Neurofilament Light Chain Related to Longitudinal Decline in Frontotemporal Lobar Degeneration.

Objective: Accurate diagnosis and prognosis of frontotemporal lobar degeneration (FTLD) during life is an urgent concern in the context of emerging disease-modifying treatment trials. Few CSF markers have been validated longitudinally in patients with known pathology, and we hypothesized that CSF neurofilament light chain (NfL) would be associated with longitudinal cognitive decline in patients with known FTLD-TAR DNA binding protein ~43kD (TDP) pathology.

Methods: This case-control study evaluated CSF NfL, total tau, phosphorylated tau, and β-amyloid in patients with known FTLD-tau or FTLD-TDP pathology (n = 50) and healthy controls (n = 65) and an extended cohort of clinically diagnosed patients with likely FTLD-tau or FTLD-TDP (n = 148).

Machine learning suggests polygenic risk for cognitive dysfunction in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a multi-system disease characterized primarily by progressive muscle weakness. Cognitive dysfunction is commonly observed in patients; however, factors influencing risk for cognitive dysfunction remain elusive. Using sparse canonical correlation analysis (sCCA), an unsupervised machine-learning technique, we observed that single nucleotide polymorphisms collectively associate with baseline cognitive performance in a large ALS patient cohort (N = 327) from the multicenter Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium.

The NEALS primary lateral sclerosis registry.

Primary lateral sclerosis (PLS) is a neurodegenerative disease characterized by progressive upper motor neuron dysfunction. Because PLS patients represent only 1 to 4% of patients with adult motor neuron diseases, there is limited information about the disease's natural history. The objective of this study was to establish a large multicenter retrospective longitudinal registry of PLS patients seen at Northeast ALS Consortium (NEALS) sites to better characterize the natural progression of PLS.

Automated analysis of natural speech in amyotrophic lateral sclerosis spectrum disorders.

Objective: We implemented automated methods to analyze speech and evaluate the hypothesis that cognitive and motor factors impair prosody in partially distinct ways in patients with amyotrophic lateral sclerosis (ALS).

Methods: We recruited 213 participants, including 67 with ALS (44 with motor ALS, 23 with ALS and frontotemporal degeneration [FTD]), 33 healthy controls, and neurodegenerative reference groups with behavioral variant FTD (n = 90) and nonfluent/agrammatic primary progressive aphasia (n = 23). Digitized, semistructured speech samples obtained from picture descriptions were automatically segmented with a Speech Activity Detector; continuous speech segments were pitch-tracked; and duration measures for speech and silent pause segments were extracted.

Association of Cerebrospinal Fluid Neurofilament Light Protein Levels With Cognition in Patients With Dementia, Motor Neuron Disease, and Movement Disorders.

Importance: Neuronal and axonal destruction are hallmarks of neurodegenerative diseases, but it is difficult to estimate the extent and progress of the damage in the disease process.

Objective: To investigate cerebrospinal fluid (CSF) levels of neurofilament light (NFL) protein, a marker of neuroaxonal degeneration, in control participants and patients with dementia, motor neuron disease, and parkinsonian disorders (determined by clinical criteria and autopsy), and determine its association with longitudinal cognitive decline.

Design, Setting, And Participants: In this case-control study, we investigated NFL levels in CSF obtained from controls and patients with several neurodegenerative diseases.

UNC13A polymorphism contributes to frontotemporal disease in sporadic amyotrophic lateral sclerosis.

The majority (90%-95%) of amyotrophic lateral sclerosis (ALS) is sporadic, and ∼50% of patients develop symptoms of frontotemporal degeneration (FTD) associated with shorter survival. The genetic polymorphism rs12608932 in UNC13A confers increased risk of sporadic ALS and sporadic FTD and modifies survival in ALS. Here, we evaluate whether rs12608932 is also associated with frontotemporal disease in sporadic ALS.

Elevated CSF GAP-43 is Alzheimer's disease specific and associated with tau and amyloid pathology.

Introduction: The level of the presynaptic protein growth-associated protein 43 (GAP-43) in cerebrospinal fluid (CSF) has previously been shown to be increased in Alzheimer's disease (AD) and thus may serve as an outcome measure in clinical trials and facilitate earlier disease detection.

Methods: We developed an enzyme-linked immunosorbent assay for CSF GAP-43 and measured healthy controls (n = 43), patients with AD (n = 275), or patients with other neurodegenerative diseases (n = 344). In a subpopulation (n = 93), CSF GAP-43 concentrations from neuropathologically confirmed cases were related to Aβ plaques, tau, α-synuclein, and TDP-43 pathologies.

Amyotrophic lateral sclerosis-specific quality of life-short form (ALSSQOL-SF): A brief, reliable, and valid version of the ALSSQOL-R.

Introduction: The Amyotrophic Lateral Sclerosis (ALS)-Specific Quality of Life instrument and its revised version (ALSSQOL and ALSSQOL-R) have strong psychometric properties, and have demonstrated research and clinical utility. In this study we aimed to develop a short form (ALSSQOL-SF) suitable for limited clinic time and patient stamina.

Methods: The ALSSQOL-SF was created using Item Response Theory and confirmatory factor analysis on 389 patients.

Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated.

Lewy bodies commonly occur in Alzheimer's disease, and Alzheimer's disease pathology is frequent in Lewy body diseases, but the burden of co-pathologies across neurodegenerative diseases is unknown. We assessed the extent of tau, amyloid-β, α-synuclein and TDP-43 proteinopathies in 766 autopsied individuals representing a broad spectrum of clinical neurodegenerative disease. We interrogated pathological Alzheimer's disease (n = 247); other tauopathies (n = 95) including Pick's disease, corticobasal disease and progressive supranuclear palsy; the synucleinopathies (n = 164) including multiple system atrophy and Lewy body disease; the TDP-43 proteinopathies (n = 188) including frontotemporal lobar degeneration with TDP-43 inclusions and amyotrophic lateral sclerosis; and a minimal pathology group (n = 72).

Perfusion alterations converge with patterns of pathological spread in transactive response DNA-binding protein 43 proteinopathies.

Amyotrophic lateral sclerosis (ALS) and the behavioral variant of frontotemporal dementia (bvFTD) commonly share the presence of transactive response DNA-binding protein 43 (TDP-43) inclusions. Structural magnetic resonance imaging studies demonstrated evidence for TDP-43 pathology spread, but while structural imaging usually reveals overt neuronal loss, perfusion imaging may detect more subtle neural activity alterations. We evaluated perfusion as an early marker for incipient pathology-associated brain alterations in TDP-43 proteinopathies.

Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology.

Neurogranin (Ng) is a post-synaptic protein that previously has been shown to be a biomarker for synaptic function when measured in cerebrospinal fluid (CSF). The CSF concentration of Ng is increased in Alzheimer's disease dementia (ADD), and even in the pre-dementia stage. In this prospective study, we used an enzyme-linked immunosorbent assay that quantifies Ng in CSF to test the performance of Ng as a marker of synaptic function.

Cerebrospinal fluid α-synuclein contributes to the differential diagnosis of Alzheimer's disease.

Introduction: The ability of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers (amyloid β peptide 1-42, total tau, and phosphorylated tau) to discriminate AD from related disorders is limited. Biomarkers for other concomitant pathologies (e.g.

Genetic test utilization and diagnostic yield in adult patients with neurological disorders.

To determine the diagnostic yield of different genetic test modalities in adult patients with neurological disorders, we evaluated all adult patients seen for genetic diagnostic evaluation in the outpatient neurology practice at the University of Pennsylvania between January 2016 and April 2017 as part of the newly created Penn Neurogenetics Program. Subjects were identified through our electronic medical system as those evaluated by the Program's single clinical genetic counselor in that period. A total of 377 patients were evaluated by the Penn Neurogenetics Program in different settings and genetic testing recommended.

Circulating brain-enriched microRNAs as novel biomarkers for detection and differentiation of neurodegenerative diseases.

Background: Minimally invasive specific biomarkers of neurodegenerative diseases (NDs) would facilitate patient selection and disease progression monitoring. We describe the assessment of circulating brain-enriched microRNAs as potential biomarkers for Alzheimer's disease (AD), frontotemporal dementia (FTD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).

Methods: In this case-control study, the plasma samples were collected from 250 research participants with a clinical diagnosis of AD, FTD, PD, and ALS, as well as from age- and sex-matched control subjects (n = 50 for each group), recruited from 2003 to 2015 at the University of Pennsylvania Health System, including the Alzheimer's Disease Center, the Parkinson's Disease and Movement Disorders Center, the Frontotemporal Degeneration Center, and the Amyotrophic Lateral Sclerosis Clinic.

Poly(GP) proteins are a useful pharmacodynamic marker for -associated amyotrophic lateral sclerosis.

There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a GC repeat expansion in the gene as the most common genetic cause of ALS has opened up new avenues for therapeutic intervention for this form of ALS. GC repeat expansion RNAs and proteins of repeating dipeptides synthesized from these transcripts are believed to play a key role in -associated ALS (c9ALS).

Defining SOD1 ALS natural history to guide therapeutic clinical trial design.

Importance: Understanding the natural history of familial amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (ALS) will provide key information for optimising clinical trials in this patient population.

Objective: To establish an updated natural history of ALS.

Design, Setting And Participants: Retrospective cohort study from 15 medical centres in North America evaluated records from 175 patients with ALS with genetically confirmed SOD1 mutations, cared for after the year 2000.

Semi-automated quantification of C9orf72 expansion size reveals inverse correlation between hexanucleotide repeat number and disease duration in frontotemporal degeneration.

We investigated whether chromosome 9 open reading frame 72 hexanucleotide repeat expansion (C9orf72 expansion) size in peripheral DNA was associated with clinical differences in frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) linked to C9orf72 repeat expansion mutations. A novel quantification workflow was developed to measure C9orf72 expansion size by Southern blot densitometry in a cross-sectional cohort of C9orf72 expansion carriers with FTD (n = 39), ALS (n = 33), both (n = 35), or who are unaffected (n = 21). Multivariate linear regressions were performed to assess whether C9orf72 expansion size from peripheral DNA was associated with clinical phenotype, age of disease onset, disease duration and age at death.

Impaired cognitive flexibility in amyotrophic lateral sclerosis.

Background And Objective: Up to half of patients with amyotrophic lateral sclerosis (ALS) may have cognitive difficulty, but most cognitive measures are confounded by a motor component. Studies relating impaired cognition in ALS to disease in gray matter and white matter are rare. Our objective was to assess executive function in patients with ALS using a simple, untimed measure with minimal motor demands, and to relate performance to structural disease.

C9orf72 promoter hypermethylation is neuroprotective: Neuroimaging and neuropathologic evidence.

Objective: To use in vivo neuroimaging and postmortem neuropathologic analysis in C9orf72 repeat expansion patients to investigate the hypothesis that C9orf72 promoter hypermethylation is neuroprotective and regionally selective.

Methods: Twenty patients with a C9orf72 repeat expansion participating in a high-resolution MRI scan and a clinical examination and a subset of patients (n = 11) were followed longitudinally with these measures. Gray matter (GM) density was related to C9orf72 promoter hypermethylation using permutation-based testing.

Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways.

Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. We report the results of a moderate-scale sequencing study aimed at increasing the number of genes known to contribute to predisposition for ALS. We performed whole-exome sequencing of 2869 ALS patients and 6405 controls.

Deficits in sentence expression in amyotrophic lateral sclerosis.

Quantitative examinations of speech production in amyotrophic lateral sclerosis (ALS) are rare. To identify language features minimally confounded by a motor disorder, we investigated linguistic and motor sources of impaired sentence expression in ALS, and we related deficits to gray matter (GM) and white matter (WM) MRI abnormalities. We analyzed a semi-structured speech sample in 26 ALS patients and 19 healthy seniors for motor- and language-related deficits.

Hypermethylation of repeat expanded C9orf72 is a clinical and molecular disease modifier.

C9orf72 promoter hypermethylation inhibits the accumulation of pathologies which have been postulated to be neurotoxic. We tested here whether C9orf72 hypermethylation is associated with prolonged disease in C9orf72 mutation carriers. C9orf72 methylation was quantified from brain or blood using methylation-sensitive restriction enzyme digest-qPCR in a cross-sectional cohort of 118 C9orf72 repeat expansion carriers and 19 non-carrier family members.

Linear associations between clinically assessed upper motor neuron disease and diffusion tensor imaging metrics in amyotrophic lateral sclerosis.

Objective: To assess the relationship between clinically assessed Upper Motor Neuron (UMN) disease in Amyotrophic Lateral Sclerosis (ALS) and local diffusion alterations measured in the brain corticospinal tract (CST) by a tractography-driven template-space region-of-interest (ROI) analysis of Diffusion Tensor Imaging (DTI).

Methods: This cross-sectional study included 34 patients with ALS, on whom DTI was performed. Clinical measures were separately obtained including the Penn UMN Score, a summary metric based upon standard clinical methods.