Validation of newly derived polygenic risk scores for dementia in a prospective study of older individuals.

INTRODUCTION: Recent genome-wide association studies identified new dementia-associated variants. We assessed the performance of updated polygenic risk scores (PRSs) using these variants in an independent cohort. METHODS: We used Cox models and area under the curve (AUC) to validate new PRSs (PRS-83SNP, PRS-SBayesR, and PRS-CS) compared with an older PRS-23SNP in 12,031 initially-healthy participants ≥70 years of age. Dementia was rigorously adjudicated according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. RESULTS: PRS-83SNP, PRS-SBayesR, and PRS-CS were associated with incident dementia, with fully adjusted (including apolipoprotein E [APOE] ε4) hazard ratios per standard deviation (SD) of 1.35 (1.23-1.47), 1.37 (1.25-1.50), and 1.42 (1.30-1.56), respectively. The AUC of a model containing conventional/non-genetic factors and APOE was 74.7%. This was improved to 75.7% (p = 0.007), 76% (p = 0.004), and 76.1% (p = 0.003) with addition of PRS-83SNP, PRS-SBayesR, and PRS-CS, respectively. The PRS-23SNP did not improve AUC (74.7%, p = 0.95). CONCLUSION: New PRSs for dementia significantly improve risk-prediction performance, but still account for less risk than APOE genotype overall.

Plasma Neurofilament Light Chain and Clinical Diagnosis in Frontotemporal Dementia Syndromes.

BACKGROUND: Frontotemporal dementia (FTD) syndromes, mimics, phenocopy (phFTD), and slowly progressive behavioral variant FTD (bvFTD) can be difficult to distinguish clinically. Biomarkers such as neurofilament light chain (NfL) may be helpful. OBJECTIVE: To study plasma NfL levels in people with FTD syndromes and determine if plasma NfL can distinguish between FTD syndromes and phFTD. METHODS: Plasma NfL levels were estimated using both Simoa® Quanterix HD-X™ and SR-X™ machines grouped via final diagnosis after investigation and review. RESULTS: Fifty participants were studied: bvFTD = 20, semantic variant FTD (svFTD) = 11, non-fluent variant FTD (nfvFTD) = 9, FTD with motor neuron disease (MND) = 4, phFTD = 2, slow progressors = 3, FTD mimic = 1, mean age 67.2 (SD 8.4) years. NfL levels were significantly higher in the FTD group compared to phenocopy group (p = 0.003). Median NfL (IQR) pg/mL was comparable in the FTD syndromes: bvFTD 41.10 (50.72), svFTD 44.38 (16.61), and nfvFTD 42.61 (22.93), highest in FTD with MND 79.67 (45.32) and lowest in both phFTD 13.99 (0.79) and slow progressors 17.97 (3.62). CONCLUSION: Plasma NfL appears to differentiate FTD syndromes and mimics. However, a lower NfL may predict a slower, but not necessarily absence of neurodegeneration, and therefore appears limited in distinguishing slow progressors from FTD phenocopies. Larger numbers of patients from all clinical groups are required to strengthen diagnostic utility.

A phase 1b open-label study of sodium selenate as a disease-modifying treatment for possible behavioral variant frontotemporal dementia.

Introduction: Sodium selenate increases tau dephosphorylation through protein phosphatase 2 activation. Here we report an open-label Phase 1b study of sodium selenate as a disease-modifying treatment for behavioral variant frontotemporal dementia (bvFTD). Methods: Twelve participants with bvFTD received sodium selenate (15 mg, three times a day) for 52 weeks. Safety assessments were carried out throughout the trial. Primary outcomes were frequency of adverse events (AEs), serious adverse events (SAEs), and discontinuations. Secondary outcomes of potential efficacy included cognitive and behavioral assessments, magnetic resonance imaging (MRI) whole brain volume, and cerebrospinal fluid (CSF) and blood total tau (t-tau), phosphorylated tau (p-tau), and neurofilament light (NfL) levels, which were measured at baseline and at week 52. Results: Sodium selenate was safe and well tolerated. All participants completed the study, and the majority (64.7%) of reported AEs were mild. One SAE occurred, which was not treatment related. Small declines in MRI and cognitive and behavioral measures were observed over the treatment period. There was no evidence for change in CSF protein levels (t-tau, p-tau, or NfL). Further analysis showed two distinct groups when measuring disease progression markers over the course of the study-one (n = 4) with substantial brain atrophy (2.5% to 6.5% reduction) and cognitive and behavioral decline over the 12-month treatment period, and the second group (n = 7) with no detectable change in cognitive and behavioral measures and less brain atrophy (0.3% to 1.7% reduction). Conclusion: Sodium selenate is safe and well tolerated in patients with bvFTD. Randomized-controlled trials are warranted to investigate potential efficacy.

Frontotemporal Dementia Differential Diagnosis in Clinical Practice: A Single-Center Retrospective Review of Frontal Behavioral Referrals.

Background and Objectives: Many neurodegenerative syndromes present with impairment of frontal networks, especially frontoinsular networks affecting social and emotional cognition. People presenting with frontal network impairments may be considered for a frontotemporal dementia (FTD) diagnosis. We sought to examine the diagnostic mix of patients referred with frontal network impairments to a single cognitive neurology service. Methods: A retrospective review was conducted of all patients seen between January 2010 and December 2019 at the Eastern Cognitive Disorders Clinic, a quaternary cognitive neurology clinic in Melbourne, Australia. Patients were included if they met the following criteria: (1) were referred for suspected FTD or with a preexisting diagnosis of a FTD syndrome, (2) were referred for 'frontal behaviors' (i.e., disinhibition, disorganization, poor judgment, loss of empathy, apathy) and/or had an informant report of behavior change, and (3) had available referral documents and clinical consensus diagnosis. Referral diagnosis was compared against final diagnosis adjudicated by a consensus multidisciplinary team. Case details including age of symptom onset, Cambridge Behavioural Inventory-Revised scores, psychiatric history, and Charlson Comorbidity Index were compared against the final diagnosis. Results: In total, 161 patients aged 42-82 years (mean = 64.5, SD = 9.0; 74.5% men) met inclusion criteria. The commonest final diagnosis was a FTD syndrome (44.6%: 26.7% behavioral variant FTD (bvFTD), 9.3% progressive supranuclear palsy, 6.2% semantic dementia, 1.2% corticobasal syndrome, and 1.2% FTD/motor neuron disease). A primary psychiatric disorder (PPD) was the next commonest diagnosis (15.5%), followed by vascular cognitive impairment (VCI, 10.6%), Alzheimer disease (AD, 9.9%), and other neurologic diagnoses (6.2%). A final diagnosis of bvFTD was associated with higher rates of medical comorbidities and more eating behavior abnormalities compared with a diagnosis of PPD. Screening cognitive tests and preexisting psychiatric history did not distinguish these 2 groups. Discussion: A broad spectrum of neurologic and psychiatric disorders may present with impairments to frontal networks. Almost half of patients referred had a final FTD syndrome diagnosis, with bvFTD the commonest final diagnosis. People with PPD, VCI, and AD present with similar clinical profiles but are distinguishable using MRI and FDG-PET imaging. Medical and psychiatric comorbidities are common in people with bvFTD.