Association of CSF α-Synuclein Seeding Amplification Assay Results With Clinical Features of Possible and Probable Dementia With Lewy Bodies.

BACKGROUND AND OBJECTIVES: The clinical diagnosis of dementia with Lewy bodies (DLB) depends on identifying significant cognitive decline accompanied by core features of parkinsonism, visual hallucinations, cognitive fluctuations, and REM sleep behavior disorder (RBD). Hyposmia is one of the several supportive features. α-Synuclein seeding amplification assays (αSyn-SAAs) may enhance diagnostic accuracy by detecting pathologic αSyn seeds in CSF. In this study, we examine how different clinical features associate with CSF αSyn-SAA positivity in a large group of clinically diagnosed participants with DLB. METHODS: Cross-sectional and longitudinal CSF samples from the multicentered observational cohort study of the DLB Consortium and similar studies within the Parkinson's Disease Biomarker Program, contributed by academic medical centers in the United States, underwent αSyn-SAA testing. Participants included those clinically diagnosed with DLB and 2 control cohorts. Associations between core DLB features and olfaction with αSyn-SAA positivity were evaluated using logistic regression. RESULTS: CSF samples from 191 participants diagnosed with DLB (mean age 69.9 ± 6.8, 15% female), 50 age-matched and sex-matched clinical control participants, and 49 younger analytical control participants were analyzed. Seventy-two percent (137/191) of participants with DLB had positive αSyn-SAAs vs 4% of the control groups. Among participants with DLB, those who were αSyn-SAA-positive had lower Montreal Cognitive Assessment scores (18.8 ± 5.7 vs 21.2 ± 5.2, p = 0.01), had worse parkinsonism on the Movement Disorders Society Unified Parkinson's Disease Rating Scale part III (33.8 ± 15.1 vs 25.6 ± 16.4, p = 0.001), were more likely to report RBD (114/133 [86%] vs 33/53 [62%], p < 0.0001), and had worse hyposmia on the University of Pennsylvania Smell Identification Test (UPSIT) (94/105 [90%] below 15th percentile vs 14/44 [32%], p < 0.0001). UPSIT percentile had the highest area under the curve (0.87, 95% CI 0.81-0.94) in predicting αSyn-SAA positivity and participants scoring at or below the 15th percentile of age and sex normative values had 18.3 times higher odds (95% CI 7.52-44.6) of having a positive αSyn-SAA test. Among 82 participants with longitudinal CSF samples, 81 (99%) had the same αSyn-SAA result for initial and follow-up specimens. DISCUSSION: A substantial proportion of clinically diagnosed participants with DLB had negative αSyn-SAA results. Hyposmia was the strongest clinical predictor of αSyn-SAA positivity. Hyposmia and αSyn-SAA may have utility in improving the diagnostic assessment of individuals with potential DLB. CLASSIFICATION OF EVIDENCE: This study provided Class III evidence that CSF αSyn-SAA distinguishes patients with clinically diagnosed DLB from normal controls.

Gene specific effects on brain volume and cognition of TMEM106B in frontotemporal lobar degeneration.

Background and Objectives: TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN mutation carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study is to evaluate and compare the effect of TMEM106B on gray matter volume and cognition in each of the common genetic FTD groups and in sporadic FTD patients. Methods: Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic mutation in C9orf72, GRN, MAPT, VCP, TBK1, TARDBP, symptomatic non-mutation carriers, and non-carrier family controls. All participants were genotyped for the TMEM106B rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between TMEM106B and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex and CDR®+NACC-FTLD sum of boxes. Subsequently, associations between TMEM106B and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by TMEM106B predictor interactions were fitted. Results: The minor allele of TMEM106B rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in GRN mutation carriers under the recessive dosage model. This was most pronounced in the thalamus in the left hemisphere, with a retained association when considering presymptomatic GRN mutation carriers only. The minor allele of TMEM106B rs1990622 also associated with greater cognitive scores among all C9orf72 mutation carriers and in presymptomatic C9orf72 mutation carriers, under the recessive dosage model. Discussion: We identified associations of TMEM106B with gray matter volume and cognition in the presence of GRN and C9orf72 mutations. This further supports TMEM106B as modifier of TDP-43 pathology. The association of TMEM106B with outcomes of interest in presymptomatic GRN and C9orf72 mutation carriers could additionally reflect TMEM106B's impact on divergent pathophysiological changes before the appearance of clinical symptoms.

Gene-Specific Effects on Brain Volume and Cognition of TMEM106B in Frontotemporal Lobar Degeneration.

BACKGROUND AND OBJECTIVES: TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN pathogenic variant carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study was to evaluate and compare the effect of TMEM106B on gray matter volume and cognition in each of the common genetic FTD groups and in patients with sporadic FTD. METHODS: Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic variant in C9orf72, GRN, MAPT, VCP, TBK1, TARDBP, symptomatic nonpathogenic variant carriers, and noncarrier family controls. All participants were genotyped for the TMEM106B rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between TMEM106B and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex, and CDR+NACC-FTLD sum of boxes. Subsequently, associations between TMEM106B and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by TMEM106B predictor interactions were fitted. RESULTS: The minor allele of TMEM106B rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in GRN pathogenic variant carriers under the recessive dosage model (N = 82, beta = 3.25, 95% CI [0.37-6.19], p = 0.034). This was most pronounced in the thalamus in the left hemisphere (beta = 0.03, 95% CI [0.01-0.06], p = 0.006), with a retained association when considering presymptomatic GRN pathogenic variant carriers only (N = 42, beta = 0.03, 95% CI [0.01-0.05], p = 0.003). The minor allele of TMEM106B rs1990622 also associated with greater cognitive scores among all C9orf72 pathogenic variant carriers (N = 229, beta = 0.36, 95% CI [0.05-0.066], p = 0.021) and in presymptomatic C9orf72 pathogenic variant carriers (N = 106, beta = 0.33, 95% CI [0.03-0.63], p = 0.036), under the recessive dosage model. DISCUSSION: We identified associations of TMEM106B with gray matter volume and cognition in the presence of GRN and C9orf72 pathogenic variants. The association of TMEM106B with outcomes of interest in presymptomatic GRN and C9orf72 pathogenic variant carriers could additionally reflect TMEM106B's effect on divergent pathophysiologic changes before the appearance of clinical symptoms.

Does Informant-Based Reporting of Cognitive Decline Correlate with Age-Adjusted Hippocampal Volume in Mild Cognitive Impairment and Alzheimer's Disease?

BACKGROUND: Informant-based measures are effective screening tools for cognitive impairment. The Alzheimer's Questionnaire (AQ) is a subjective, informant-based measure that detects amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) with high sensitivity and specificity and has been shown to predict amyloid burden. OBJECTIVE: To determine whether informant-based report of cognitive decline correlates with hippocampal volume changes in MCI and AD. METHODS: Retrospective chart review of 139 clinically referred patients with clinical diagnoses of aMCI or mild dementia due to AD was conducted. Diagnostic status (clinical diagnosis made by a neurologist), NeuroQuant measured MRI brain with percentile rank hippocampal volume, Montreal Cognitive Assessment (MoCA) total, AQ-Total score, and demographic variables were extracted from medical records. Spearman correlation was used to assess the relationship between hippocampal volume and AQ-Total. The AQ was used to assign diagnostic status. Thus, the relationship between the AQ and diagnostic status was excluded. RESULTS: The sample include 88 female and 51 male participants. The mean age was 74.37±9.45, mean MOCA was 22.65±4.18, mean education was 14.80±3.35, and mean AQ score was 10.54±5.22. Hippocampal volume and the AQ correlation was r = -0.33 [95%CI -0.47 to -0.17], p < 0.0001. CONCLUSION: In a mixed-clinical sample of patients presenting to an outpatient memory disorders center, higher endorseme-nts of functional impairments by caregivers were significantly associated with smaller hippocampal volumes. When used in conjunction with other available measures, these findings further support the role of the AQ in clinical decision-making and demonstrate an additional relationship between clinical measures and volumetric MRI.

Psychosis in Parkinson's disease.

Psychosis in Parkinson's disease (PD) is a fairly common and vexing problem. Although it can occur at any stage of the illness, it is a particularly important issue for patients who are in the later stages of PD and have been chronically treated with anti-PD medications. The exact pathophysiology of PD-related psychosis remains a mystery. Neurochemical imbalances, sleep disturbances, and visual processing abnormalities in PD have been implicated in its pathogenesis. Treatment of psychotic symptoms should occur only after potential medical and environmental causes of delirium have been eliminated or addressed. Initial pharmacologic changes should include limiting the patient's anti-PD medications to those that are necessary to preserve motor function. Should that fail, an atypical antipsychotic agent is presently the treatment of choice. An emerging treatment option is the use of acetylcholinesterase inhibitors. This article reviews what is known about the epidemiology, risk factors, pathophysiology, and treatment of PD-related psychosis.

Subcallosal cingulate deep brain stimulation for treatment-resistant unipolar and bipolar depression.

CONTEXT: Deep brain stimulation (DBS) may be an effective intervention for treatment-resistant depression (TRD), but available data are limited. OBJECTIVE: To assess the efficacy and safety of subcallosal cingulate DBS in patients with TRD with either major depressive disorder (MDD) or bipolar II disorder (BP). DESIGN: Open-label trial with a sham lead-in phase. SETTING: Academic medical center. Patients  Men and women aged 18 to 70 years with a moderate-to-severe major depressive episode after at least 4 adequate antidepressant treatments. Ten patients with MDD and 7 with BP were enrolled from a total of 323 patients screened. Intervention  Deep brain stimulation electrodes were implanted bilaterally in the subcallosal cingulate white matter. Patients received single-blind sham stimulation for 4 weeks followed by active stimulation for 24 weeks. Patients then entered a single-blind discontinuation phase; this phase was stopped after the first 3 patients because of ethical concerns. Patients were evaluated for up to 2 years after the onset of active stimulation. MAIN OUTCOME MEASURES: Change in depression severity and functioning over time, and response and remission rates after 24 weeks were the primary efficacy end points; secondary efficacy end points were 1 year and 2 years of active stimulation. RESULTS: A significant decrease in depression and increase in function were associated with chronic stimulation. Remission and response were seen in 3 patients (18%) and 7 (41%) after 24 weeks (n = 17), 5 (36%) and 5 (36%) after 1 year (n = 14), and 7 (58%) and 11 (92%) after 2 years (n = 12) of active stimulation. No patient achieving remission experienced a spontaneous relapse. Efficacy was similar for patients with MDD and those with BP. Chronic DBS was safe and well tolerated, and no hypomanic or manic episodes occurred. A modest sham stimulation effect was found, likely due to a decrease in depression after the surgical intervention but prior to entering the sham phase. CONCLUSIONS: The findings of this study support the long-term safety and antidepressant efficacy of subcallosal cingulate DBS for TRD and suggest equivalent safety and efficacy for TRD in patients with BP. Trial Registration  clinicaltrials.gov Identifier: NCT00367003.

Depression: a shared risk factor for cardiovascular and Alzheimer disease.

Depression has been linked to cardiovascular disease and cognitive impairment, including Alzheimer disease, but the exact nature of the relationship is poorly understood. Although depression seems to progress little after the onset of Alzheimer disease, depression in earlier life increases the risk of dementia and cognitive impairment many years in the future. Depression is also associated with reduced vascular function and is a poorly recognized but significant risk factor for stroke.

Catechol-o-methyltransferase valine(158)methionine genotype and resting regional cerebral blood flow in medication-free patients with schizophrenia.

BACKGROUND: A valine(158)methionine (val(158)met) polymorphism in catechol-O-methyltransferase (COMT) modulates cortical dopaminergic catabolism and has been associated with schizophrenia. Consistent with schizophrenia itself, during cognitive tasks, the risk (val) allele predicts less efficient prefrontal cortex (PFC) physiology and worse performance, while during aversive stimuli viewing, this allele predicts less limbic activation. Task-independent effects of this polymorphism in schizophrenia have not yet been characterized. METHODS: Twenty-five medication-free patients (28 +/- 6 years; 19 male patients) and 47 healthy individuals (29 +/- 8 years; 33 male individuals) were genotyped for the COMT val(158)met polymorphism and underwent two 60-second radiolabeled water ([(15)O]H(2)O) regional cerebral blood flow (rCBF) positron emission tomography scans (10 mCi/scan) during rest. Data were analyzed with a random-effects general linear model using COMT genotype as a covariate. RESULTS: In patients, but not healthy individuals, val (risk) allele load predicted less regional cerebral blood flow in the right dorsolateral PFC, right superior temporal gyrus, and left precuneus, but greater rCBF in the amygdala and parahippocampal gyrus. CONCLUSIONS: In schizophrenia, brain structures important for executive and affective processing show activity that is differentially predicted by COMT allelic variation in an opposing manner even at rest, providing evidence for the salience of prefrontal dopaminergic tone in task-independent, basal-level neural activity.

Deep brain stimulation and the role of the neuropsychologist.

Deep brain stimulation (DBS) now plays an important role in the treatment of Parkinson's disease, tremor, and dystonia. DBS may also have a role in the treatment of other disorders such as obsessive-compulsive disorder, Tourette's syndrome, and depression. The neuropsychologist plays a crucial role in patient selection, follow-up, and management of intra-operative and post-operative effects (Pillon, 2002; Saint-Cyr & Trepanier, 2000). There is now emerging evidence that DBS can induce mood, cognitive, and behavioral changes. These changes can have dramatic effects on patient outcome. There have been methodological problems with many of the studies of DBS on mood, cognition, and behavior. The neuropsychologist needs to be aware of these issues when following up patients, and constructing future studies. Additionally, this article will review all aspects of the DBS procedure that can result in mood, cognitive, and behavioral effects and what role(s) the neuropsychologist should play in screening and follow-up.