ABSTRACT
In behavioral-variant frontotemporal degeneration (bvFTD) and amyotrophic lateral sclerosis (ALS), the presence of secondary motor or cognitive-behavioral symptoms, respectively, is associated with shorter survival. However, factors influencing the risk and hazard of secondary symptom development remain largely unexplored. We performed a retrospective evaluation of the entire disease course of individuals with amyotrophic lateral sclerosis (n=172) and behavioral-variant frontotemporal degeneration (n=69). Only individuals who had neuropathological confirmation of a TDP-43 proteinopathy at autopsy or had a C9orf72 repeat expansion were included for analysis. We examined the odds and hazard of secondary symptom development and assessed whether they were modified by the presence of a C9orf72 repeat expansion or initial clinical syndrome. Binary logistic regression and Cox proportional hazard analyses revealed increased odds (OR=4.25 [1.97-9.14]; p<0.001) and an increased hazard (HR= 4.77 [2.33-9.79], p<0.001) for developing secondary symptoms in C9orf72 expansion carriers compared to noncarriers. Initial clinical syndrome (bvFTD or ALS), age at symptom onset, and sex were not associated with development of secondary motor or cognitive-behavioral symptoms. These findings highlight the need for clinician vigilance to detect the onset of secondary motor symptoms and cognitive-behavioral in patients carrying a C9orf72 repeat expansion, regardless of initial clinical syndrome, and may warrant dual referrals between cognitive and neuromuscular clinics in these cases.
ABSTRACT
OBJECTIVE: Amyotrophic Lateral Sclerosis (ALS) is a heterogeneous neurodegenerative condition featuring variable degrees of motor and cognitive impairment. We assessed the impact of specific, empirically derived occupational skills and requirements on cognitive and motor functioning in ALS. METHODS: Individuals with ALS (n = 150) were recruited from the University of Pennsylvania's Comprehensive ALS Clinic. The Edinburgh Cognitive and Behavioral ALS Screen (ECAS) measured cognition, and the Penn Upper Motor Neuron (PUMNS) and ALS Functional Rating Scales (ALSFRS-R) measured motor symptoms. We derived 17 factors representing distinct occupational skills and requirements from the Occupational Information Network (O*NET), which were related to cognitive and motor scores using multiple linear regression. RESULTS: Occupational roles involving greater reasoning ability (ß = 2.12, p < .05), social ability (ß = 1.73, p < .05), analytic skills, (ß = 3.12, p < .01) and humanities knowledge (ß = 1.83, p<.01) were associated with better performance on the ECAS, while jobs involving more exposure to environmental hazards (ß=-2.57, p < .01) and technical skills (ß=-2.16, p<.01) were associated with lower ECAS scores. Jobs requiring more precision skills (ß = 1.91, p < .05) were associated with greater motor dysfunction on the PUMNS. CONCLUSIONS: Occupational histories involving more cognitively complex skills and activities were related to preserved cognitive functioning in ALS consistent with the cognitive reserve hypothesis, while jobs with greater exposure to environmental hazards and technical demands were linked to poorer cognitive functioning. Jobs involving more repetitive movements were associated with worse motor functioning, possibly due to overuse. Occupational history provides insight into protective and risk factors for variable degrees of cognitive and motor dysfunction in ALS.
Subject(s)
Amyotrophic Lateral Sclerosis , Cognitive Reserve , Humans , Amyotrophic Lateral Sclerosis/psychology , Amyotrophic Lateral Sclerosis/physiopathology , Amyotrophic Lateral Sclerosis/complications , Amyotrophic Lateral Sclerosis/diagnosis , Cognitive Reserve/physiology , Male , Female , Middle Aged , Aged , Neuropsychological Tests , Cognitive Dysfunction/etiology , Cognitive Dysfunction/physiopathology , Cognitive Dysfunction/diagnosis , Cognitive Dysfunction/psychology , Adult , OccupationsABSTRACT
INTRODUCTION/AIMS: The aim of this study was to examine clinical utilization and discontinuation rates of sodium phenylbutyrate-taurursodiol (PB-TURSO) in a single Amyotrophic Lateral Sclerosis (ALS) center. PB-TURSO was approved by the United States Food and Drug Administration (FDA) in September 2022. Prior experience has been limited to clinical trials or expanded access protocols. In this manuscript, we discuss insurance approval rates, patient uptake, and discontinuation of PB-TURSO in a large academic center. METHODS: Records of patients seen for clinical visits between January 2022 and May 2023 were reviewed. Demographic and clinical characteristics of our clinic population and those initiating PB-TURSO were obtained from our clinical database. RESULTS: A total of 228 patients were seen during the observation period and 122 requested PB-TURSO prescriptions. 77% (94) were approved by insurance. 66% (65) of those who were approved or received free drug chose to start medication. 51% (34) of those who initiated PB-TURSO continued to take it through the end of the observation period. Four patients discontinued due to death during the observation period. Of the 29 patients who survived and discontinued, the main reasons for discontinuation were GI symptoms (17, 58.6%) and taste (8, 29.6%). DISCUSSION: PB-TURSO was approved by insurance for most patients. The discontinuation rate was high and was driven largely by GI side effects and taste. Future considerations would include deeper examination of demographic trends, patient costs, side effects, and potential benefits in clinical practice.
Subject(s)
Amyotrophic Lateral Sclerosis , Humans , Male , Female , Amyotrophic Lateral Sclerosis/drug therapy , Middle Aged , Aged , Phenylbutyrates/therapeutic use , Adult , Retrospective Studies , Drug CombinationsABSTRACT
BACKGROUND AND OBJECTIVES: Genetic testing is now the standard of care for many neurologic conditions. Health care disparities are unfortunately widespread in the US health care system, but disparities in the utilization of genetic testing for neurologic conditions have not been studied. We tested the hypothesis that access to and results of genetic testing vary according to race, ethnicity, sex, socioeconomic status, and insurance status for adults with neurologic conditions. METHODS: We analyzed retrospective data from patients who underwent genetic evaluation and testing through our institution's neurogenetics program. We tested for differences between demographic groups in 3 steps of a genetic evaluation pathway: (1) attending a neurogenetic evaluation, (2) completing genetic testing, and (3) receiving a diagnostic result. We compared patients on this genetic evaluation pathway with the population of all neurology outpatients at our institution, using univariate and multivariable logistic regression analyses. RESULTS: Between 2015 and 2022, a total of 128,440 patients were seen in our outpatient neurology clinics and 2,540 patients underwent genetic evaluation. Black patients were less than half as likely as White patients to be evaluated (odds ratio [OR] 0.49, p < 0.001), and this disparity was similar after controlling for other demographic factors in multivariable analysis. Patients from the least wealthy quartile of zip codes were also less likely to be evaluated (OR 0.67, p < 0.001). Among patients who underwent evaluation, there were no disparities in the likelihood of completing genetic testing, nor in the likelihood of a diagnostic result after adjusting for age. Analyses restricted to specific indications for genetic testing supported these findings. DISCUSSION: We observed unequal utilization of our clinical neurogenetics program for patients from marginalized and minoritized demographic groups, especially Black patients. Among patients who do undergo evaluation, all groups benefit similarly from genetic testing when it is indicated. Understanding and removing barriers to accessing genetic testing will be essential to health care equity and optimal care for all patients with neurologic disorders.
Subject(s)
Nervous System Diseases , Neurology , Adult , Humans , Retrospective Studies , Nervous System Diseases/diagnosis , Nervous System Diseases/genetics , Ambulatory Care Facilities , Genetic TestingABSTRACT
Advances in gene-specific therapeutics for patients with neuromuscular disorders (NMDs) have brought increased attention to the importance of genetic diagnosis. Genetic testing practices vary among adult neuromuscular clinics, with multi-gene panel testing currently being the most common approach; follow-up testing using broad-based methods, such as exome or genome sequencing, is less consistently offered. Here, we use five case examples to illustrate the unique ability of broad-based testing to improve diagnostic yield, resulting in identification of SORD-neuropathy, HADHB-related disease, ATXN2-ALS, MECP2 related progressive gait decline and spasticity, and DNMT1-related cerebellar ataxia, deafness, narcolepsy, and hereditary sensory neuropathy type 1E. We describe in each case the technological advantages that enabled identification of the causal gene, and the resultant clinical and personal implications for the patient, demonstrating the importance of offering exome or genome sequencing to adults with NMDs.
ABSTRACT
Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron death due to nuclear loss and cytoplasmic aggregation of the splice factor TDP-43. Pathologic TDP-43 associates with stress granules (SGs) and downregulating the SG-associated protein Ataxin-2 (Atxn2) using antisense oligonucleotides (ASO) prolongs survival in the TAR4/4 sporadic ALS mouse model, a strategy now in clinical trials. Here, we used AAV-mediated RNAi delivery to achieve lasting and targeted Atxn2 knockdown after a single injection. To achieve this, a novel AAV with improved transduction potency of our target cells was used to deliver Atxn2 -targeting miRNAs. Mouse dosing studies demonstrated 55% Atxn2 knockdown in frontal cortex and 25% knockdown throughout brainstem and spinal cord after intracerebroventricular injection at a dose 40x lower than used in other recent studies. In TAR4/4 mice, miAtxn2 treatment increased mean and median survival by 54% and 45% respectively (p<0.0003). Mice showed robust improvement across strength-related measures ranging from 24-75%. Interestingly, treated mice showed increased vertical activity above wildtype, suggesting unmasking of an FTD phenotype with improved strength. Histologically, lower motor neuron survival improved with a concomitant reduction in CNS inflammatory markers. Additionally, phosphorylated TDP-43 was reduced to wildtype levels. Bulk RNA sequencing revealed correction of 153 genes in the markedly dysregulated transcriptome of mutant mice, several of which are described in the human ALS literature. In slow progressing hemizygous mice, treatment rescued weight loss and improved gait at late time points. Cumulatively the data support the utility of AAV-mediated RNAi against Atxn2 as a robust and translatable treatment strategy for sporadic ALS.
ABSTRACT
The role of genetic testing in neurologic clinical practice has increased dramatically in recent years, driven by research on genetic causes of neurologic disease and increased availability of genetic sequencing technology. Genetic testing is now indicated for adults with a wide range of common neurologic conditions. The potential clinical impacts of a genetic diagnosis are also rapidly expanding, with a growing list of gene-specific treatments and clinical trials, in addition to important implications for prognosis, surveillance, family planning, and diagnostic closure. The goals of this review are to provide practical guidance for clinicians about the role of genetics in their practice and to provide the neuroscience research community with a broad survey of current progress in this field. We aim to answer three questions for the neurologist in practice: Which of my patients need genetic testing? What testing should I order? And how will genetic testing help my patient? We focus on common neurologic disorders and presentations to the neurology clinic. For each condition, we review the most current guidelines and evidence regarding indications for genetic testing, expected diagnostic yield, and recommended testing approach. We also focus on clinical impacts of genetic diagnoses, highlighting a number of gene-specific therapies recently approved for clinical use, and a rapidly expanding landscape of gene-specific clinical trials, many using novel nucleotide-based therapeutic modalities like antisense oligonucleotides and gene transfer. We anticipate that more widespread use of genetic testing will help advance therapeutic development and improve the care, and outcomes, of patients with neurologic conditions.
Subject(s)
Nervous System Diseases , Neurosciences , Adult , Humans , Nervous System Diseases/diagnosis , Nervous System Diseases/genetics , Nervous System Diseases/therapy , Genetic Testing , Neurologists , Ambulatory Care FacilitiesABSTRACT
OBJECTIVE: To evaluate automated digital speech measures, derived from spontaneous speech (picture descriptions), in assessing bulbar motor impairments in patients with ALS-FTD spectrum disorders (ALS-FTSD). METHODS: Automated vowel algorithms were employed to extract two vowel acoustic measures: vowel space area (VSA), and mean second formant slope (F2 slope). Vowel measures were compared between ALS with and without clinical bulbar symptoms (ALS + bulbar (n = 49, ALSFRS-r bulbar subscore: x¯ = 9.8 (SD = 1.7)) vs. ALS-nonbulbar (n = 23), behavioral variant frontotemporal dementia (bvFTD, n = 25) without a motor syndrome, and healthy controls (HC, n = 32). Correlations with bulbar motor clinical scales, perceived listener effort, and MRI cortical thickness of the orobuccal primary motor cortex (oral PMC) were examined. We compared vowel measures to speaking rate, a conventional metric for assessing bulbar dysfunction. RESULTS: ALS + bulbar had significantly reduced VSA and F2 slope than ALS-nonbulbar (|d|=0.94 and |d|=1.04, respectively), bvFTD (|d|=0.89 and |d|=1.47), and HC (|d|=0.73 and |d|=0.99). These reductions correlated with worse bulbar clinical scores (VSA: R = 0.33, p = 0.043; F2 slope: R = 0.38, p = 0.011), greater listener effort (VSA: R=-0.43, p = 0.041; F2 slope: p > 0.05), and cortical thinning in oral PMC (F2 slope: ß = 0.0026, p = 0.017). Vowel measures demonstrated greater sensitivity and specificity for bulbar impairment than speaking rate, while showing independence from cognitive and respiratory impairments. CONCLUSION: Automatic vowel measures are easily derived from a brief spontaneous speech sample, are sensitive to mild-moderate stage of bulbar disease in ALS-FTSD, and may present better sensitivity to bulbar impairment compared to traditional assessments such as speaking rate.
Subject(s)
Amyotrophic Lateral Sclerosis , Dystonic Disorders , Frontotemporal Dementia , Humans , Frontotemporal Dementia/diagnosis , Frontotemporal Dementia/diagnostic imaging , Amyotrophic Lateral Sclerosis/complications , Amyotrophic Lateral Sclerosis/diagnosis , Speech , Magnetic Resonance ImagingABSTRACT
BACKGROUND: TDP-43 proteinopathies represent a spectrum of neurological disorders, anchored clinically on either end by amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). The ALS-FTD spectrum exhibits a diverse range of clinical presentations with overlapping phenotypes, highlighting its heterogeneity. This study was aimed to use disease progression modeling to identify novel data-driven spatial and temporal subtypes of brain atrophy and its progression in the ALS-FTD spectrum. METHODS: We used a data-driven procedure to identify 13 anatomic clusters of brain volume for 57 behavioral variant FTD (bvFTD; with either autopsy-confirmed TDP-43 or TDP-43 proteinopathy-associated genetic variants), 103 ALS, and 47 ALS-FTD patients with likely TDP-43. A Subtype and Stage Inference (SuStaIn) model was trained to identify subtypes of individuals along the ALS-FTD spectrum with distinct brain atrophy patterns, and we related subtypes and stages to clinical, genetic, and neuropathological features of disease. RESULTS: SuStaIn identified three novel subtypes: two disease subtypes with predominant brain atrophy in either prefrontal/somatomotor regions or limbic-related regions, and a normal-appearing group without obvious brain atrophy. The limbic-predominant subtype tended to present with more impaired cognition, higher frequencies of pathogenic variants in TBK1 and TARDBP genes, and a higher proportion of TDP-43 types B, E and C. In contrast, the prefrontal/somatomotor-predominant subtype had higher frequencies of pathogenic variants in C9orf72 and GRN genes and higher proportion of TDP-43 type A. The normal-appearing brain group showed higher frequency of ALS relative to ALS-FTD and bvFTD patients, higher cognitive capacity, higher proportion of lower motor neuron onset, milder motor symptoms, and lower frequencies of genetic pathogenic variants. The overall SuStaIn stages also correlated with evidence for clinical progression including longer disease duration, higher King's stage, and cognitive decline. Additionally, SuStaIn stages differed across clinical phenotypes, genotypes and types of TDP-43 pathology. CONCLUSIONS: Our findings suggest distinct neurodegenerative subtypes of disease along the ALS-FTD spectrum that can be identified in vivo, each with distinct brain atrophy, clinical, genetic and pathological patterns.
Subject(s)
Amyotrophic Lateral Sclerosis , Frontotemporal Dementia , Neurodegenerative Diseases , Humans , Amyotrophic Lateral Sclerosis/diagnostic imaging , Amyotrophic Lateral Sclerosis/genetics , Frontotemporal Dementia/diagnostic imaging , Frontotemporal Dementia/genetics , Neurodegenerative Diseases/pathology , Brain/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Atrophy/genetics , Atrophy/complications , Atrophy/pathologyABSTRACT
Background: TDP-43 proteinopathies represents a spectrum of neurological disorders, anchored clinically on either end by amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). The ALS-FTD spectrum exhibits a diverse range of clinical presentations with overlapping phenotypes, highlighting its heterogeneity. This study aimed to use disease progression modeling to identify novel data-driven spatial and temporal subtypes of brain atrophy and its progression in the ALS-FTD spectrum. Methods: We used a data-driven procedure to identify 13 anatomic clusters of brain volumes for 57 behavioral variant FTD (bvFTD; with either autopsy-confirmed TDP-43 or TDP-43 proteinopathy-associated genetic variants), 103 ALS, and 47 ALS-FTD patients with likely TDP-43. A Subtype and Stage Inference (SuStaIn) model was trained to identify subtypes of individuals along the ALS-FTD spectrum with distinct brain atrophy patterns, and we related subtypes and stages to clinical, genetic, and neuropathological features of disease. Results: SuStaIn identified three novel subtypes: two disease subtypes with predominant brain atrophy either in prefrontal/somatomotor regions or limbic-related regions, and a normal-appearing group without obvious brain atrophy. The Limbic-predominant subtype tended to present with more impaired cognition, higher frequencies of pathogenic variants in TBK1 and TARDBP genes, and a higher proportion of TDP-43 type B, E and C. In contrast, the Prefrontal/Somatomotor-predominant subtype had higher frequencies of pathogenic variants in C9orf72 and GRN genes and higher proportion of TDP-43 type A. The normal-appearing brain group showed higher frequency of ALS relative to ALS-FTD and bvFTD patients, higher cognitive capacity, higher proportion of lower motor neuron onset, milder motor symptoms, and lower frequencies of genetic pathogenic variants. Overall SuStaIn stages also correlated with evidence for clinical progression including longer disease duration, higher King's stage, and cognitive decline. Additionally, SuStaIn stages differed across clinical phenotypes, genotypes and types of TDP-43 pathology. Conclusions: Our findings suggest distinct neurodegenerative subtypes of disease along the ALS-FTD spectrum that can be identified in vivo, each with distinct brain atrophy, clinical, genetic and pathological patterns.
ABSTRACT
Background: Amyotrophic Lateral Sclerosis (ALS) is a heterogeneous neurodegenerative condition featuring variable degrees of motor decline and cognitive impairment. We test the hypothesis that cognitive reserve (CR), defined by occupational histories involving more complex cognitive demands, may protect against cognitive decline, while motor reserve (MR), defined by working jobs requiring complex motor skills, may protect against motor dysfunction. Methods: Individuals with ALS (n=150) were recruited from the University of Pennsylvania's Comprehensive ALS Clinic. Cognitive performance was evaluated using the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), and motor functioning was measured using Penn Upper Motor Neuron (PUMNS) scale and ALS Functional Rating Scales (ALSFRS-R). The Occupational Information Network (O*NET) Database was used to derive 17 factors representing distinct worker characteristics, occupational requirements, and worker requirements, which were related to ECAS, PUMNS, and ALSFRS-R scores using multiple linear regression. Results: A history of working jobs involving greater reasoning ability (ß=2.12, p<.05), social ability (ß=1.73, p<.05), analytic skills, (ß=3.12, p<.01) and humanities knowledge (ß=1.83, p<.01) was associated with better performance on the ECAS, while jobs involving more exposure to environmental hazards (ß=-2.57, p<.01) and technical skills (ß=-2.16, p<.01) were associated with lower ECAS Total Scores. Jobs involving greater precision skills (ß=1.91, p<.05) were associated with greater disease severity on the PUMNS. Findings for the ALSFRS-R did not survive correction for multiple comparisons. Discussion: Jobs requiring greater reasoning abilities, social skills, and humanities knowledge were related to preserved cognitive functioning consistent with CR, while jobs with greater exposure to environmental hazards and technical demands were linked to poorer cognitive functioning. We did not find evidence of MR as no protective effects of occupational skills and requirements were found for motor symptoms, and jobs involving greater precision skills and reasoning abilities were associated with worse motor functioning. Occupational history provides insight into protective and risk factors for variable degrees of cognitive and motor dysfunction in ALS.
ABSTRACT
Alternative splicing of neuronal genes is controlled partly by the coordinated action of polypyrimidine tract binding proteins (PTBPs). While PTBP1 is ubiquitously expressed, PTBP2 is predominantly neuronal. Here, we define the PTBP2 footprint in the human transcriptome using brain tissue and human induced pluripotent stem cell-derived neurons (iPSC-neurons). We map PTBP2 binding sites, characterize PTBP2-dependent alternative splicing events, and identify novel PTBP2 targets including SYNGAP1, a synaptic gene whose loss-of-function leads to a complex neurodevelopmental disorder. We find that PTBP2 binding to SYNGAP1 mRNA promotes alternative splicing and nonsense-mediated decay, and that antisense oligonucleotides (ASOs) that disrupt PTBP binding redirect splicing and increase SYNGAP1 mRNA and protein expression. In SYNGAP1 haploinsufficient iPSC-neurons generated from two patients, we show that PTBP2-targeting ASOs partially restore SYNGAP1 expression. Our data comprehensively map PTBP2-dependent alternative splicing in human neurons and cerebral cortex, guiding development of novel therapeutic tools to benefit neurodevelopmental disorders.
Subject(s)
Induced Pluripotent Stem Cells , Nerve Tissue Proteins , Humans , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Induced Pluripotent Stem Cells/metabolism , RNA Splicing , Alternative Splicing/genetics , Brain/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , ras GTPase-Activating Proteins/genetics , Heterogeneous-Nuclear Ribonucleoproteins/genetics , Heterogeneous-Nuclear Ribonucleoproteins/metabolism , Polypyrimidine Tract-Binding Protein/genetics , Polypyrimidine Tract-Binding Protein/metabolismABSTRACT
Background and objectives: Patients with ALS-FTD spectrum disorders (ALS-FTSD) have mixed motor and cognitive impairments and require valid and quantitative assessment tools to support diagnosis and tracking of bulbar motor disease. This study aimed to validate a novel automated digital speech tool that analyzes vowel acoustics from natural, connected speech as a marker for impaired articulation due to bulbar motor disease in ALS-FTSD. Methods: We used an automatic algorithm called Forced Alignment Vowel Extraction (FAVE) to detect spoken vowels and extract vowel acoustics from 1 minute audio-recorded picture descriptions. Using automated acoustic analysis scripts, we derived two articulatory-acoustic measures: vowel space area (VSA, in Bark 2 ) which represents tongue range-of-motion (size), and average second formant slope of vowel trajectories (F2 slope) which represents tongue movement speed. We compared vowel measures between ALS with and without clinically-evident bulbar motor disease (ALS+bulbar vs. ALS-bulbar), behavioral variant frontotemporal dementia (bvFTD) without a motor syndrome, and healthy controls (HC). We correlated impaired vowel measures with bulbar disease severity, estimated by clinical bulbar scores and perceived listener effort, and with MRI cortical thickness of the orobuccal part of the primary motor cortex innervating the tongue (oralPMC). We also tested correlations with respiratory capacity and cognitive impairment. Results: Participants were 45 ALS+bulbar (30 males, mean age=61±11), 22 ALS-nonbulbar (11 males, age=62±10), 22 bvFTD (13 males, age=63±7), and 34 HC (14 males, age=69±8). ALS+bulbar had smaller VSA and shallower average F2 slopes than ALS-bulbar (VSA: | d |=0.86, p =0.0088; F2 slope: | d |=0.98, p =0.0054), bvFTD (VSA: | d |=0.67, p =0.043; F2 slope: | d |=1.4, p <0.001), and HC (VSA: | d |=0.73, p =0.024; F2 slope: | d |=1.0, p <0.001). Vowel measures declined with worsening bulbar clinical scores (VSA: R=0.33, p =0.033; F2 slope: R=0.25, p =0.048), and smaller VSA was associated with greater listener effort (R=-0.43, p =0.041). Shallower F2 slopes were related to cortical thinning in oralPMC (R=0.50, p =0.03). Neither vowel measure was associated with respiratory nor cognitive test scores. Conclusions: Vowel measures extracted with automatic processing from natural speech are sensitive to bulbar motor disease in ALS-FTD and are robust to cognitive impairment.
ABSTRACT
OBJECTIVE: Plasma phosphorylated tau (p-tau181 ) is reliably elevated in Alzheimer's disease (AD), but less explored is its specificity relative to other neurodegenerative conditions. Here, we find novel evidence that plasma p-tau181 is elevated in amyotrophic lateral sclerosis (ALS), a neurodegenerative condition typically lacking tau pathology. We performed a detailed evaluation to identify the clinical correlates of elevated p-tau181 in ALS. METHODS: Patients were clinically or pathologically diagnosed with ALS (n = 130) or AD (n = 79), or were healthy non-impaired controls (n = 26). Receiver operating characteristic (ROC) curves were analyzed and area under the curve (AUC) was used to discriminate AD from ALS. Within ALS, Mann-Whitney-Wilcoxon tests compared analytes by presence/absence of upper motor neuron and lower motor neuron (LMN) signs. Spearman correlations tested associations between plasma p-tau181 and postmortem neuron loss. RESULTS: A Wilcoxon test showed plasma p-tau181 was higher in ALS than controls (W = 2,600, p = 0.000015), and ROC analyses showed plasma p-tau181 poorly discriminated AD and ALS (AUC = 0.60). In ALS, elevated plasma p-tau181 was associated with LMN signs in cervical (W = 827, p = 0.0072), thoracic (W = 469, p = 0.00025), and lumbosacral regions (W = 851, p = 0.0000029). In support of LMN findings, plasma p-tau181 was associated with neuron loss in the spinal cord (rho = 0.46, p = 0.017), but not in the motor cortex (p = 0.41). Cerebrospinal spinal fluid p-tau181 and plasma neurofilament light chain were included as reference analytes, and demonstrate specificity of findings. INTERPRETATION: We found strong evidence that plasma p-tau181 is elevated in ALS and may be a novel marker specific to LMN dysfunction. ANN NEUROL 2022;92:807-818.
Subject(s)
Alzheimer Disease , Amyotrophic Lateral Sclerosis , Humans , Amyotrophic Lateral Sclerosis/diagnosis , tau Proteins , Alzheimer Disease/pathology , ROC Curve , Area Under Curve , Biomarkers , Nerve DegenerationABSTRACT
The neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TAR DNA-binding protein-43 (TDP-43) inclusions (FTLD-TDP) share the neuropathological hallmark of aggregates of TDP-43. However, factors governing the severity and regional distribution of TDP-43 pathology, which may account for the divergent clinical presentations of ALS and FTLD-TDP, are not well understood. Here, we investigated the influence of genotypes at TMEM106B, a locus associated with risk for FTLD-TDP, and hexanucleotide repeat expansions in C9orf72, a known genetic cause for both ALS and FTLD-TDP, on global TDP-43 pathology and regional distribution of TDP-43 pathology in 899 postmortem cases from a spectrum of neurodegenerative diseases. We found that, among the 110 ALS cases, minor (C)-allele homozygotes at the TMEM106B locus sentinel SNP rs1990622 had more TDP-43 pathology globally, as well as in select brain regions. C9orf72 expansions similarly associated with greater TDP-43 pathology in ALS. However, adjusting for C9orf72 expansion status did not affect the relationship between TMEM106B genotype and TDP-43 pathology. To elucidate the direction of causality for this association, we directly manipulated TMEM106B levels in an inducible cell system that expresses mislocalized TDP-43 protein. We found that partial knockdown of TMEM106B, to levels similar to what would be expected in rs1990622 C allele carriers, led to development of more TDP-43 cytoplasmic aggregates, which were more insoluble, in this system. Taken together, our results support a causal role for TMEM106B in modifying the development of TDP-43 proteinopathy.
Subject(s)
Alzheimer Disease/etiology , C9orf72 Protein/physiology , DNA-Binding Proteins/physiology , Lewy Body Disease/etiology , Membrane Proteins/physiology , Nerve Tissue Proteins/physiology , TDP-43 Proteinopathies/etiology , Aged , Aged, 80 and over , Alzheimer Disease/pathology , Cohort Studies , Female , Humans , Lewy Body Disease/pathology , Male , Middle Aged , TDP-43 Proteinopathies/pathologyABSTRACT
Amyotrophic lateral sclerosis (ALS) has historically posed unique challenges for gene-therapy-based approaches, due to a paucity of therapeutic targets as well as the difficulty of accessing both the brain and spinal cord. Recent advances in our understanding of disease mechanism and ALS genetics, however, have combined with tremendous strides in CNS targeting, gene delivery, and gene editing and knockdown techniques to open new horizons of therapeutic possibility. Gene therapy clinical trials are currently underway for ALS patients with SOD1 mutations, C9orf72 hexanucleotide repeat expansions, ATXN2 trinucleotide expansions, and FUS mutations, as well as sporadic disease without known genetic cause. In this review, we provide an in-depth exploration of the state of ALS-directed gene therapy, including antisense oligonucleotides, RNA interference, CRISPR, adeno-associated virus (AAV)-mediated trophic support, and antibody-based methods. We discuss how each of these approaches has been implemented across known genetic causes as well as sporadic ALS, reviewing preclinical studies as well as completed and ongoing human clinical trials. We highlight the transformative potential of these evolving technologies as the gene therapy field advances toward a true disease-modifying treatment for this devastating illness.
Subject(s)
Amyotrophic Lateral Sclerosis , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/therapy , C9orf72 Protein/genetics , Dependovirus/genetics , Genetic Therapy/methods , Humans , Oligonucleotides, Antisense/genetics , Oligonucleotides, Antisense/therapeutic useABSTRACT
BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disease affecting about 5 million people worldwide with no disease-modifying therapies. We sought blood-based biomarkers in order to provide molecular characterization of individuals with PD for diagnostic confirmation and prediction of progression. METHODS AND FINDINGS: In 141 plasma samples (96 PD, 45 neurologically normal control [NC] individuals; 45.4% female, mean age 70.0 years) from a longitudinally followed Discovery Cohort based at the University of Pennsylvania (UPenn), we measured levels of 1,129 proteins using an aptamer-based platform. We modeled protein plasma concentration (log10 of relative fluorescence units [RFUs]) as the effect of treatment group (PD versus NC), age at plasma collection, sex, and the levodopa equivalent daily dose (LEDD), deriving first-pass candidate protein biomarkers based on p-value for PD versus NC. These candidate proteins were then ranked by Stability Selection. We confirmed findings from our Discovery Cohort in a Replication Cohort of 317 individuals (215 PD, 102 NC; 47.9% female, mean age 66.7 years) from the multisite, longitudinally followed National Institute of Neurological Disorders and Stroke Parkinson's Disease Biomarker Program (PDBP) Cohort. Analytical approach in the Replication Cohort mirrored the approach in the Discovery Cohort: each protein plasma concentration (log10 of RFU) was modeled as the effect of group (PD versus NC), age at plasma collection, sex, clinical site, and batch. Of the top 10 proteins from the Discovery Cohort ranked by Stability Selection, four associations were replicated in the Replication Cohort. These blood-based biomarkers were bone sialoprotein (BSP, Discovery false discovery rate [FDR]-corrected p = 2.82 × 10-2, Replication FDR-corrected p = 1.03 × 10-4), osteomodulin (OMD, Discovery FDR-corrected p = 2.14 × 10-2, Replication FDR-corrected p = 9.14 × 10-5), aminoacylase-1 (ACY1, Discovery FDR-corrected p = 1.86 × 10-3, Replication FDR-corrected p = 2.18 × 10-2), and growth hormone receptor (GHR, Discovery FDR-corrected p = 3.49 × 10-4, Replication FDR-corrected p = 2.97 × 10-3). Measures of these proteins were not significantly affected by differences in sample handling, and they did not change comparing plasma samples from 10 PD participants sampled both on versus off dopaminergic medication. Plasma measures of OMD, ACY1, and GHR differed in PD versus NC but did not differ between individuals with amyotrophic lateral sclerosis (ALS, n = 59) versus NC. In the Discovery Cohort, individuals with baseline levels of GHR and ACY1 in the lowest tertile were more likely to progress to mild cognitive impairment (MCI) or dementia in Cox proportional hazards analyses adjusting for age, sex, and disease duration (hazard ratio [HR] 2.27 [95% CI 1.04-5.0, p = 0.04] for GHR, and HR 3.0 [95% CI 1.24-7.0, p = 0.014] for ACY1). GHR's association with cognitive decline was confirmed in the Replication Cohort (HR 3.6 [95% CI 1.20-11.1, p = 0.02]). The main limitations of this study were its reliance on the aptamer-based platform for protein measurement and limited follow-up time available for some cohorts. CONCLUSIONS: In this study, we found that the blood-based biomarkers BSP, OMD, ACY1, and GHR robustly associated with PD across multiple clinical sites. Our findings suggest that biomarkers based on a peripheral blood sample may be developed for both disease characterization and prediction of future disease progression in PD.
Subject(s)
Biomarkers/blood , Parkinson Disease/blood , Proteomics , Aged , Algorithms , Amidohydrolases/blood , Carrier Proteins/blood , Disease Progression , Extracellular Matrix Proteins/blood , Female , Humans , Longitudinal Studies , Male , Middle Aged , Neurodegenerative Diseases , Osteopontin/blood , Proportional Hazards Models , Proteoglycans/blood , Reproducibility of ResultsABSTRACT
Adeno-associated virus-mediated gene replacement is emerging as a safe and effective means of correcting single-gene mutations affecting the CNS. AAV-mediated progranulin gene (GRN) delivery has been proposed as a treatment for GRN-deficient frontotemporal dementia and neuronal ceroid lipofuscinosis, and recent studies using intraparenchymal AAV-Grn delivery to brain have shown moderate success in histopathologic and behavioral rescue in mouse models. Here, we used AAV9 to deliver GRN to the lateral ventricle to achieve widespread expression in the Grn null mouse brain. We found that, despite a global increase in progranulin, overexpression resulted in dramatic and selective hippocampal toxicity and degeneration affecting neurons and glia. Hippocampal degeneration was preceded by T cell infiltration and perivascular cuffing. GRN delivery with an ependymal-targeting AAV for selective secretion of progranulin into the cerebrospinal fluid similarly resulted in T cell infiltration, as well as ependymal hypertrophy. Interestingly, overexpression of GRN in wild-type animals also provoked T cell infiltration. These results call into question the safety of GRN overexpression in the CNS, with evidence for both a region-selective immune response and cellular proliferative response. Our results highlight the importance of careful consideration of target gene biology and cellular response to overexpression prior to progressing to the clinic.
Subject(s)
Dependovirus/genetics , Progranulins/metabolism , T-Lymphocytes/metabolism , Animals , Brain/metabolism , Disease Models, Animal , Female , Frontotemporal Dementia/genetics , Frontotemporal Dementia/therapy , Genetic Therapy , Male , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Models, Theoretical , Neurodegenerative Diseases/genetics , Neurodegenerative Diseases/therapy , Progranulins/cerebrospinal fluid , Progranulins/deficiency , Progranulins/geneticsABSTRACT
We report a woman who presented with rapidly progressive dementia and hypoglycorrhachia and discuss the approach and differential diagnosis for her condition. Rapidly progressive dementia poses a variety of challenges to the treating clinician, not only due to the speed of disease progression, but also due to the poor prognosis if intervention is delayed. The differential diagnosis of a patient presenting with rapid cognitive and functional decline is broad and includes degenerative, infectious, toxic, and neoplastic etiologies, some of which can be identified clinically through history and physical examination. Diagnostic evaluation using gadolinium-enhanced MRI, electroencephalography, and serum and cerebrospinal fluid testing is often required. The utility of testing for cerebrospinal fluid 14-3-3 antigen and tau is also reviewed.