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Sarcopenia is associated with multiple adverse outcomes. Traditional methods to determine low muscle mass for the diagnosis of sarcopenia are mainly based on dual‐energy X‐ray absorptiometry (DXA), whole‐body magnetic resonance imaging (MRI) and bioelectrical impedance analysis. These tests are not always available and are rather time consuming and expensive. However, many brain and head diseases require a head MRI. In this study, we aim to provide a more accessible way to detect sarcopenia by comparing the traditional method of DXA lean mass estimation versus the tongue and masseter muscle mass assessed in a standard brain MRI. The H70 study is a longitudinal study of older people living in Gothenburg, Sweden. In this cross‐sectional analysis, from 1203 participants aged 70 years at baseline, we included 495 with clinical data and MRI images available. We used the appendicular lean soft tissue index (ALSTI) in DXA images as our reference measure of lean mass. Images from the masseter and tongue were analysed and segmented using 3D Slicer. For the statistical analysis, the Spearman correlation coefficient was used, and concordance was estimated with the Kappa coefficient. The final sample consisted of 495 participants, of which 52.3% were females. We found a significant correlation coefficient between both tongue (0.26) and masseter (0.33) with ALSTI (P< 0.001). The sarcopenia prevalence confirmed using the alternative muscle measure in MRI was calculated using the ALSTI (tongue = 2.0%, masseter = 2.2%, ALSTI = 2.4%). Concordance between sarcopenia with masseter and tongue versus sarcopenia with ALSTI as reference has a Kappa of 0.989 (P< 0.001) for masseter and a Kappa of 1 for the tongue muscle (P< 0.001). Comorbidities evaluated with the Cumulative Illness Rating Scale were significantly associated with all the muscle measurements: ALSTI (odds ratio [OR] 1.16, 95% confidence interval [CI] 1.07–1.26, P< 0.001), masseter (OR 1.16, 95% CI 1.07–1.26, P< 0.001) and tongue (OR 1.13, 95% CI 1.04–1.22, P= 0.002); the higher the comorbidities, the higher the probability of having abnormal muscle mass. ALSTI was significantly correlated with tongue and masseter muscle mass. When performing the sarcopenia diagnostic algorithm, the prevalence of sarcopenia calculated with head muscles did not differ from sarcopenia calculated using DXA, and almost all participants were correctly classified using both methods.

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.

Identifying nutritional compounds which can reduce cognitive decline in older people is a hugely important topic.

Long-term sequelae clustering phenotypes are important for precise health care management in COVID-19 survivors. We reported findings for 1000 survivors 20 months after diagnosis of COVID-19 in a community-based cohort in China. Sequelae symptoms were collected from a validated questionnaire covering 27 symptoms involved in five organ systems including self-reported physical condition, dyspnea, cognitive function and mental health. The generalized symptoms were reported with the highest rate (60.7%), followed by the mental (48.3%), cardiopulmonary (39.8%), neurological (37.1%; cognitive impairment, 15.6%), and digestive symptoms (19.1%). Four clusters were identified by latent class analysis: 44.9% no or mild group (cluster 1), 29.2% moderate group with mainly physical impairment (cluster 2), 9.6% moderate group with mainly cognitive and mental health impairment (cluster 3), and 16.3% severe group (cluster 4). Physical comorbidities or history of mental disorders, longer hospitalization periods and severe acute illness predicted severe group. For moderate group, adults less than 60 years, with physical comorbidities and severe acute illness were more likely to have physical symptoms, while adult women with longer hospitalization stays had increased risk of cognitive and mental health impairment. Overall, among more than half of community COVID-19 survivors who presented moderate or severe sequelae 20 months after recovery, three-tenth had physical vulnerability that may require physical therapy aiming to improve functioning, one-tenth mental or cognitive vulnerable cases need psychotherapy and cognitive rehabilitation, and one-sixth severe group needs multidisciplinary clinical management. The remaining half is free to clinical intervention. Our findings introduced an important framework to map numerous symptoms to precise classification of the clinical sequelae phenotype and provide information to guide future stratified recovery interventions.

To authenticate to the full-text of this article, please visit this link: http://dx.doi.org/10.1111/j.1532-5415.2010.02733.x Byline: Arvid Rongve (*), Bradley F. Boeve ([dagger]), Dag Aarsland ([double dagger]s.) Keywords: dementia; sleep disorder; dementia with Lewy bodies; Parkinson's disease dementia; Alzheimer's disease Abstract: OBJECTIVES: To identify sleep disturbances in participants with subtypes of dementia and explore clinical correlates. DESIGN: Cross-sectional. SETTING: Outpatient clinics in western Norway and the Mayo Clinic Study of Aging, Olmsted County, Minnesota. PARTICIPANTS: One hundred fifty-one community-dwelling western Norway residents referred for geriatric medicine, geriatric psychiatry or neurology evaluation and 420 participants without dementia from the Mayo Clinic Study of Aging. MEASUREMENTS: Dementia was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria. The Mayo Sleep Questionnaire, an interview to detect sleep disturbances, was administered to diagnose probable rapid eye movement (REM) sleep behavior disorder, probable periodic leg movements during sleep, probable restless legs syndrome, probable sleepwalking, probable sleep-related leg cramps, probable obstructive sleep apnea, and excessive daytime sleepiness. Insomnia was assessed using the Neuropsychiatric Inventory, an interview to detect neuropsychiatric symptoms in dementia. RESULTS: Seventy-one percent of the participants with dementia and 55.7% of control participants had sleep disturbances (P=.001). Most frequently reported in the mild dementia participants were insomnia (29.9%), probable sleep-related leg cramps (24.1%), excessive daytime sleepiness (22.6%), probable restless legs syndrome (20.7%), and probable REM sleep behavior disorder (18.5%). There were more sleep-related problems reported in participants with Lewy body dementias (LBD) (dementia with Lewy bodies and Parkinson's disease dementia) than in those with Alzheimer's disease (P=.008). Having any sleep disorder correlated with depression (P=.03) and anxiety (P=.02). CONCLUSION: Sleep problems are common in dementia, particularly in subjects with LBD, and are associated with psychiatric symptoms. Further research is needed to understand these associations and identify treatment strategies. Author Affiliation: (*)Research Department, Psychiatric Clinic, Helse-Fonna HF Haugesund Hospital, Haugesund, Norway ([dagger])Mayo Clinic, Rochester, Minnesota ([double dagger])Stavanger University Hospital, Stavanger, Norway (s.)University of Bergen, Bergen, Norway. Article note: Address correspondence to Arvid Rongve, Helse-Fonna HF Haugesund Hospital, Research Department Psychiatric Clinic, N-5504 Haugesund, Norway. E-mail: arvid.rongve@gmail.com

Background: Neuropsychiatric symptoms are common and important to people with Parkinson’s disease (PD), but their etiology is poorly understood. Plasma neurofilament light (NfL) and p-tau181 are biomarkers of neuro-axonal degeneration and tau pathology respectively, which have yet to be explored in association with the affective and psychotic symptoms in PD.Objective: To investigate the relationship between plasma NfL and p-tau181 with the affective and psychotic symptoms in PD.Methods: We assessed the baseline concentration of plasma NfL and p-tau181 in a cohort of 108 patients with PD and 38 healthy controls. A subgroup of patients (n?=?63) were assessed annually with clinical measures for up to 7 years. Psychotic symptoms were assessed using the Non-Motor Symptom Scale and affective symptoms were measured in the Hospital Anxiety and Depression Scale.Results: Baseline plasma NfL was a significant predictor of psychotic symptoms longitudinally across the study adjusted for age, Hoehn and Yahr stage, duration of follow up, duration of disease, baseline levodopa and dopamine agonist medication, and baseline cognition: (OR 8.15 [95% CI 1.40–47.4], p?=?0.020). There was no association between NfL concentration and the cumulative prevalence of affective symptoms. Plasma p-tau181 concentration was not associated with psychotic or affective symptoms.Conclusion: These findings suggest psychotic symptoms are associated with greater neurodegeneration in PD. Further studies are needed to explore NfL as a potential biomarker for psychosis in PD.

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOEε4 allele.

Education and cognition demonstrate consistent inverse associations with Alzheimer’s disease (AD). The biological underpinnings, however, remain unclear. Blood metabolites reflect the end point of biological processes and are accessible and malleable. Identifying metabolites with etiological relevance to AD and disentangling how these relate to cognitive factors along the AD causal pathway could, therefore, offer unique insights into underlying causal mechanisms.

IMPORTANCE: One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design. OBJECTIVE: To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria. EXPOSURES: Alzheimer disease biomarkers detected on PET or in CSF. MAIN OUTCOMES AND MEASURES: Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations. RESULTS: Among the 19 097 participants (mean [SD] age, 69.1 [9.8] years; 10 148 women [53.1%]) included, 10 139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P = .04). Gaussian mixture modeling–based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P = .004), subjective cognitive decline (9%; 95% CI, 3%-15%; P = .005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P = .004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, −2% to 9%; P = .18). CONCLUSIONS AND RELEVANCE: This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.

Treating hallucinations in people with Parkinson's disease can keep them from having to live in a nursing home. In a study of 178 patients with Parkinson's disease, hallucinations was one of the strongest risk factors for nursing home placement.

IMPORTANCE: Plasma phosphorylated tau (p-tau) has proven to be an accurate biomarker for Alzheimer disease (AD) pathologic characteristics, offering a less expensive and less invasive alternative to cerebrospinal fluid (CSF) and positron emission tomography biomarkers for amyloid-β and tau. Alzheimer disease comorbid pathologic characteristics are common and are associated with more rapid cognitive decline in patients with dementia with Lewy bodies (DLB); therefore, it is anticipated that plasma p-tau concentrations may have utility in assessing cognitive impairment in individuals with this disorder. OBJECTIVE: To measure the concentrations of plasma p-tau (p-tau181 and p-tau231) and evaluate their associations with cognitive decline in individuals with probable DLB. DESIGN, SETTING, AND PARTICIPANTS: This multicenter longitudinal cohort study included participants from the European-DLB (E-DLB) Consortium cohort enrolled at 10 centers with harmonized diagnostic procedures from January 1, 2002, to December 31, 2020, with up to 5 years of follow-up. A total of 1122 participants with plasma samples were available. Participants with acute delirium or terminal illness and patients with other previous major psychiatric or neurologic disorders were excluded, leaving a cohort of 987 clinically diagnosed participants with probable DLB (n = 371), Parkinson disease (n = 204), AD (n = 207), as well as healthy controls (HCs) (n = 205). MAIN OUTCOMES AND MEASURES: The main outcome was plasma p-tau181 and p-tau231 levels measured with in-house single molecule array assays. The Mini-Mental State Examination (MMSE) was used to measure cognition. RESULTS: Among this cohort of 987 patients (512 men [51.9%]; mean [SD] age, 70.0 [8.8] years), patients with DLB did not differ significantly regarding age, sex, or years of education from those in the AD group, but the DLB group was older than the HC group and included more men than the AD and HC groups. Baseline concentrations of plasma p-tau181 and p-tau231 in patients with DLB were significantly higher than those in the HC group but lower than in the AD group and similar to the Parkinson disease group. Higher plasma concentrations of both p-tau markers were found in a subgroup of patients with DLB with abnormal CSF amyloid-β42 levels compared with those with normal levels (difference in the groups in p-tau181, −3.61 pg/mL; 95% CI, −5.43 to −1.79 pg/mL; P = .049; difference in the groups in p-tau231, −2.51 pg/mL; 95% CI, −3.63 to −1.39 pg/mL; P = .02). There was no difference between p-tau181 level and p-tau231 level across confirmed AD pathologic characteristcs based on reduced Aβ42 level in CSF in individuals with DLB. In DLB, a significant association was found between higher plasma p-tau181 and p-tau231 levels and lower MMSE scores at baseline (for p-tau181, −0.092 MMSE points; 95% CI, −0.12 to −0.06 MMSE points; P = .001; for p-tau231, −0.16 MMSE points; 95% CI, −0.21 to −0.12 MMSE points; P &lt; .001), as well as more rapid MMSE decline over time. Plasma p-tau181 level was associated with a decrease of −0.094 MMSE points per year (95% CI, −0.144 to −0.052 MMSE points; P = .02), whereas plasma p-tau231 level was associated with an annual decrease of −0.130 MMSE points (95% CI, −0.201 to −0.071 MMSE points; P = .02), after adjusting for sex and age. CONCLUSIONS AND RELEVANCE: This study suggests that plasma p-tau181 and p-tau231 levels may be used as cost-effective and accessible biomarkers to assess cognitive decline in individuals with DLB.

Objective: This study explored the relationship between aggressive behavior and other neuropsychiatric symptoms in patients with Alzheimer's disease. Method: Consecutively assessed outpatients with probable or possible Alzheimer's disease (N=75) were assessed with the Behavioral Pathology in Alzheimer's Disease Rating Scale and the Hamilton Depression Rating Scale. Results: Twenty-five patients (33%) had verbal outbursts and 13 patients (17%) engaged in physical aggression in the month prior to assessment. Aggressive patients and nonaggressive patients did not differ regarding age, education, gender, level of depression, or severity of dementia. In the entire group, dysphoria was found in 33%, delusional ideation in 39%, and hallucinations in 16%. Aggressive behavior was more frequent among patients with hallucinations than among those without. Scores on hallucinations and activity disturbance predicted 12% of the variance in total aggressive behavior. When data from patients taking psychotropic medication were excluded from the analysis, hallucination and delusion scores predicted 22% of the variance in the aggression score. Physical aggression was associated with activity disturbance and hallucinations, and verbal aggression was associated with delusional ideation. No other clinical correlates of aggression were identified. Conclusions: Aggressive behavior is a frequent behavioral symptom in Alzheimer's disease. About one-fourth of the variance in aggression could be attributed to psychosis.

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD + P). AD + P affects ~50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD − P). Although the estimated heritability of AD + P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5445 AD + P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6(rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p= 1.26 × 10−8) and one spanning the 3′-UTR of an alternatively spliced transcript of SUMF1(rs201109606, O.R. 0.65 (0.56–0.76), p= 3.24 × 10−8), had genome-wide significant associations with AD + P. Gene-based analysis identified a significant association with APOE, due to the APOErisk haplotype ε4. AD + P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD + P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.

Late-onset Alzheimer’s disease is a prevalent age-related polygenic disease that accounts for 50–70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer’s disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer’s disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer’s disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer’s disease to identify further genetic variants that contribute to Alzheimer’s pathology.

Ethnic phenotypic differences in Parkinson’s disease (PD) are important to understand the heterogeneity of PD and develop biomarkers and clinical trials. To investigate (i) whether there are non-motor symptoms (NMS)- and comorbidity-based phenotypic differences between Black, Asian and Minority Ethnic (BAME) and White PD patients and (ii) whether clinically available biomarkers may help differentiate and explain the differences between the groups. This is a multicentre (four sites, London), real-life, cross-sectional study including PD patients of BAME or White ethnicity. The primary outcome was a detailed NMS assessment; additional measurements included disease and motor stage, comorbidity, sociodemographic parameters and brain MRI imaging. 271 PD patients (54 Asian, 71 Black, and 146 White) were included balanced for age, gender, and disease severity (HY). Black patients had a shorter disease duration compared to White and Asian populations. The SCOPA-Motor activities of daily living scores as well as the NMSS scores were significantly higher in both Black (total score and domain “miscellaneous”) and Asian (total score and domains “sleep/fatigue”, “mood/apathy” and “perception/hallucinations”) than White individuals. Both BAME populations had higher prevalence of arterial hypertension, and the Black population had a higher prevalence of diabetes mellitus. Brain MRI revealed a greater severity of white matter changes in Black compared to the White and Asian cohorts. These findings suggest differences in phenotype of PD in BAME populations with greater burden of NMS and motor disability and a higher rate of cardiovascular comorbidities.

•What is the primary question addressed by this study?What are the differentially expressed genes and dysfunctional molecular networks in serum small extracellular vesicles (SEV) from people living with dementia with Lewy bodies (DLB)?•What is the main finding of this study?Statistically significant differential expression levels of 40 post-mortem DLB brain differentially expressed genes (DEG) could be detected in serum SEVs from people living with DLB. Our findings highlight the contributions of immunosenescence, ubiquitin proteasome system (UPS) dysfunction, DNA repair and RNA post-transcriptional modification deficits towards DLB pathology.•What is the meaning of the finding?Measuring circulating SEV RNA has opened a new avenue for discovering blood-based diagnostic biomarkers for DLB, and diagnostic biomarker potential of identified DEGs warrant further evaluation in large clinical cohorts of people with DLB.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer’s disease and Parkinson’s disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

Constipation is regarded as one of the prodromal features of Parkinson’s disease (PD) and there is emerging evidence linking gastrointestinal dysfunction and cognitive impairment (CI) in PD. We explored whether constipation is associated with development of CI in two independent cohorts of de novoPD patients (n = 196 from the Non-motor International Longitudinal Study [NILS] and n = 423 from the Parkinson’s Progression Markers Initiative [PPMI] study). Constipation was clinically defined using the Non-Motor Symptoms Scale (NMSS) item-21 [NILS] and Scales for Outcomes in PD-Autonomic (SCOPA-AUT) item-5 [PPMI]. We assessed baseline group differences (PD with or without constipation) in CI, global non-motor symptoms burden, motor dysfunction, and striatal dopaminergic denervation. Kaplan-Meier method estimated group differences in cumulative proportion of patients with incident CI over three years. In PPMI, we subsequently performed univariate and multivariate Cox survival analyses to evaluate whether constipation predicts incident mild cognitive impairment or dementia over a 6-year period, including constipation and other known predictors of CI as covariates. Patients with constipation had greater motor and global non-motor burden in both cohorts at baseline (p <  0.05). Kaplan-Meier plots showed faster conversion to CI in patients with constipation in both cohorts (p <  0.05). In PPMI, 37 subjects developed dementia during a mean follow-up of 4.9 years, and constipation was an independent predictor of dementia onset (hazard ratio = 2.311; p = 0.02). Constipation in de novoPD patients is associated with development of cognitive decline and may serve as a clinical biomarker for identification of patients at risk for cognitive impairment.

Drug repositioning and repurposing can enhance traditional drug development efforts and could accelerate the identification of new treatments for individuals with Alzheimer disease (AD) dementia and mild cognitive impairment. Transcriptional profiling offers a new and highly efficient approach to the identification of novel candidates for repositioning and repurposing. In the future, novel AD transcriptional signatures from cells isolated at early stages of disease, or from human neurons or microglia that carry mutations that increase the risk of AD, might be used as probes to identify additional candidate drugs. Phase II trials assessing repurposed agents must consider the best target population for a specific candidate therapy as well as the mechanism of action of the treatment. In this Review, we highlight promising compounds to prioritize for clinical trials in individuals with AD, and discuss the value of Delphi consensus methodology and evidence-based reviews to inform this prioritization process. We also describe emerging work, focusing on the potential value of transcript signatures as a cost-effective approach to the identification of novel candidates for repositioning.

Cerebrospinal fluid analyses and neuroimaging can identify the underlying pathophysiology at the earliest stage of some neurodegenerative disorders, but do not have the scalability needed for population screening. Therefore, a blood-based marker for such pathophysiology would have greater utility in a primary care setting and in eligibility screening for clinical trials. Rapid advances in ultra-sensitive assays have enabled the levels of pathological proteins to be measured in blood samples, but research has been predominantly focused on Alzheimer disease (AD). Nonetheless, proteins that were identified as potential blood-based biomarkers for AD, for example, amyloid-β, tau, phosphorylated tau and neurofilament light chain, are likely to be relevant to other neurodegenerative disorders that involve similar pathological processes and could also be useful for the differential diagnosis of clinical symptoms. This Review outlines the neuropathological, clinical, molecular imaging and cerebrospinal fluid features of the most common neurodegenerative disorders outside the AD continuum and gives an overview of the current status of blood-based biomarkers for these disorders.

What is the primary question addressed by this study?•What are the differentially expressed genes and dysfunctional molecular networks in postmortem brains of people with Lewy body dementia (LBD)?What is the main finding of this study?•This study has identified and verified 12 novel differentially expressed genes in LBD brains. Down-regulation of several inflammatory markers revealed the absence of chronic neuroinflammation in LBD.What is the meaning of the finding?•The findings advance molecular level mechanistic understanding and indicate potential biomarkers for LBD that warrant further investigation.

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.

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Alzheimer’s disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rg= 0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver, and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomization results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.

Today, meta-analyses demonstrate that cognitive training is safe and effective to enhance vulnerable cognitive functions in patients with Parkinson’s disease (PD), so that cognitive interventions can be regarded as a promising approach to treat or even prevent cognitive dysfunction in PD. However, many research gaps exist. Thus, this article aims to identify relevant research topics with regard to cognitive interventions in PD patients for the next 20 years. The most important to do's include the development of (non-digital and digital, maybe also artificial intelligence based) standardized cognitive interventions for PD patients in different cognitive stages and the conduct of large randomized controlled trials (RCTs) in these groups, also considering different patient profiles (e.g., motor subtypes) and the living setting (inpatient versus outpatient). The impact of cognitive and combined interventions in individuals with prodromal PD is of high relevance. Studies should elucidate underlying mechanisms of cognitive and neural plasticity induced by cognitive interventions and propose prediction models on which patients profit from which intervention. Health-economic analyses are also urgently needed. More generally, increasing the awareness of the concept of cognitive reserve and possibilities for the prevention of cognitive dysfunction is an important goal.

Heterozygous mutations in glucocerebrosidase gene (GBA)are a major genetic risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Recently, there has been a considerable focus on the relationship between GBAmutations and emergence of cognitive impairment and neuropsychiatric symptoms in these diseases. Here, we review the literature in this area, with a particular focus, including meta‐analysis, on the key neuropsychiatric symptoms of cognitive impairment, psychosis, and depression in Parkinson's disease. Our meta‐analysis demonstrated that GBAmutations are associated with a 2.4‐fold increased risk of cognitive impairment. In addition, our novel meta‐analyses of psychosis and depression showed a 1.8‐ and 2.2‐fold increased risk respectively associated with GBAmutations, although due to possible bias and heterogeneity the depression findings should be interpreted with caution. While the precise mechanisms which increase susceptibility to neurodegeneration in GBAcarriers are not known, evidence of greater cortical Lewy body pathology, reduced patterns of cortical activation, and hippocampal pathology in animal models are all consistent with a direct effect of GBAmutations on these symptoms. Extension of this work in DLB and individuals without neurodegeneration will be important in further characterizing how GBAmutations increase risk for PD and DLB and influence disease course.

The cerebrospinal fluid neurogranin (Ng)/β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) ratio may reflect synaptic affection resulting from reduced beta-amyloid (Aβ) clearance. We hypothesize that increased Ng/BACE1 ratio predicts the earliest cognitive decline in Alzheimer's disease.

The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and 123iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.

Dementia is a frequent problem encountered in advanced stages of Parkinson disease (PD). In recent years, research has focused on the pre-dementia stages of cognitive impairment in PD, including mild cognitive impairment (MCI). Several longitudinal studies have shown that MCI is a harbinger of dementia in PD, although the course is variable, and stabilization of cognition — or even reversal to normal cognition — is not uncommon. In addition to limbic and cortical spread of Lewy pathology, several other mechanisms are likely to contribute to cognitive decline in PD, and a variety of biomarker studies, some using novel structural and functional imaging techniques, have documented in vivo brain changes associated with cognitive impairment. The evidence consistently suggests that low cerebrospinal fluid levels of amyloid-β42, a marker of comorbid Alzheimer disease (AD), predict future cognitive decline and dementia in PD. Emerging genetic evidence indicates that in addition to the APOE*ε4 allele (an established risk factor for AD), GBA mutations and SCNA mutations and triplications are associated with cognitive decline in PD, whereas the findings are mixed for MAPT polymorphisms. Cognitive enhancing medications have some effect in PD dementia, but no convincing evidence that progression from MCI to dementia can be delayed or prevented is available, although cognitive training has shown promising results.

In 2007, the clinical and research profile of illusions, hallucinations, delusions and related symptoms in Parkinson disease (PD) was raised with the publication of a consensus definition of PD psychosis. Symptoms that were previously deemed benign and clinically insignificant were incorporated into a continuum of severity, leading to the rapid expansion of literature focusing on clinical aspects, mechanisms and treatment. Here, we review this literature and the evolving view of PD psychosis. Key topics include the prospective risk of dementia in individuals with PD psychosis, and the causal and modifying effects of PD medication. We discuss recent developments, including recognition of an increase in the prevalence of psychosis with disease duration, addition of new visual symptoms to the psychosis continuum, and identification of frontal executive, visual perceptual and memory dysfunction at different disease stages. In addition, we highlight novel risk factors — for example, autonomic dysfunction — that have emerged from prospective studies, structural MRI evidence of frontal, parietal, occipital and hippocampal involvement, and approval of pimavanserin for the treatment of PD psychosis. The accumulating evidence raises novel questions and directions for future research to explore the clinical management and biomarker potential of PD psychosis.

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.(Reprinted with permission from Lancet2015; 386:1683-97)

BackgroundParkinson’s Disease (PD) psychosis refers to the spectrum of illusions, formed hallucinations and delusions that occur in PD. Visual hallucinations and illusions are thought to be caused by specific cognitive and higher visual function deficits and patients who develop such symptoms early in the disease course have greater rates of cognitive decline and progression to dementia. To date, no studies have investigated whether such deficits are found prior to the onset of PD psychosis.MethodHere we compare baseline cognitive, biomarker (structural imaging and cerebrospinal fluid) and other PD psychosis risk factor data in patients who go on to develop illusions or hallucinations within 3–4 years of follow-up in the Parkinson’s Progression Markers Initiative cohort of newly diagnosed PD.ResultsOf n=423 patients with PD, n=115 (27%) reported predominantly illusions with the median time of onset at 19.5 months follow-up. At study entry these patients had reduced CSF amyloid Aß1-42, lower olfaction scores, higher depression scores and increased REM sleep behaviour disorder symptoms compared to patients without early onset PD psychosis but no differences in cognitive, higher visual or structural imaging measures. A subset of patients with early onset formed hallucinations (n=21) had reduced higher visual function at baseline, cortical thinning in parietal, occipital and frontal cortex and reduced hippocampal volume.ConclusionsThe findings suggest early onset illusions and formed hallucinations are linked to amyloid pathology in PD and point to a difference in the underlying pathophysiological mechanism of illusions and formed hallucinations, with implications for their respective links to future cognitive decline.

Background:Postsynaptic cholinergic deficits, including reduced cortical muscarinic M1 receptor coupling to G-proteins, are neurochemical findings postulated to underlie the limited efficacy of presynaptically-targeted cholinergic replacement therapies in Alzheimer’s disease (AD). While the loss of M1-G-protein coupling has been associated with β-amyloid (Aβ) burden in AD, the status of M1 coupling to G-proteins in Parkinson’s disease-related or mixed dementias is unclear. Objective:To test the hypothesis that M1 receptor uncoupling is correlated with Aβ burden, we aimed to study muscarinic M1 neurochemical parameters in neurodegenerative dementias characterized by low and high Aβ loads. Methods:M1 receptors, M1 coupling to G-proteins as well as Aβ were measured in postmortem frontal cortex of a cohort of longitudinally assessed patients with Parkinson’s Disease Dementia (PDD, low Aβ load) and AD with significant subcortical cerebrovascular disease (AD + CVD, high Aβ load). Results:We found unchanged levels of M1 receptors in both dementia groups, while M1 coupling was reduced only in AD + CVD (p < 0.01). Furthermore, Aβ concentration was significantly increased only in AD + CVD, and correlated negatively with M1-G-protein coupling in the dementia groups. Conclusions:Our study suggests that loss of M1 coupling to G-proteins may be a neurochemical feature of neurodegenerative dementias with high cortical Aβ burden, and that cholinergic replacement therapies may be more efficacious for PDD due to low Aβ burden.

Background:Neuropsychological comparisons between patients with mild cognitive impairment due to Parkinson’s disease (MCI-PD) and Alzheimer’s disease (MCI-AD) is mostly based on indirect comparison of patients with these disorders and normal controls (NC).Objective:The focus of this study was to make a direct comparison between patients with these diseases.Methods:The study compared 13 patients with MCI-PD and 19 patients with MCI-AD with similar age, education and gender. The participants were recruited and assessed at the same university clinic with equal methods.Results:The main finding was that on group level, MCI-AD scored significantly poorer on learning and memory tests than MCI-PD, whereas MCI-PD were impaired on 1 of 3 measures of executive functioning.Conclusion:MCI-AD performed poorer learning and memory tests, whereas MCI-PD only scored below the employed cut-off on one single executive test. In general, MCI-PD was noticeably less cognitively impaired than MCI-AD.

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.

Parkinson’s disease (PD) is characterized by motor symptoms, but focused and extensive research in the last years has provided new knowledge in the field of non-motor symptoms. Non-motor symptoms include neuropsychiatric symptoms such as depression, anxiety, psychosis, apathy, impulse control disorders, and occur in the majority of patients with PD. They are associated with impaired quality of life for patients and relatives, additional deterioration of function and increased use of health resources. Medical and surgical therapies commonly used for treatment of PD can induce or worsen such symptoms. This paper discusses the epidemiology, clinical features and treatment approaches for neuropsychiatric symptoms (NPS) in PD in the perspective of clinical practice and management. The prevalence rates of various NPS are high, various demographic, clinical and treatment related variables have shown to be associated with higher risk of NPS. Randomized controlled trials of pharmacological and non-pharmacological treatments of NPS in PD are sparse. Current evidence supports tricyclic antidepressants as efficacious treatment of depression in PD and antipsychotic clozapine as efficacious choice for psychosis. Further studies to evaluate various other management strategies of NPS in PD are required. Neuropsychiatric symptoms in PD should be considered an integral part of the disease; hence a multidisciplinary approach is essential to improve the overall outcome of PD also through raised awareness and enriched knowledge on NPS.

Alzheimer disease (AD) and Parkinson disease (PD) are the most common neurodegenerative disorders. For both diseases, early intervention is thought to be essential to the success of disease-modifying treatments. Cerebrospinal fluid (CSF) can reflect some of the pathophysiological changes that occur in the brain, and the number of CSF biomarkers under investigation in neurodegenerative conditions has grown rapidly in the past 20 years. In AD, CSF biomarkers are increasingly being used in clinical practice, and have been incorporated into the majority of clinical trials to demonstrate target engagement, to enrich or stratify patient groups, and to find evidence of disease modification. In PD, CSF biomarkers have not yet reached the clinic, but are being studied in patients with parkinsonism, and are being used in clinical trials either to monitor progression or to demonstrate target engagement and downstream effects of drugs. CSF biomarkers might also serve as surrogate markers of clinical benefit after a specific therapeutic intervention, although additional data are required. It is anticipated that CSF biomarkers will have an important role in trials aimed at disease modification in the near future. In this Review, we provide an overview of CSF biomarkers in AD and PD, and discuss their role in clinical trials.

Our aim was to assess cortical thickness in a large multicenter cohort of drug-naive patients with early Parkinson disease (PD), with and without mild cognitive impairment (MCI), and explore the cognitive correlates of regional cortical thinning.

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.

To investigate the use of formal care during the first three years after diagnosis of mild dementia and identify cost-predicting factors.