Safety, tolerability, and efficacy of NLY01 in early untreated Parkinson's disease: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Converging lines of evidence suggest that microglia are relevant to Parkinson's disease pathogenesis, justifying exploration of therapeutic agents thought to attenuate pathogenic microglial function. We sought to test the safety and efficacy of NLY01-a brain-penetrant, pegylated, longer-lasting version of exenatide (a glucagon-like peptide-1 receptor agonist) that is believed to be anti-inflammatory via reduction of microglia activation-in Parkinson's disease. METHODS: We report a 36-week, randomised, double-blind, placebo-controlled study of NLY01 in participants with early untreated Parkinson's disease conducted at 58 movement disorder clinics in the USA. Participants meeting UK Brain Bank or Movement Disorder Society research criteria for Parkinson's disease were randomly allocated (1:1:1) to one of two active treatment groups (2·5 mg or 5·0 mg NLY01) or matching placebo, based on a central computer-generated randomisation scheme using permuted block randomisation with varying block sizes. All participants, investigators, coordinators, study staff, and sponsor personnel were masked to treatment assignments throughout the study. The primary efficacy endpoint for the primary analysis population (defined as all randomly assigned participants who received at least one dose of study drug) was change from baseline to week 36 in the sum of Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) parts II and III. Safety was assessed in the safety population (all randomly allocated participants who received at least one dose of the study drug) with documentation of adverse events, vital signs, electrocardiograms, clinical laboratory assessments, physical examination, and scales for suicidality, sleepiness, impulsivity, and depression. This trial is complete and registered at ClinicalTrials.gov, NCT04154072. FINDINGS: The study took place between Jan 28, 2020, and Feb 16, 2023. 447 individuals were screened, of whom 255 eligible participants were randomly assigned (85 to each study group). One patient assigned to placebo did not receive study treatment and was not included in the primary analysis. At 36 weeks, 2·5 mg and 5·0 mg NLY01 did not differ from placebo with respect to change in sum scores on MDS-UPDRS parts II and III: difference versus placebo -0·39 (95% CI -2·96 to 2·18; p=0·77) for 2·5 mg and 0·36 (-2·28 to 3·00; p=0·79) for 5·0 mg. Treatment-emergent adverse events were similar across groups (reported in 71 [84%] of 85 patients on 2·5 mg NLY01, 79 [93%] of 85 on 5·0 mg, and 73 [87%] of 84 on placebo), with gastrointestinal disorders the most commonly observed class in active groups (52 [61%] for 2·5 mg, 64 [75%] for 5·0 mg, and 30 [36%] for placebo) and nausea the most common event overall (33 [39%] for 2·5 mg, 49 [58%] for 5·0 mg, and 16 [19%] for placebo). No deaths occurred during the study. INTERPRETATION: NLY01 at 2·5 and 5·0 mg was not associated with any improvement in Parkinson's disease motor or non-motor features compared with placebo. A subgroup analysis raised the possibility of motor benefit in younger participants. Further study is needed to determine whether these exploratory observations are replicable. FUNDING: D&D Pharmatech-Neuraly.

Disparities in Huntington Disease Severity: Analysis Using the ENROLL-HD Dataset.

Background and Objectives: Social and structural determinants of health (SDOH) have been associated with disability in neurologic diseases. However, the association between these factors and disability in Huntington disease (HD) has not been studied. This study aimed to evaluate the association of racial and sociodemographic factors with disease severity in patients with HD in North America. Methods: We conducted a cross-sectional study of genetically confirmed participants with HD (36+ CAG repeats) in the North American region using the ENROLL-HD 2020 periodic dataset. In this analysis, our exposure variable was the participant's race/ethnicity. The main outcome measure was disease severity, as measured by the Total Functional Capacity Score (TFC), which measures the level of disability of patients with HD. We used multivariate regression models to adjust for sociodemographic factors that may mediate or moderate a causal effect between race/ethnicity and disease severity. Results: Among 4,717 gene-positive participants in the North American region, 89.5% identified as White, 3.4% as Hispanic or Latino, and 2.3% as African American/Black. The average TFC score was 10.22 (SD 3.22); 48% of participants completed either secondary education (including college) or a professional degree, and 55% lived in a city and not in a town, village, or rural location. In multivariate regression models, we found that Black participants and those with less than a high school degree entered the ENROLL-HD study with lower TFC scores than White participants. We also found that compared with those with at least a high school degree, those who completed some form of higher education or professional degree had higher TFC scores (p < 0.001). This multivariate analysis did not find an association between geographic location and TFC score. Discussion: Our study found that Black participants in North America presented to ENROLL-HD with more advanced disease than White patients. We also found that higher education was associated with less advanced disease when entering the ENROLL-HD study. The role of race/ethnicity and education in HD symptom severity warrants further investigation. These findings underscore the importance of further studying the role of social and structural determinants of health in patients with HD, particularly those from historically marginalized communities.

Health Services in Huntington Disease: A Systematic Literature Review.

Purpose of Review: Clinical trials for Huntington disease (HD) have primarily focused on managing chorea and, more recently, the development of disease-modifying therapies (DMTs). Nonetheless, understanding health services among patients with HD is essential for assessing new therapeutics, development of quality metrics, and overall quality of life of patients and families with HD. Health services assess health care utilization patterns, outcomes, and health care-associated costs, which can help shape the development of therapeutics and aid in policies that affect patients with a specific condition. In this systematic literature review, we analyze data of published studies looking at causes of hospitalization, outcomes, and health care costs in HD. Recent Findings: The search yielded 8 articles published in the English language and comprising data from the United States, Australia, New Zealand, and Israel. The most common cause of hospitalization among patients with HD was dysphagia or dysphagia-related complications (e.g., aspiration pneumonia or malnutrition), followed by psychiatric or behavioral symptoms. Patients with HD had more prolonged hospitalizations than non-HD patients, and it was most prominent among those with advanced disease. Patients with HD were more likely to be discharged to a facility. A small percentage received inpatient palliative care consultation, and behavioral symptoms were a primary cause of discharge to another facility. Interventions such as gastrostomy tube placement had associated morbidity, and it was common among patients with HD with a diagnosis of dementia. Palliative care consultation and specialized nursing care were associated with more routine discharges and fewer hospitalizations. In terms of cost, patients with HD with private and public insurances had the highest expenditure with more advanced disease, and expenses were associated with hospitalization and medication costs. Summary: In addition to DMTs, HD clinical trial development should also consider the leading causes of hospitalization, morbidity, and mortality in patients with HD, including dysphagia and psychiatric disease. No research study, to our knowledge, has systematically reviewed health services research studies in HD. Evidence from health services research is needed to evaluate the efficacy of pharmacologic and supportive therapies. This type of research is also critical in understanding health care costs associated with the disease and to better advocate and shape policies that can benefit this patient population.

Temporal order of clinical and biomarker changes in familial frontotemporal dementia.

Unlike familial Alzheimer's disease, we have been unable to accurately predict symptom onset in presymptomatic familial frontotemporal dementia (f-FTD) mutation carriers, which is a major hurdle to designing disease prevention trials. We developed multimodal models for f-FTD disease progression and estimated clinical trial sample sizes in C9orf72, GRN and MAPT mutation carriers. Models included longitudinal clinical and neuropsychological scores, regional brain volumes and plasma neurofilament light chain (NfL) in 796 carriers and 412 noncarrier controls. We found that the temporal ordering of clinical and biomarker progression differed by genotype. In prevention-trial simulations using model-based patient selection, atrophy and NfL were the best endpoints, whereas clinical measures were potential endpoints in early symptomatic trials. f-FTD prevention trials are feasible but will likely require global recruitment efforts. These disease progression models will facilitate the planning of f-FTD clinical trials, including the selection of optimal endpoints and enrollment criteria to maximize power to detect treatment effects.

Vim-Thalamic Deep Brain Stimulation for Cervical Dystonia and Upper-Limb Tremor: Quantification by Markerless-3D Kinematics and Accelerometry.

Background: Deep Brain Stimulation (DBS) for dystonia is usually targeted to the globus pallidus internus (GPi), though stimulation of the ventral-intermediate nucleus of the thalamus (Vim) can be an effective treatment for phasic components of dystonia including tremor. We report on a patient who developed a syndrome of bilateral upper limb postural and action tremor and progressive cervical dystonia with both phasic and tonic components which were responsive to Vim DBS. We characterize and quantify this effect using markerless-3D-kinematics combined with accelerometry. Methods: Stereo videography was used to record our subject in 3D. The DeepBehavior toolbox was applied to obtain timeseries of joint position for kinematic analysis [1]. Accelerometry was performed simultaneously for comparison with prior literature. Results: Bilateral Vim DBS improved both dystonic tremor magnitude and tonic posturing. DBS of the hemisphere contralateral to the direction of dystonic head rotation (left Vim) had greater efficacy. Assessment of tremor magnitude by 3D-kinematics was concordant with accelerometry and was able to quantify tonic dystonic posturing. Discussion: In this case, Vim DBS treated both cervical dystonic tremor and dystonic posturing. Markerless-3D-kinematics should be further studied as a method of quantifying and characterizing tremor and dystonia.

Autoimmune and Paraneoplastic Chorea: A Review of the Literature.

Autoimmune chorea syndromes represent a vast array of paraneoplastic, parainfectious and idiopathic disorders. It is increasingly apparent that familiarity with these disorders is critically important, as they may be treatable or may be part of a syndrome requiring further work-up and monitoring. These disorders are mediated by an aberrant immunologic attack with resultant neuronal dysfunction, manifesting as chorea. These conditions are typically accompanied by other neurologic or systemic manifestations. In this review we outline the clinical features, epidemiologic factors, and delineate the specific antibodies associated with each of these autoimmune mediated disorders. We highlight up to date information regarding this heterogeneous group of disorders, including a discussion of parainfectious Sydenham's chorea; paraneoplastic syndromes associated with CRMP-5 (collapsin response mediated protein-5/CV2) and ANNA-1 (antineuronal nuclear antibody / Hu) antibodies, in addition to neuronal antibody-associated disorders including anti-NMDAR, LGI1 (leucine-rich glioma inactivated-1) and CASPR2 (contactin associated protein-2). We discuss the more recently described entities of IgLON5, which has evidence of both immunologic and degenerative pathophysiology, in addition to PDE-10A antibody-associated chorea. We also outline chorea secondary to systemic diseases including Systemic Lupus Erythematosus (SLE) and Primary Antiphospholipid Syndrome (PAPS). We provide a framework for diagnosis and treatment.

DNA methylation-based surrogates of plasma proteins are associated with Parkinson's disease risk.

BACKGROUND: The epigenome may reflect Parkinson's disease (PD) risk, which serves as a point of convergence of genetic and environmental risk factors. Here, we investigate whether blood DNA methylation (DNAm) markers are associated with PD risk. METHODS: We selected 12 plasma proteins known as predictors of cardiovascular conditions and mortality to evaluate their effects on PD risk in a case-control study. In lieu of protein level measures, however, we assessed the influence of their DNAm surrogates. Primary analysis was restricted to 569 PD patients and 238 controls with DNAm data available. Using univariate logistic regression, we evaluated associations between the DNAm markers and PD. RESULTS: Of the 12 DNAm surrogates, the most robustly associated were DNAm EFEMP-1 and DNAm CD56, which were associated with PD with and without controlling for blood cell composition. DNAm EFEMP-1 was associated with a decreased risk of PD (OR = 0.83 per SD, 95% CI = 0.70, 0.98) whereas DNAm CD56 was associated with an increased risk of PD (OR = 1.41, 95% CI = 1.11, 1.79). CONCLUSIONS: Several DNAm markers, selected as part of a panel to track cardiovascular outcomes and mortality, were associated with PD risk. DNAm markers may inform of factors that are affected differentially in early PD patients compared with controls.

Plasma Neurofilament Light for Prediction of Disease Progression in Familial Frontotemporal Lobar Degeneration.

OBJECTIVE: We tested the hypothesis that plasma neurofilament light chain (NfL) identifies asymptomatic carriers of familial frontotemporal lobar degeneration (FTLD)-causing mutations at risk of disease progression. METHODS: Baseline plasma NfL concentrations were measured with single-molecule array in original (n = 277) and validation (n = 297) cohorts. C9orf72, GRN, and MAPT mutation carriers and noncarriers from the same families were classified by disease severity (asymptomatic, prodromal, and full phenotype) using the CDR Dementia Staging Instrument plus behavior and language domains from the National Alzheimer's Disease Coordinating Center FTLD module (CDR+NACC-FTLD). Linear mixed-effect models related NfL to clinical variables. RESULTS: In both cohorts, baseline NfL was higher in asymptomatic mutation carriers who showed phenoconversion or disease progression compared to nonprogressors (original: 11.4 ± 7 pg/mL vs 6.7 ± 5 pg/mL, p = 0.002; validation: 14.1 ± 12 pg/mL vs 8.7 ± 6 pg/mL, p = 0.035). Plasma NfL discriminated symptomatic from asymptomatic mutation carriers or those with prodromal disease (original cutoff: 13.6 pg/mL, 87.5% sensitivity, 82.7% specificity; validation cutoff: 19.8 pg/mL, 87.4% sensitivity, 84.3% specificity). Higher baseline NfL correlated with worse longitudinal CDR+NACC-FTLD sum of boxes scores, neuropsychological function, and atrophy, regardless of genotype or disease severity, including asymptomatic mutation carriers. CONCLUSIONS: Plasma NfL identifies asymptomatic carriers of FTLD-causing mutations at short-term risk of disease progression and is a potential tool to select participants for prevention clinical trials. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02372773 and NCT02365922. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in carriers of FTLD-causing mutations, elevation of plasma NfL predicts short-term risk of clinical progression.

Gene-Environment Interactions in Progressive Supranuclear Palsy.

Several genetic and environmental factors have been reported in progressive supranuclear palsy (PSP), although none were identified as a definitive cause. We aimed to explore potential gene-environment interactions in PSP. Two hundred and ninety two PSP cases and 292 controls matched for age, sex, and race from the ENGENE-PSP were analyzed to determine the association between PSP and minor alleles of 5 single nucleotide polymorphisms (SNPs) in 4 genes (MAPT, MOBP, EIF2AK3, and STX6), which were previously associated with PSP risk. Interactions between these SNPs and environmental factors, including previously reported occupational and agricultural risk factors for PSP, were assessed for PSP odds and age of symptom onset. Minor alleles of MAPTrs242557 and EIF2AK3rs7571971 were individually associated with increased odds; MAPTrs8070723 minor alleles were associated with lower PSP odds. There were several gene-environment interactions for PSP odds and age of symptom onset, however, they did not remain significant after FDR-correction. Larger scale studies are required to determine potential interactions.

Brain volumetric deficits in MAPT mutation carriers: a multisite study.

OBJECTIVE: MAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach. METHODS: We studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers' clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson's disease (1), and mild cognitive impairment (1). We performed voxel-based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype. RESULTS: Symptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes emerged in a subset of presymptomatic carriers as early as their thirties. Low white matter volumes arose infrequently among presymptomatic carriers. INTERPRETATION: A subset of presymptomatic MAPT mutation carriers showed low volumes in mesial temporal lobe, the region ubiquitously atrophied in all symptomatic carriers. With each decade of age, an increasing percentage of presymptomatic carriers showed low mesial temporal volume, suggestive of early neurodegeneration.

Altered Pallidocortical Low-Beta Oscillations During Self-Initiated Movements in Parkinson Disease.

BACKGROUND: Parkinson disease (PD) patients have difficulty with self-initiated (SI) movements, presumably related to basal ganglia thalamocortical (BGTC) circuit dysfunction, while showing less impairment with externally cued (EC) movements. OBJECTIVES: We investigate the role of BGTC in movement initiation and the neural underpinning of impaired SI compared to EC movements in PD using multifocal intracranial recordings and correlating signals with symptom severity. METHODS: We compared time-resolved neural activities within and between globus pallidus internus (GPi) and motor cortex during between SI and EC movements recorded invasively in 13 PD patients undergoing deep brain stimulation implantation. We compared cortical (but not subcortical) dynamics with those recorded in 10 essential tremor (ET) patients, who do not have impairments in movement initiation. RESULTS: SI movements in PD are associated with greater low-beta (13-20 Hz) power suppression during pre-movement period in GPi and motor cortex compared to EC movements in PD and compared to SI movements in ET (motor cortex only). SI movements in PD are uniquely associated with significant low-beta pallidocortical coherence suppression during movement execution that correlates with bradykinesia severity. In ET, motor cortex neural dynamics during EC movements do not significantly differ from that observed in PD and do not significantly differ between SI and EC movements. CONCLUSION: These findings implicate low beta BGTC oscillations in impaired SI movements in PD. These results provide a physiological basis for the strategy of using EC movements in PD, circumventing diseased neural circuits associated with SI movements and instead engaging circuits that function similarly to those without PD.

Understanding the relationship between freezing of gait and other progressive supranuclear palsy features.

INTRODUCTION: Freezing of gait (FoG) leads to falls and reduces quality of life, but little is known about FoG in progressive supranuclear palsy (PSP). This study aim was to identify the clinical parameters associated with FoG in PSP patients. METHODS: 349 patients meeting the National Institute for Neurological Disorders and Society for PSP (NINDS-SPSP) clinical diagnostic criteria were divided into two groups: PSP with FoG (n = 159) and PSP without FoG (n = 190). To determine if FoG in PSP associates with demographics, motor performance, visual difficulties, and executive function, we used the Frontal Assessment Battery (FAB), Mattis Dementia Rating Scale (DRS), Unified Parkinson's Disease Rating Scale (UPDRS), PSP Rating Scale (PSPRS), Modified Hoehn & Yahr staging, and Schwab and England Activities Daily Living (S&EADL) scale. UPDRS was used to identify FoG. Individual items of each clinical assessment with p-value < 0.05 in the univariate logistic regression analyses were included in the backward stepwise multivariate regression analysis. RESULTS: Both groups were similar in demographics. 45.6% of patients had FoG, which was present at onset and increased with disease duration. There were no between-group significant associations between FoG and visual disturbances, executive function and overall cognition, but on univariate analyses, FoG was significantly associated with bradykinesia, rigidity, gait, and posture. In the multivariate model FoG was associated with disease duration and speech. CONCLUSIONS: Our findings indicate that disease duration and speech have the most significant association with FoG. These findings may suggest that FoG and speech difficulties in PSP share a similar pathophysiology.

Progressive Supranuclear Palsy and Statin Use.

INTRODUCTION: Statins were proposed to be neuroprotective; however, the effects are unknown in progressive supranuclear palsy (PSP), a pure tauopathy. METHODS: Data of 284 PSP cases and 284 age-matched, sex-matched, and race-matched controls were obtained from the environmental and genetic PSP (ENGENE-PSP) study. Cases were evaluated with the PSP Rating Scale, Unified Parkinson's Disease Rating Scale, Mattis Dementia Rating Scale, and Neuropsychiatric Inventory. Statin associations with PSP risk, onset age, and disease features were analyzed. RESULTS: Univariate models showed lower PSP risk for type 1 statin users (simvastatin, lovastatin, pravastatin). After adjusting for confounding variables, statin use and lower PSP risk association remained only at a trend level. For PSP cases, type 1 statins were associated with 1-year older onset age; type 2 statins (atorvastatin, rosuvastatin) were associated with the lower PSP Rating Scale and Unified Parkinson's Disease Rating Scale. CONCLUSION: Statins may have inverse associations with PSP risk and motor impairment. Randomized prospective studies are required to confirm this effect. © 2020 International Parkinson and Movement Disorder Society.

Genetic screening of a large series of North American sporadic and familial frontotemporal dementia cases.

INTRODUCTION: The Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) consortia are two closely connected studies, involving multiple North American centers that evaluate both sporadic and familial frontotemporal dementia (FTD) participants and study longitudinal changes. METHODS: We screened the major dementia-associated genes in 302 sporadic and 390 familial (symptomatic or at-risk) participants enrolled in these studies. RESULTS: Among the sporadic patients, 16 (5.3%) carried chromosome 9 open reading frame 72 (C9orf72), microtubule-associated protein tau (MAPT), and progranulin (GRN) pathogenic variants, whereas in the familial series we identified 207 carriers from 146 families. Of interest, one patient was found to carry a homozygous C9orf72 expansion, while another carried both a C9orf72 expansion and a GRN pathogenic variant. We also identified likely pathogenic variants in the TAR DNA binding protein (TARDBP), presenilin 1 (PSEN1), and valosin containing protein (VCP) genes, and a subset of variants of unknown significance in other rare FTD genes. DISCUSSION: Our study reports the genetic characterization of a large FTD series and supports an unbiased sequencing screen, irrespective of clinical presentation or family history.

Utility of the global CDR® plus NACC FTLD rating and development of scoring rules: Data from the ARTFL/LEFFTDS Consortium.

INTRODUCTION: We created global rating scoring rules for the CDR® plus NACC FTLD to detect and track early frontotemporal lobar degeneration (FTLD) and to conduct clinical trials in FTLD. METHODS: The CDR plus NACC FTLD rating was applied to 970 sporadic and familial participants from the baseline visit of Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS). Each of the eight domains of the CDR plus NACC FTLD was equally weighed in determining the global score. An interrater reliability study was completed for 40 participants. RESULTS: The CDR plus NACC FTLD showed very good interrater reliability. It was especially useful in detecting clinical features of mild non-fluent/agrammatic variant primary progressive aphasia participants. DISCUSSION: The global CDR plus NACC FTLD score could be an attractive outcome measure for clinical trials in symptomatic FTLD, and may be useful in natural history studies and clinical trials in FTLD spectrum disorders.

Assessment of executive function declines in presymptomatic and mildly symptomatic familial frontotemporal dementia: NIH-EXAMINER as a potential clinical trial endpoint.

INTRODUCTION: Identifying clinical measures that track disease in the earliest stages of frontotemporal lobar degeneration (FTLD) is important for clinical trials. Familial FTLD provides a unique paradigm to study early FTLD. Executive dysfunction is a clinically relevant hallmark of FTLD and may be a marker of disease progression. METHODS: Ninety-three mutation carriers with no symptoms or minimal/questionable symptoms (MAPT, n = 31; GRN, n = 28; C9orf72, n = 34; Clinical Dementia Rating scale plus NACC FTLD Module < 1) and 78 noncarriers enrolled through Advancing Research and Treatment in Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects studies completed the Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (NIH-EXAMINER) and the UDS neuropsychological battery. Linear mixed-effects models were used to identify group differences in cognition at baseline and longitudinally. We examined associations between cognition, clinical functioning, and magnetic resonance imaging volumes. RESULTS: NIH-EXAMINER scores detected baseline and differences in slopes between carriers and noncarriers, even in carriers with a baseline Clinical Dementia Rating scale plus NACC FTLD Module = 0. NIH-EXAMINER declines were associated with worsening clinical symptoms and brain volume loss. DISCUSSION: The NIH-EXAMINER is sensitive to cognitive changes in presymptomatic familial FTLD and is a promising surrogate endpoint.

Individualized atrophy scores predict dementia onset in familial frontotemporal lobar degeneration.

INTRODUCTION: Some models of therapy for neurodegenerative diseases envision starting treatment before symptoms develop. Demonstrating that such treatments are effective requires accurate knowledge of when symptoms would have started without treatment. Familial frontotemporal lobar degeneration offers a unique opportunity to develop predictors of symptom onset. METHODS: We created dementia risk scores in 268 familial frontotemporal lobar degeneration family members by entering covariate-adjusted standardized estimates of brain atrophy into a logistic regression to classify asymptomatic versus demented participants. The score's predictive value was tested in a separate group who were followed up longitudinally (stable vs. converted to dementia) using Cox proportional regressions with dementia risk score as the predictor. RESULTS: Cross-validated logistic regression achieved good separation of asymptomatic versus demented (accuracy = 90%, SE = 0.06). Atrophy scores predicted conversion from asymptomatic or mildly/questionably symptomatic to dementia (HR = 1.51, 95% CI: [1.16,1.98]). DISCUSSION: Individualized quantification of baseline brain atrophy is a promising predictor of progression in asymptomatic familial frontotemporal lobar degeneration mutation carriers.

Clinical and volumetric changes with increasing functional impairment in familial frontotemporal lobar degeneration.

INTRODUCTION: The Advancing Research and Treatment in Frontotemporal Lobar Degeneration and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects longitudinal studies were designed to describe the natural history of familial-frontotemporal lobar degeneration due to autosomal dominant mutations. METHODS: We examined cognitive performance, behavioral ratings, and brain volumes from the first time point in 320 MAPT, GRN, and C9orf72 family members, including 102 non-mutation carriers, 103 asymptomatic carriers, 43 mildly/questionably symptomatic carriers, and 72 carriers with dementia. RESULTS: Asymptomatic carriers showed similar scores on all clinical measures compared with noncarriers but reduced frontal and temporal volumes. Those with mild/questionable impairment showed decreased verbal recall, fluency, and Trail Making Test performance and impaired mood and self-monitoring. Dementia was associated with impairment in all measures. All MAPT carriers with dementia showed temporal atrophy, but otherwise, there was no single cognitive test or brain region that was abnormal in all subjects. DISCUSSION: Imaging changes appear to precede clinical changes in familial-frontotemporal lobar degeneration, but specific early clinical and imaging changes vary across individuals.