acetaminophen, extended release morphine, buprenorphine transdermal patch, and/or pregabaline., Measurements: Cohen-Mansfield Agitation Inventory subscales and items., Results: Analyses demonstrated that Factor 3 (Verbally agitated behaviors) showed the largest significant difference (DF = 1204.0, t = -4.308, p <0.001), followed by Factor 2 (Physically non-aggressive behaviors) (DF = 1198.0, t = -2.672, p = 0.008), and Factor 1 (Aggressive behaviors) (DF = 1196.0, t = -2.093, p = 0.037) after 8 weeks, by a linear random intercept mixed model in two-way repeated-measures configuration with adjustment for heteroscedasticity., Conclusion: We found that verbal agitation behaviors such as complaining, negativism, repetitious sentences and questions, constant request for attention, and cursing or verbal aggression responded to pain treatment. In addition, restlessness and pacing were sensible to analgesics. Such behaviors should therefore lead to an assessment of pain, and pain treatment. Further studies comparing how pain treatment should be balanced against other strategies including psychotropic drugs are needed., (Copyright © 2014 American Association for Geriatric Psychiatry. All rights reserved.)

Objectives: To determine whether the 5HTTLPR serotonin transporter polymorphism is associated with delusions and hallucinations in people with dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD)., Design: Prospective cohort study., Participants: A total of 187 individuals, recruited from centres in Norway, Sweden, and the United Kingdom were included in this study; 97 with clinically or neuropathologically diagnosed DLB/PDD and 90 cognitively normal individuals as a comparison group., Measurements: All participants with dementia underwent serial evaluation of neuropsychiatric symptoms to assess the presence of persistent delusions and hallucinations using the Columbia University Scale for Psychopathology in Alzheimer disease, the Neuropsychiatric Inventory, or the Present Behavioural Examination. Severity of cognitive impairment was measured using the Mini Mental State Examination (MMSE). Individuals were genotyped for the 5HTTLPR polymorphism., Results: Logistic regression demonstrated that homozygosity for the L/L genotype and lower MMSE were associated with an increased risk for delusions (odds ratio: 11.5 and 1.16, respectively). Neither was significantly associated with hallucinations., Conclusions: This study is the first to demonstrate the 5HTTLPR polymorphism is associated with delusions in Lewy body dementias, with important implications regarding the mechanisms underlying this symptom across the AD/DLB/PDD spectrum. Further studies are warranted to investigate this relationship further and examine treatment opportunities., (Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate short- and long-term mortality risk associated with the use of antipsychotics in dementia outpatients, assessing the risk over specific time frames and quantifying the risk by the individual antipsychotics., Methods: This population-based study used data from the Norwegian Prescription Database. The study sample included 26,940 dementia outpatients aged 65 years or older prescribed antidementia drugs and psychotropics from Norwegian pharmacies between 2004 and 2010., Results: Cox survival analyses, adjusted for age, gender, mean daily defined dose, and severe medical conditions, showed that antipsychotic use compared with other psychotropics involved approximately twice the mortality risk in outpatients with dementia. Furthermore, these results are consistent for all investigated time points after first dispensing the drugs (hazard ratio [HR]30 days = 2.1 [95% confidence interval {CI}: 1.6-2.9] to HR 730-2,400 days = 1.7 [95% CI: 1.6-1.9]). Haloperidol was associated with higher mortality risk (HR 30 days = 1.7 [95% CI: 1.0-3.0] to HR 730-2,400 days = 1.4 [95% CI: 1.0-1.9]) than risperidone., Conclusion: This first study to observe antipsychotic use and mortality in dementia outpatients over more than 6 years clearly shows that antipsychotics involve increased short- and long-term mortality risk. Physicians may justly consider antipsychotics to be the best option for some dementia patients among available nonpharmacologic and pharmacologic treatments. However, although causal conclusions are precluded due to limited adjustments in the analyses, the findings support the current treatment recommendations that antipsychotics should be avoided or used with great caution., (Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the use of formal care during the first three years after diagnosis of mild dementia and identify cost-predicting factors., Design: Prospective longitudinal study over three years., Setting: An incidence-based bottom-up cost-of-illness study where information about formal health care services was drawn from the municipalities' registers during the first three years after the diagnosis of mild dementia., Participants: 109 patients with mild dementia at baseline, diagnosed according to consensus criteria based on standardized assessments., Measurement: The use of formal care as registered by the municipalities' registration systems. Costs were estimated by applying unit costs, including municipal expenses and out-of-pocket contributions. Clinical data were collected at baseline to identify cost-predicting factors., Results: Costs for formal care were increasing from € 535 per month of survival (MOS) at baseline to € 3,611 per MOS during the third year, with a mean of € 2,420 during the whole observation period. The major cost driver (74%) was institutional care. The costs for people with dementia with Lewy bodies (€ 3,247 per MOS) were significantly higher than for people with Alzheimer disease (€ 1,855 per MOS). The most important cost-predicting factors we identified were the living situation, a diagnosis of non-Alzheimer disease, comorbidity, and daily living functioning. The use of cholinesterase inhibitors was related to lower costs., Conclusion: Formal care costs increased significantly over time with institutional care being the heaviest cost driver. Studies with longer observation periods will be necessary to evaluate the complete socioeconomic impact of the course of dementia., (Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Context: Depression is common in dementia, especially in the early stages, with important clinical implications, but the etiology is unknown and most likely heterogeneous. Antidepressant use in the elderly without dementia has previously been shown to be associated with high risks of adverse events and with structural brain alterations., Objective: To investigate cortical changes associated with depression and antidepressant use in patients with mild Alzheimer's disease (AD) and Lewy body dementia (LBD)., Methods: 74 subjects with mild AD and LBD from geriatric and psychiatry outpatient clinics in Western Norway were included. The Montgomery-Asberg Depression Rating Scale (MADRS) was used to assess depression. Automatic preprocessing using Freesurfer included steps for white and grey matter surface reconstruction. The resulting cortical thickness was analyzed using linear modeling., Results: Clusters of depression-associated thinning were found in prefrontal and temporal areas. Treatment-associated thinning was observed in the parahippocampal region and was significant even after correction for age, sex, AD/LBD diagnosis, and MADRS scores., Conclusion: Depression in mild AD and LBD is associated with cortical thinning in prefrontal and temporal areas. The findings suggest that depressive symptoms in mild dementia could develop due to neurodegeneration in the same neural circuits that are critical for depression across different brain disorders. Antidepressant use in patients with mild AD and LBD is associated with parahippocampal thinning. Taken together with low efficacy of antidepressants in cognitively impaired patients and high risks of adverse events, our results suggest a need to re-evaluate the treatment approaches for depression and the role of antidepressants in patients with dementia., (Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

White matter changes (WMC) are the focus of intensive research and have been linked to cognitive impairment and depression in the elderly. Cumbersome manual outlining procedures make research on WMC labor intensive and prone to subjective bias. We present a fast, fully automated method for WMC segmentation using a cascade of reduced support vector machines (SVMs) with active learning. Data of 102 subjects was used in this study. Two MRI sequences (T1-weighted and FLAIR) and masks of manually outlined WMC from each subject were used for the image analysis. The segmentation framework comprises pre-processing, classification (training and core segmentation) and post-processing. After pre-processing, the model was trained on two subjects and tested on the remaining 100 subjects. The effectiveness and robustness of the classification was assessed using the receiver operating curve technique. The cascade of SVMs segmentation framework outputted accurate results with high sensitivity (90%) and specificity (99.5%) values, with the manually outlined WMC as reference. An algorithm for the segmentation of WMC is proposed. This is a completely competitive and fast automatic segmentation framework, capable of using different input sequences, without changes or restrictions of the image analysis algorithm., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Prevalence of Alzheimer's disease in people with Down's syndrome is very high, and many such individuals who are older than 40 years have pathological changes characteristic of Alzheimer's disease. Evidence to support treatment with Alzheimer's drugs is inadequate, although memantine is beneficial in transgenic mice. We aimed to assess safety and efficacy of memantine on cognition and function in individuals with Down's syndrome., Methods: In our prospective randomised double-blind trial, we enrolled adults (>40 years) with karyotypic or clinically diagnosed Down's syndrome, with and without dementia, at four learning disability centres in the UK and Norway. We randomly allocated participants (1:1) to receive memantine or placebo for 52 weeks by use of a computer-generated sequence and a minimisation algorithm to ensure balanced allocation for five prognostic factors (sex, dementia, age group, total Down's syndrome attention, memory, and executive function scales [DAMES] score, and centre). The primary outcome was change in cognition and function, measured with DAMES scores and the adaptive behaviour scale (ABS) parts I and II. We analysed differences in DAMES and ABS scores between groups with analyses of covariance or quantile regression in all patients who completed the 52 week assessment and had available follow-up data. This study is registered, number ISRCTN47562898., Findings: We randomly allocated 88 patients to receive memantine (72 [82%] had DAMES data and 75 [85%] had ABS data at 52 weeks) and 85 to receive placebo (74 [87%] and 73 [86%]). Both groups declined in cognition and function but rates did not differ between groups for any outcomes. After adjustment for baseline score, there were non-significant differences between groups of -4·1 (95% CI -13·1 to 4·8) in DAMES scores, -8·5 (-20·1 to 3·1) in ABS I scores, and 2·0 (-7·2 to 11·3) in ABS II scores, all in favour of controls. 10 (11%) of 88 participants in the memantine group and six (7%) of 85 controls had serious adverse events (p=0·33). Five participants in the memantine group and four controls died from serious adverse events (p=0·77)., Interpretation: There is a striking absence of evidence about pharmacological treatment of cognitive impairment and dementia in people older than 40 years with Down's syndrome. Despite promising indications, memantine is not an effective treatment. Therapies that are effective for Alzheimer's disease are not necessarily effective in this group of patients., Funding: Lundbeck., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

An estimated 24 million people worldwide have dementia, the majority of whom are thought to have Alzheimer's disease. Thus, Alzheimer's disease represents a major public health concern and has been identified as a research priority. Although there are licensed treatments that can alleviate symptoms of Alzheimer's disease, there is a pressing need to improve our understanding of pathogenesis to enable development of disease-modifying treatments. Methods for improving diagnosis are also moving forward, but a better consensus is needed for development of a panel of biological and neuroimaging biomarkers that support clinical diagnosis. There is now strong evidence of potential risk and protective factors for Alzheimer's disease, dementia, and cognitive decline, but further work is needed to understand these better and to establish whether interventions can substantially lower these risks. In this Seminar, we provide an overview of recent evidence regarding the epidemiology, pathogenesis, diagnosis, and treatment of Alzheimer's disease, and discuss potential ways to reduce the risk of developing the disease., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Several recent studies have shown that dementia is common in Parkinson's disease (PD), and that in some patients, cognitive impairment occurs even at the time of diagnosis. The point prevalence of dementia in PD is close to 30% and the incidence rate is increased 4-6 times as compared to controls. The cumulative prevalence is very high, at least 75% of PD patients who survive for more than 10 years will develop dementia. The mean time from onset of PD to dementia is approximately 10 years. However, there are considerable variations, and some patients develop dementia early in the disease course. Earlier onset of dementia is associated with more structural brain changes. The most established risk factors for early dementia are old age, severity of motor symptoms, in particular postural and gait disturbances, mild cognitive impairment and visual hallucinations. The genetic contributions to dementia are currently not clear and need to be explored in future studies.