BackgroundCurrently there are no disease-modifying treatments for Parkinson’s disease dementia (PDD), a condition linked to aggregation of the protein α-synuclein in subcortical and cortical brain areas. One of the leading genetic risk factors for Parkinson's disease is being a carrier in the gene for β-Glucocerebrosidase (GCase; gene name GBA1). Studies in cell culture and animal models have shown that raising the levels of GCase can decrease levels of α-synuclein. Ambroxol is a pharmacological chaperone for GCase and is able to raise the levels of GCase and could therefore be a disease-modifying treatment for PDD. The aims of this trial are to determine if Ambroxol is safe and well-tolerated by individuals with PDD and if Ambroxol affects cognitive, biochemical, and neuroimaging measures.MethodsThis is a phase II, single-centre, double-blind, randomized placebo-controlled trial involving 75 individuals with mild to moderate PDD. Participants will be randomized into Ambroxol high-dose (1050 mg/day), low-dose (525 mg/day), or placebo treatment arms. Assessments will be undertaken at baseline, 6-months, and 12-months follow up times. Primary outcome measures will be the Alzheimer’s disease Assessment Scale-cognitive subscale (ADAS-Cog) and the ADCS Clinician’s Global Impression of Change (CGIC). Secondary measures will include the Parkinson’s disease Cognitive Rating Scale, Clinical Dementia Rating, Trail Making Test, Stroop Test, Unified Parkinson’s disease Rating Scale, Purdue Pegboard, Timed Up and Go, and gait kinematics. Markers of neurodegeneration will include MRI and CSF measures. Pharmacokinetics and pharmacodynamics of Ambroxol will be examined through plasma levels during dose titration phase and evaluation of GCase activity in lymphocytes.DiscussionIf found effective and safe, Ambroxol will be one of the first disease-modifying treatments for PDD.Trial registrationClinicalTrials.gov NCT02914366, 26 Sep 2016/retrospectively registered.

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Objective: The Montreal Cognitive Assessment (MoCA) is a general cognitive screening tool that has shown sensitivity in detecting mild levels of cognitive impairment in various clinical populations. Although mood dysfunction is common in referrals to memory clinics, the influence of mood on the MoCA has to date been largely unexplored. Method: In this study, we examined the impact of mood dysfunction on the MoCA using a memory clinic sample of individuals with depressive symptoms who did not meet criteria for a neurodegenerative disease. Results: Half of the group with depressive symptoms scored below the MoCA-suggested cutoff for cognitive impairment. As a group, they scored below healthy controls, but above individuals with Alzheimer's disease and frontotemporal dementia. A MoCA subtask analysis revealed a pattern of executive/attentional dysfunction in those with depressive symptoms. Conclusions: This observed negative impact of depressive symptomatology on the MoCA has interpretative implications for its utility as a cognitive screening tool in a memory clinic setting. Bien qu'une dysfonction de l'humeur soit fréquente chez les patients référés à des cliniques de la mémoire, l'influence de l'humeur sur le MoCA n'a encore jamais été explorée. Méthode: Nous avons examiné l'impact d'un trouble de l'humeur sur le MoCA chez un échantillon de patients d'une clinique de la mémoire présentant des symptômes de dépression qui ne rencontraient pas les critères diagnostiques d'une maladie neurodégénérative. Résultats: La moitié du groupe présentant des symptômes de dépression avait un score sous le niveau suggéré par le MoCA pour le diagnostic d'une atteinte cognitive. En tant que groupe, leur score était inférieur à celui des témoins en bonne santé, mais supérieur à celui des patients atteints de la maladie d'Alzheimer ou de démence fronto-temporale. L'analyse des sous-tâches a montré un profil de dysfonction exécutive/de l'attention chez ceux qui présentaient des symptômes dépressifs. Conclusions: L'impact négatif de la symptomatologie dépressive sur le MoCa que nous avons observé a des implications sur l'interprétation de ce test concernant son utilité comme outil de dépistage cognitif dans le contexte d'une clinique de la mémoire.

ObjectivesThe 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.MethodsThe 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.ResultsThe 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.ConclusionPreclinical 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.