Using only demographic data and selected diagnosis and procedure codes readily available in administrative claims data, it is possible to identify individuals with a high probability of eventually being diagnosed with PD.
Parkinson disease (PD) is a complex neurodegenerative disorder. Cognitive dysfunction and psychosis are leading contributors to nursing home placement. 1 Psychosis onset is associated with cognitive decline, levodopa supplementation, and visual dysfunction. 2 Treatment of PD psychosis (PDP) centers on levodopa dose adjustment, use of second-generation antipsychotics (SGAs), and cholinesterase inhibitors. SGAs function via serotonergic modulation and dopamine receptors blockade. Quetiapine, a structural analogue to clozapine, is often used to treat PDP, although evidence of its efficacy is mixed in randomized controlled trials. 3 Furthermore, there is a concern for increased morbidity and mortality with use of quetiapine and other SGAs in patients with dementia or those with PD, prompting a black box warning by the Food and Drug Administration (FDA). 4 The FDA approved pimavanserin (Acadia Pharmaceuticals Inc., San Diego, CA) on April 29, 2016, as the first agent indicated for treatment of PDP. Its mechanism of action is novel, behaving as a selective inverse agonist of the serotonin 5-HT2A receptor and having no appreciable blockade of D2 receptors. 5 Pimavanserin's safety was recently highlighted in a report by the Institute for Safe Medication Practices, 6 including an expanded set of adverse events and risk of increased mortality. This report has led to concerns among prescribers, patients, and caregivers. Here we report on our institutional experience with pimavanserin for the treatment of PDP since its FDA approval. Methods We conducted a retrospective study with inclusion criteria of (1) PD diagnosis and (2) prescribed pimavanserin, quetiapine, or both agents during April 29, 2016-April 29, 2018. Standard protocol approvals, registrations, and patient consents All patients received their care at the University of California San Diego Health System. Anonymized records were obtained from the Epic electronic health record system. Since we only utilized de-identified electronic health records, no consents were required or obtained. Data analyzed included age, sex, and whether patients were living or deceased. Descriptive statistics are reported for the group characteristics along with 2-sample t tests for significance (p < 0.05) (table). Logistic regression with adjustment for age and sex was used to calculate odds ratios for mortality between each drug exposure group and controls. Results Of 4,478 patients with PD, 676 fulfilled the selection criteria. Despite a higher percentage mortality between quetiapine vs pimavanserin and combination vs pimavanserin, these differences were not different (p = 0.17 and p = 0.28, respectively). Mean age of the deceased cohorts was also similar
Despite recent advances in fluid biomarker research in Alzheimer’s disease (AD), there are no fluid biomarkers or imaging tracers with utility for diagnosis and/or theragnosis available for other tauopathies. Using immunoprecipitation and mass spectrometry, we show that 4 repeat (4R) isoform-specific tau species from microtubule-binding region (MTBR-tau275 and MTBR-tau282) increase in the brains of corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), frontotemporal lobar degeneration (FTLD)-MAPT and AD but decrease inversely in the cerebrospinal fluid (CSF) of CBD, FTLD-MAPT and AD compared to control and other FTLD-tau (for example, Pick’s disease). CSF MTBR-tau measures are reproducible in repeated lumbar punctures and can be used to distinguish CBD from control (receiver operating characteristic area under the curve (AUC) = 0.889) and other FTLD-tau, such as PSP (AUC = 0.886). CSF MTBR-tau275 and MTBR-tau282 may represent the first affirmative biomarkers to aid in the diagnosis of primary tauopathies and facilitate clinical trial designs.
Introduction: We sought to provide an overview of the published and currently ongoing movement disorders clinical trials employing gene therapy, defined as a technology aiming to modulate the expression of one or more genes to achieve a therapeutic benefit.Methods: We systematically reviewed movement disorders gene therapy clinical trials from PubMed and ClinicalTrials.gov using a searching strategy that included Parkinson disease (PD), Huntington disease (HD), amino acid decarboxylase (AADC) deficiency, multiple system atrophy (MSA), progressive supranuclear palsy (PSP), dystonia, tremor, ataxia, and other movement disorders. Data extracted included study characteristics, investigational product, route of administration, safety/tolerability, motor endpoints, and secondary outcomes (i.e., neuroimaging, biomarkers).Results: We identified a total of 46 studies focusing on PD (21 published and nine ongoing), HD (2 published and 5 ongoing), AADC deficiency (4 published and 2 ongoing), MSA (2 ongoing), and PSP (1 ongoing). In PD, intraparenchymal infusion of viral vector-mediated gene therapies demonstrated to be safe and showed promising preliminary data in trials aiming at restoring the synthesis of dopamine, enhancing the production of neurotrophic factors, or modifying the functional interaction between different nodes of the basal ganglia. In HD, monthly intrathecal delivery of an antisense oligonucleotide (ASO) targeting the huntingtin protein (HTT) mRNA proved to be safe and tolerable, and demonstrated a dose-dependent reduction of the cerebrospinal fluid levels of mutated HTT, while a small phase-I study testing implantable capsules of cells engineered to synthesize ciliary neurotrophic factor failed to show consistent drug delivery. In AADC deficiency, gene replacement studies demonstrated to be relatively safe in restoring catecholamine and serotonin synthesis, with promising outcomes. Ongoing movement disorders clinical trials are focusing on a variety of gene therapy approaches including alternative viral vector serotypes, novel recombinant genes, novel delivery techniques, and ASOs for the treatment of HD, MSA, and distinct subtypes of PD (LRRK2 mutation or GBA1 mutation carriers).Conclusion: Initial phase-I and -II studies tested the safety and feasibility of gene therapy in PD, HD, and AADC deficiency. The ongoing generation of clinical trials aims to test the efficacy of these approaches and explore additional applications for gene therapy in movement disorders.
ABSTRACT:We report a 47 year old woman who was initially diagnosed as having multiple sclerosis. She has subsequently been found to be heterozygous for adrenoleukodystrophy (ALD). The female carrier state for ALD may be associated with intermittent symptoms and it is therefore important to consider ALD in patients diagnosed as multiple sclerosis. RESUME: Une adrenoleucodystrophie imitant une sclerose en plaques Nous rapportons l'histoire d'une femme de 47 ans dont le diagnostic initial fut de sclerose en plaques. Plus tard il fut dSmontre" qu'elle e"tait h6t6rozygote pour l'adrSnoleucodystrophie (ALD). L'6tat de porteur chez la femme peut etre associe' a des Episodes intermittents ce qui devrait nous inciter a considdrer ce diagnostic differentiel dans ces cas precis.Can. J. Neurol. Sci. 1985; 12: 73-74 The diagnosis of multiple sclerosis (MS) is based on clinical criteria, with supporting evidence from physiological and laboratory studies (McDonald and Halliday, 1977). More recently Poser et al. (1983) have provided new diagnostic criteria for the diagnosis of MS in patients participating in therapeutic trials. The non-specific nature of these criteria emphasizes the importance for the practising neurologist to consider conditions which may mimic MS clinically and in the laboratory. We report a patient in whom MS was initially diagnosed but who was later found to be heterozygous for adrenoleukodystrophy (ALD).The patient was not seen again until 1983, when her 11 year old son presented with a rapidly progressive CNS illness, which was diagnosed as adrenoleukodystrophy.Further evaluation of the family revealed that the patient's sister had an episode of lower extremity numbness in 1978 and on examination had hyperreflexia at the knees and extensor plantar responses. Both her maternal grandfather and 2 greatuncles had been confined to wheelchairs because of progressive spinal cord dysfunction (Fig. 1 DISCUSSIONAdrenoleukodystrophy (ALD) is an x-linked disorder of very long chain fatty acid metabolism which is manifested by central and peripheral nervous system demyelination and adrenal atrophy. Several phenotypes have been described : 1) a progressive CNS demyelination with some degree of adrenal dysfunction in young boys, 2) a myelopathy in female carriers, 3) a progressive myelopathy in adult males, 4) cerebral and spinal dysfunction in adolescent males, 5) x-linked Addison's Disease without neurological impairment, and 6) a connatal form with possible autosomal recessive inheritance.The demyelination in ALD heterozygous females has been shown to extend above the spinal cord. Moloney and Masterson (1982) demonstrated a prolongation of the BAER I-V interwave latency in 3 obligate ALD heterzygotes, indicating brain stem involvement.
Objective Tau hyperphosphorylation at threonine 217 (pT217) in cerebrospinal fluid (CSF) has recently been linked to early amyloidosis and could serve as a highly sensitive biomarker for Alzheimer’s disease (AD). However, it remains unclear whether other tauopathies induce pT217 modifications. To determine if pT217 modification is specific to AD, CSF pT217 was measured in AD and other tauopathies. Methods Using immunoprecipitation and mass spectrometry methods, we compared CSF T217 phosphorylation occupancy (pT217/T217) and amyloid‐beta (Aβ) 42/40 ratio in cognitively normal individuals and those with symptomatic AD, progressive supranuclear palsy, corticobasal syndrome, and sporadic and familial frontotemporal dementia. Results Individuals with AD had high CSF pT217/T217 and low Aβ42/40. In contrast, cognitively normal individuals and the majority of those with 4R tauopathies had low CSF pT217/T217 and normal Aβ 42/40. We identified a subgroup of individuals with increased CSF pT217/T217 and normal Aβ 42/40 ratio, most of whom were MAPT R406W mutation carriers. Diagnostic accuracies of CSF Aβ 42/40 and CSF pT217/T217, alone and in combination were compared. We show that CSF pT217/T217 × CSF Aβ 42/40 is a sensitive composite biomarker that can separate MAPT R406W carriers from cognitively normal individuals and those with other tauopathies. Interpretation MAPT R406W is a tau mutation that leads to 3R+4R tauopathy similar to AD, but without amyloid neuropathology. These findings suggest that change in CSF pT217/T217 ratio is not specific to AD and might reflect common downstream tau pathophysiology common to 3R+4R tauopathies.
Background Parkinson disease (PD) psychosis (PDP) is a disabling non-motor symptom. Pharmacologic treatment is limited to pimavanserin, quetiapine, and clozapine, which do not worsen parkinsonism. A Food and Drug Administration black box warning exists for antipsychotics, suggesting increased mortality in elderly patients with dementia. However, the reasons for higher mortality are unknown. Aim Expanding on prior work exploring mortality in treated PDP patients, we conducted a retrospective comparison to understand the links between treatment regimen, clinical characteristics, and negative outcomes. Methods Electronic medical record data extraction included clinically diagnosed PD patients between 4/29/16-4/29/19 and excluded patients with primary psychiatric diagnoses or atypical parkinsonism. Mortality and clinical characteristics during the study period were compared between untreated patients and those receiving pimavanserin, quetiapine, or both agents (combination). Mortality analyses were adjusted for age, sex, levodopa equivalent daily dose (LEDD), and dementia. Results The pimavanserin group (n = 34) had lower mortality than the untreated group (n = 66) (odds ratio = 0.171, 95% confidence interval: 0.025–0.676, p = 0.026). The untreated group had similar mortality compared to the quetiapine (n = 147) and combination (n = 68) groups. All treated groups had a higher LEDD compared to the untreated group, but no other differences in demographics, hospitalizations, medical comorbidities, medications, or laboratory values were found between the untreated and treated groups. Conclusions PDP patients receiving pimavanserin had lower mortality than untreated patients. We found no other clear differences in clinical characteristics to explain the mortality risk. Prospective randomized trials are needed to definitively identify the optimal PDP treatment regimen and associated risks.
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