Neurologists have conceived amyloid and tau aggregation to be pathogenic in Alzheimer's disease, synuclein in Parkinson's disease, and tau in progressive supranuclear palsy. ...the reasoning followed ...that clearing protein aggregates is likely to be beneficial. Nilotinib, a drug designed for the treatment of chronic myeloid leukaemia, became a candidate for repurposing in Parkinson's disease once the inhibition of cAbl tyrosine kinase, an enzyme activated in models of neurodegeneration, was shown to enhance the autophagic degradation of α-synuclein.2 A 6 month, randomised, double-blind, placebo-controlled trial in patients with Parkinson's disease showed that, compared with placebo, nilotinib at a dose of 300 mg actually worsened motor function, as per the MDS-UPDRS part III scores, with the difference becoming significant at 1 month (p<0·01).3 The trialists recommended against further testing of nilotinib. ...because nilotinib might not have sufficiently reduced CSF levels of α-synuclein, other cAbl tyrosine kinase inhibitors are being investigated.4 The emphasis on anti-synuclein therapeutics led to the creation of an ultrasensitive real-time quaking-induced conversion (RT-QuIC) assay, which detects misfolded α-synuclein in patients with Parkinson's disease and dementia with Lewy bodies with nearly perfect sensitivity and specificity.5 From the CSF of 52 patients with rapid-eye-movement sleep behaviour disorder and 40 healthy controls matched for age, sex, and duration of follow up, researchers at the Universitat de Barcelona (Barcelona, Spain) showed that the RT-QuIC assay was positive in 47 (90%) patients and in four (10%) controls, resulting in a sensitivity of 90·4% and a specificity of 90·0%.6 After approximately 3 years, 32 (62%) of 52 patients with rapid-eye-movement sleep behaviour disorder (and none of the healthy controls) were diagnosed with Parkinson's disease or dementia with Lewy bodies, of whom 31 (97%) were positive for α-synuclein at baseline.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Levodopa‐induced dyskinesia is a common complication in Parkinson disease. Pathogenic mechanisms include phasic stimulation of dopamine receptors, nonphysiological levodopa‐to‐dopamine conversion in ...serotonergic neurons, hyperactivity of corticostriatal glutamatergic transmission, and overstimulation of nicotinic acetylcholine receptors on dopamine‐releasing axons. Delay in initiating levodopa is no longer recommended, as dyskinesia development is a function of disease duration rather than cumulative levodopa exposure. We review current and in‐development treatments for peak‐dose dyskinesia but suggest that improvements in levodopa delivery alone may reduce its future prevalence. Ann Neurol 2018;84:797–811
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
While this medication is only meant to alleviate your symptoms, not treat your disease, the pharmacogenomic analysis indicated that you can expect to achieve optimal benefits, with a small risk of ...developing low blood pressure at doses higher than 750 mg/day. ...we will continue optimising the control of your symptoms only with carbidopa and levodopa. For treating your specific type of disease Our continuously updated biorepository searches for the 16 recognised biological types of Parkinson's disease that account for approximately 25% of known presentations. Because treatments are available to correct the biological abnormalities underpinning each of these disease types, our centre automatically applies a battery of treatment-linked bioassays to identify candidates likely to benefit from them.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
IMPORTANCE: Functional neurological disorders (FND) are common sources of disability in medicine. Patients have often been misdiagnosed, correctly diagnosed after lengthy delays, and/or subjected to ...poorly delivered diagnoses that prevent diagnostic understanding and lead to inappropriate treatments, iatrogenic harm, unnecessary and costly evaluations, and poor outcomes. OBSERVATIONS: Functional Neurological Symptom Disorder/Conversion Disorder was adopted by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, replacing the term psychogenic with functional and removing the criterion of psychological stress as a prerequisite for FND. A diagnosis can now be made in an inclusionary manner by identifying neurological signs that are specific to FNDs without reliance on presence or absence of psychological stressors or suggestive historical clues. The new model highlights a wider range of past sensitizing events, such as physical trauma, medical illness, or physiological/psychophysiological events. In this model, strong ideas and expectations about these events correlate with abnormal predictions of sensory data and body-focused attention. Neurobiological abnormalities include hypoactivation of the supplementary motor area and relative disconnection with areas that select or inhibit movements and are associated with a sense of agency. Promising evidence has accumulated for the benefit of specific physical rehabilitation and psychological interventions alone or in combination, but clinical trial evidence remains limited. CONCLUSIONS AND RELEVANCE: Functional neurological disorders are a neglected but potentially reversible source of disability. Further research is needed to determine the dose and duration of various interventions, the value of combination treatments and multidisciplinary therapy, and the therapeutic modality best suited for each patient.
Keywords: Parkinson's disease; REM sleep behavior disorder Article Note: Relevant conflicts of interest/financial disclosures: Nothing to report. Byline: Conor Fearon, Anthony E. Lang, Alberto Espay
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
To assess the neurobiological substrate of initial cognitive decline in Parkinson's disease (PD) to inform patient management, clinical trial design, and development of treatments.
We longitudinally ...assessed, up to 3 years, 423 newly diagnosed patients with idiopathic PD, untreated at baseline, from 33 international movement disorder centers. Study outcomes were four determinations of cognitive impairment or decline, and biomarker predictors were baseline dopamine transporter (DAT) single photon emission computed tomography (SPECT) scan, structural magnetic resonance imaging (MRI; volume and thickness), diffusion tensor imaging (mean diffusivity and fractional anisotropy), cerebrospinal fluid (CSF; amyloid beta Aβ, tau and alpha synuclein), and 11 single nucleotide polymorphisms (SNPs) previously associated with PD cognition. Additionally, longitudinal structural MRI and DAT scan data were included. Univariate analyses were run initially, with false discovery rate = 0.2, to select biomarker variables for inclusion in multivariable longitudinal mixed-effect models.
By year 3, cognitive impairment was diagnosed in 15-38% participants depending on the criteria applied. Biomarkers, some longitudinal, predicting cognitive impairment in multivariable models were: (1) dopamine deficiency (decreased caudate and putamen DAT availability); (2) diffuse, cortical decreased brain volume or thickness (frontal, temporal, parietal, and occipital lobe regions); (3) co-morbid Alzheimer's disease Aβ amyloid pathology (lower CSF Aβ 1-42); and (4) genes (COMT val/val and BDNF val/val genotypes).
Cognitive impairment in PD increases in frequency 50-200% in the first several years of disease, and is independently predicted by biomarker changes related to nigrostriatal or cortical dopaminergic deficits, global atrophy due to possible widespread effects of neurodegenerative disease, co-morbid Alzheimer's disease plaque pathology, and genetic factors.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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