Early symptoms in symptomatic and preclinical genetic frontotemporal lobar degeneration.

OBJECTIVES: The clinical heterogeneity of frontotemporal dementia (FTD) complicates identification of biomarkers for clinical trials that may be sensitive during the prediagnostic stage. It is not known whether cognitive or behavioural changes during the preclinical period are predictive of genetic status or conversion to clinical FTD. The first objective was to evaluate the most frequent initial symptoms in patients with genetic FTD. The second objective was to evaluate whether preclinical mutation carriers demonstrate unique FTD-related symptoms relative to familial mutation non-carriers. METHODS: The current study used data from the Genetic Frontotemporal Dementia Initiative multicentre cohort study collected between 2012 and 2018. Participants included symptomatic carriers (n=185) of a pathogenic mutation in chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN) or microtubule-associated protein tau (MAPT) and their first-degree biological family members (n=588). Symptom endorsement was documented using informant and clinician-rated scales. RESULTS: The most frequently endorsed initial symptoms among symptomatic patients were apathy (23%), disinhibition (18%), memory impairments (12%), decreased fluency (8%) and impaired articulation (5%). Predominant first symptoms were usually discordant between family members. Relative to biologically related non-carriers, preclinical MAPT carriers endorsed worse mood and sleep symptoms, and C9orf72 carriers endorsed marginally greater abnormal behaviours. Preclinical GRN carriers endorsed less mood symptoms compared with non-carriers, and worse everyday skills. CONCLUSION: Preclinical mutation carriers exhibited neuropsychiatric symptoms compared with non-carriers that may be considered as future clinical trial outcomes. Given the heterogeneity in symptoms, the detection of clinical transition to symptomatic FTD may be best captured by composite indices integrating the most common initial symptoms for each genetic group.

Genetic Variation in the Ontario Neurodegenerative Disease Research Initiative.

BACKGROUND/OBJECTIVE: Apolipoprotein E (APOE) E4 is the main genetic risk factor for Alzheimer's disease (AD). Due to the consistent association, there is interest as to whether E4 influences the risk of other neurodegenerative diseases. Further, there is a constant search for other genetic biomarkers contributing to these phenotypes, such as microtubule-associated protein tau (MAPT) haplotypes. Here, participants from the Ontario Neurodegenerative Disease Research Initiative were genotyped to investigate whether the APOE E4 allele or MAPT H1 haplotype are associated with five neurodegenerative diseases: (1) AD and mild cognitive impairment (MCI), (2) amyotrophic lateral sclerosis, (3) frontotemporal dementia (FTD), (4) Parkinson's disease, and (5) vascular cognitive impairment. METHODS: Genotypes were defined for their respective APOE allele and MAPT haplotype calls for each participant, and logistic regression analyses were performed to identify the associations with the presentations of neurodegenerative diseases. RESULTS: Our work confirmed the association of the E4 allele with a dose-dependent increased presentation of AD, and an association between the E4 allele alone and MCI; however, the other four diseases were not associated with E4. Further, the APOE E2 allele was associated with decreased presentation of both AD and MCI. No associations were identified between MAPT haplotype and the neurodegenerative disease cohorts; but following subtyping of the FTD cohort, the H1 haplotype was significantly associated with progressive supranuclear palsy. CONCLUSION: This is the first study to concurrently analyze the association of APOE isoforms and MAPT haplotypes with five neurodegenerative diseases using consistent enrollment criteria and broad phenotypic analysis.

Étude de variance génétique dans le cadre de l'initiative de recherche sur les maladies neurodégénératives en Ontario. Contexte/Objectif : L'apolipoprotéine E4 (ApoE4) constitue le principal facteur de risque génétique de la maladie d'Alzheimer. En raison de cette association systématique, il existe un intérêt certain à savoir dans quelle mesure cette classe d'apolipoprotéines peut influencer le risque d'autres maladies neurodégénératives. En outre, le milieu de la recherche n'a de cesse d'identifier d'autres biomarqueurs génétiques, par exemple les haplotypes H1 de la protéine tau associée aux microtubules, qui contribuent à certains phénotypes, Dans le cadre de cette étude, des participants à l'initiative de recherche sur les maladies neurodégénératives en Ontario ont été « génotypés ¼ afin de déterminer si l'ApoE4 ou l'haplotype H1 mentionné ci-dessus peuvent être associés à cinq maladies neurodégénératives : 1) la maladie d'Alzheimer et d'autres troubles cognitifs légers ; 2) la sclérose latérale amyotrophique ; 3) la démence fronto-temporale ; 4) la maladie de Parkinson ; 5) et finalement les déficits cognitifs d'origine vasculaire. Méthodes : Pour chaque participant, la cartographie des génotypes a été établie en fonction de leur ApoE4 respectif et de la présence d'haplotypes H1 de la protéine tau associée aux microtubules. Des analyses de régression logistique ont été ensuite effectuées dans le but d'identifier de possibles liens avec ces maladies neurodégénératives. Résultats : Nos travaux ont confirmé l'association entre l'ApoE4 et une plus grande occurrence de cas d'Alzheimer, et ce, en tenant compte de l'effet d'une dose de médicament. Ils ont aussi montré une association entre la seule ApoE4 et des troubles cognitifs légers. Cela dit, il convient de préciser que les quatre autres maladies n'ont pas été associées à cet allèle. Plus encore, nous avons trouvé que l'allèle E2 de l'apolipoprotéine était associé à une occurrence plus faible de cas d'Alzheimer et de troubles cognitifs légers. Fait à souligner, aucune association n'a été détectée entre l'haplotype H1 de la protéine tau associée aux microtubules et nos cohortes atteintes de maladies neurodégénératives. Toutefois, à la suite du sous-typage de la cohorte de participants atteints de démence fronto-temporale, il s'est avéré que l'haplotype H1 était associé de façon notable à la paralysie supra-nucléaire progressive. Conclusion : Il s'agit de la première étude à analyser simultanément, au moyen de critères de participation cohérents et d'une analyse phénotypique élargie, les associations entre les isoformes de l'ApoE, l'haplotype H1 de la protéine tau associée aux microtubules et cinq maladies neurodégénératives.

Occurrence of Amyotrophic Lateral Sclerosis in Type 1 Gaucher Disease.

OBJECTIVE: To report the association between type 1 Gaucher disease (GD1) and amyotrophic lateral sclerosis (ALS) in 3 unrelated families and to explore whether GBA variants influence the risk of ALS. METHODS: We conducted retrospective chart reviews of patients with GD1 or their family members diagnosed with ALS. To further investigate whether there is an association between ALS and GD, we performed exploratory analyses for the presence of GBA variants in 3 ALS cohorts from Toronto (Canada), Montreal (Canada), and Project MinE (international), totaling 4,653 patients with ALS and 1,832 controls. RESULTS: We describe 2 patients with GD1 and 1 obligate GBA mutation carrier (mother of GD1 patient) with ALS. We identified 0 and 8 GBA carriers in the Toronto and Montreal cohorts, respectively. The frequencies of GBA variants in patients with ALS in the Montreal and Project MinE cohorts were similar to those of Project MinE controls or Genome Aggregation Database population controls. CONCLUSIONS: The occurrence of ALS in biallelic or monoallelic GBA mutation carriers described here, in addition to common pathogenic pathways shared by GD1 and ALS, suggests that GBA variants could influence ALS risk. However, analyses of GBA variants in ALS cohorts did not reveal a meaningful association. Examination of larger cohorts and neuropathologic studies will be required to elucidate whether patients with GD1 are indeed at increased risk for ALS.

Prognosis of amyotrophic lateral sclerosis with respiratory onset.

Respiratory muscle involvement is a recognised, but often late, complication of amyotrophic lateral sclerosis (ALS). The clinical features and prognosis of 21 patients with respiratory onset ALS are reported here. On a retrospective chart review, it was found that 2.7% of patients with ALS presenting to a tertiary care specialty clinic have respiratory symptoms as their first clinical symptom of ALS. Only 14% of these individuals presented acutely and required emergency intubation. The mean survival time of the total group from symptom onset to death or permanent ventilation was 27.0 (14.9) months, which was not significantly different from the survival time in patients with bulbar onset ALS. Non-invasive positive pressure ventilation (NIPPV) significantly improved survival compared with those who did not use NIPPV. This study suggests that ALS with respiratory onset does not necessarily follow a rapidly progressive course.

Amyotrophic lateral sclerosis: update for family physicians.

OBJECTIVE: To discuss the epidemiology, pathogenesis, diagnosis, expected course, prognosis, and treatment of amyotrophic lateral sclerosis (ALS), a degenerative disorder of the nervous system associated with progressive weakness. QUALITY OF EVIDENCE: PubMed and the Cochrane Database of Systematic Reviews were searched using the MeSH headings "amyotrophic lateral sclerosis," "therapy," "epidemiology," and "etiology." Articles containing the best available evidence were reviewed. Most provided level II and III evidence. There were some level I drug trials. MAIN MESSAGE: Amyotrophic lateral sclerosis is associated with progressive dysarthria, dysphagia, and weakness in the extremities. Diagnosis is based on physical examination, electrophysiology, and excluding other confounding conditions. There is no cure for this devastating disorder. Certain treatments, however, can improve survival and quality of life. CONCLUSION: Because ALS is a complex disease, care of ALS patients is best provided at multidisciplinary clinics that specialize in managing patients with this disorder.

Preliminary evaluation of the sensitivity to change of DE-STA motor unit number estimation in the upper trapezius muscle in amyotrophic lateral sclerosis.

OBJECTIVE: To compare the sensitivity to change of decomposition-enhanced spike-triggered averaging (DE-STA) motor unit number estimation (MUNE) in the upper trapezius (UT) to that of various clinical outcome measures in subjects with amyotrophic lateral sclerosis (ALS). METHODS: Ten patients with clinically probable or definite ALS were assessed at baseline, 2, 4 and 6months with the following outcome measures: manual muscle testing in five upper extremity muscle groups, scapular elevation and elbow flexion peak force measured with hand-held dynamometry, MUNE, forced vital capacity and the Revised ALS Functional Rating Scale (ALSFRS-R). RESULTS: ALSFRS-R was the only outcome measure for which there was a significant difference between baseline and 6months (p=0.034). ALSFRS-R had the largest standardized response mean (SRM), and was thus the most sensitive to change. MUNE demonstrated a decline over 6months and a moderate SRM (-0.63). CONCLUSIONS: This study has demonstrated a moderate degree of sensitivity to change for DE-STA MUNE as applied to the UT in subjects with ALS. SIGNIFICANCE: In this preliminary study, DE-STA MUNE detected motor unit loss over 6months, with a moderate degree of sensitivity, in the upper trapezius of subjects with ALS.