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Unifying the Motor & Non-Motor Features of Parkinson's Disease

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Unifying the Motor & Non-Motor Features of Parkinson's Disease Unifying the Motor & Non-motor Features of Parkinson’s Disease Ali Shalash Professor of Neurology Chair of Ain Shams Movement Disorders Group Department of Neurology, Ain Shams Univeristy Cairo, Egypt AGENDA 1. Motor and non-motor Symptoms 2. Pathophysiology of Motor & NMS 3. Relation To Disease Course 4. NMS in motor subtypes 5. Motor & NMS fluctuation 6. Treatment of Motor & NMS: links Parkinson’s Disease • PD prevalence 1 % of populations older than 65 years (Abbas et al., 2018) • From 1990 to 2015, the number of with PD patients doubled to over 6 million, and double again to over 12 million by 2040 (Dorsey et al, 2018) • Aging populations, increasing longevity, decreasing smoking rates, and the by- products of industrialization MDS Clinical Diagnostic Criteria for PD Postuma et al 2015 MDS Clinical Diagnostic Criteria for PD Postuma et al 2015 Non-motor Symptoms of PD • Neuropsychiatric symptoms • Autonomic dysfunction • Depression up to 50-70 % • Drooling • Anxiety up to 60 % • Orthostatic hypotension 30–58% • Apathy 60 % • Urinary dysfunction • Psychosis up to 40% • Erectile dysfunction • Impulse control and related disorders • Gastrointestinal dysfunction 25–67% • Dementia, 24% to 40%. • Excessive sweating • Cognitive impairment 20-25% (other • Others than dementia mainly mild cognitive impairment) • Pain 30–85% • Fatigue 50% • Disorders of sleep and wakefulness • Olfactory dysfunction 90% • • Sleep fragmentation and insomnia Ophthalmologic dysfunction • Rapid eye movement sleep behavior disorder 65 % • Excessive daytime sleepiness Pathophysiology of Motor & NMS Neuropathology of PD: Motor Symptoms Two major pathologic processes: (a) premature selective loss of dopamine neurons: 30–70% cell loss ⇢ motor symptoms. (b) the accumulation of Lewy bodies, composed of α-synuclein Poewe, W. et al. (2017) Parkinson disease Nat. Rev. Dis. Primers doi:10.1038/nrdp.2017.13 Neuropathological staging of Lewy body disease Jellinger Neural Transmission 2019 Kosaka LBD Braak PD stage Anatomical distribution of Lewy bodies stage Medulla oblongata: lesions in the dorsal IX/X motor nucleus and/or 1 intermediate reticular zone, enteric and peripheral autonomic nervous system, spinal cord, and anterior olfactory nucleus. Brain stem– predomine Medulla oblongata and pontine tegmentum: pathology of stage 1 plus lesions nt type 2 in the caudal raphe nuclei, gigantocellular reticular nucleus, and ceruleus- subceruleus complex; involvement of the olfactory bulb. Midbrain: pathology of stage 2 plus midbrain lesions, particularly in the pars 3 compacta of the substantia nigra. Transitional Basal prosencephalon and mesocortex: pathology of stage 3 plus (limbic) 4 prosencephalic lesions. Cortical involvement confined to temporal mesocortex type (transentorhinal region) and allocortex (CA2 plexus). Neocortex: pathology of stage 4 plus lesions in high-order sensory association 5 areas of the neocortex and prefrontal neocortex. Diffuse Advanced neocortex: pathology of stage 5 plus lesions in first-order sensory cortical association areas of the neocortex and premotor areas; occasionally, mild type 6 changes in primary sensory areas and the primary motor field. Metabolic and functional abnormalities already occur in brain regions in early stages of PD that are not accompanied by Lewy pathology. Motor cortex circuitry activity changes in Parkinson disease Poewe, W. et al. (2017) Parkinson disease Nat. Rev. Dis. Primers doi:10.1038/nrdp.2017.13 Macpherson & Hikida et al 2019 Regions and neurotransmitters implicated in NMSs of PD NMS Implicated Regions Neurotransmitter Hyposmia Olfactory bulb and amygdale, perirhinal cortex Substance P. Ach colour vision retina Dopamine (DA) Hallucinations Cortex, Amygdala, hippocampus DA Pain Basal Ganglia, locus coeruleus, raphe nucleus amygdale DA 5-HT , NA and thalamus, spinal cord,epidermal nerves Anxiety LC, Basal ganglia DA, NA Depression LC, Limbic and cortical areas DA, NA Cognitive dysfunction Frontal cortex, Nucleus basalis Meynert DA Dementia Temporal, parietal and Occipital lobes, Nucleus basalis Ach Meynert Sleep Disturbance Hypothalamus and reticular formation, Diencephalon, Hypocretin, DA, 5-HT PPN, gigantocellular reticular and lateral dorsal tegmental nuclei, coeruleus–subcoeruleus complex, and DRN Bladder hyper- basal ganglia, DMV, prefrontal anterior cingulate and DA, Ach reflexia, sexual insular cortex, and the sacral spinal dorsal horn, pelvic dysfunction plexus Orthostatic Adrenal glands, DVN, nucleus ambiguus, caudal raphe NA Hypotension nuclei, ventromedial medulla, cardiac sympathetic nerves GIT, constipation DMV, Intermediate column of spinal cord, dorsal root, Sympathetic and parasympathetic ganglia (paravertebral, celiac), Gastroesophagial/enteric plexus Dysphagia Brainstem (PPN) and /or the esophageal myenteric plexus, Cholinergic SMA Titova et al 2017 Conclusion: PD is associated with BAEP and VEMP abnormalities that are correlated to the motor and some non- motor clinical characteristics. These abnormalities could be considered as potential electrophysiological biomarkers for brainstem dysfunction and its associated motor and non-motor features. Shalash et al Front Neurol 2017 Motor & Nonmotor Features Relation To Disease Course Clinical symptoms associated with PD Course Poewe, W. et al. (2017) Parkinson disease Nat. Rev. Dis. Primers doi:10.1038/nrdp.2017.13 Schapira et al 2018 Goldman et al 2020 Motor & NMS as biomarkers tackling for PD pathological changes Picillo et al 2017 Non-motor symptoms in the premotor PD Todorova et al 2013 Commonly associated—with reasonable evidence base Hyposmia (usually of late onset 10 times increase in risk of developing PD;+abnormal and idiopathic) DATScan—43% develop motor PD in 4 years Rapid eye movement sleep 25–40% risk of developing a synucleinopathy at 5 years; behaviour disorder 40–65% risk of developing a synucleinopathy at 10 years Constipation 2.7–4.5 times increased risk of PD Depression 2.4 times increased risk of developing PD Described associations Excessive daytime sleepiness 3.3 times increased risk of PD Fatigue (a sense of exhaustion as In 45%—a premotor symptom opposed to sleepiness) Pain (often unilateral and in 34% increased risk of PD affected limb) Erectile dysfunction 3.8 times increased risk of PD Postuma et al 2015 MDS Clinical Diagnostic Criteria for Prodromal PD • Frequency of NMS increased along with the disease duration and severity • NMS are correlated with motor severity • Motor and NMSs are correlated to patients QoL Barone et al PRIAMO 2009 Shalash et al 2017 Martinez-Martin MDJ 2011 Leonardi et al PRD 2012 Marinus et al, Lancet neurology 2018 Motor & NMS Subtypes Motor & NMS Subtypes Motor Types: 1. Tremor dominant type 2. Non-tremor dominant type 1. Akinetic rigid type 2. Postural instability Gait disorder type 3. Mixed or indeterminate phenotype Tremor-dominant PD is often associated with a slower rate of progression and less functional disability than non-tremor-dominant PD. Kalia, & Lang 2015 Non-motor Subtypes of PD a) Cognitive subtype in PD. b) Apathy subtype in drug naïve PD . c) Depression/Anxiety subtypes in PD. 1. Anxious depressed subtype 2. Depressed subtype 3. Anxious subtype d) REM sleep behavior disorder subtype in PD. e) Lower limb pain subtype in PD. f) Park weight subtype (combined with olfactory dysfunction & dyskinesia) 1. Phenotype A - More severe loss of olfaction (anosmia) 2. Phenotype B - Less loss of olfaction (hyposmia) Sauerbier et al, 2015 Clinical description of NMS-dominant phenotypic variants Marras & Chaudhuri MDJ 2016 Nonmotor Defining features of Ancillary features domain subtype Cognitive Early and dominant Older age (≥72 years) cognitive dysfunction Non-tremor-dominant motor phenotype associated with falls Poor semantic fluency score (<20) Lower pentagon copying score (0 < 1 < 2) Microtubule-associated protein tau (MAPT) H1/H1 genotype possibly a biomarker Neuro- Anxiety/depression: psychiatric A. Anxious-depressed B. Depressed Postural instability gait disturbance C. Anxious Younger age Marked motor fluctuations Apathetic Relatively severe motor symptoms (out of proportion to disease duration) Concomitant depression Lower cognitive status Fatigue Good response to dopaminergic drugs Sleep REM sleep behavior Symmetric disease onset disorder Increased periods of freezing Autonomic dysfunction Prone to higher prevalence and severity of orthostatic symptoms Higher rate of depression Visual hallucinations, Impairment of color vision Increased frequency of falls Olfactory A. Severe loss of Dyskinesias olfaction (anosmia) Progressive weight loss B. Moderate hyposmia No further weight loss with disease progression Autonomic Urinary dysfunction Early noradrenergic deficit- Postural hypotension NMS in Motor subtypes • Non-tremor-dominant subtypes have consistently been shown to have a broader array of NMS, more early autonomic features, Later more cognitive disturbance. • Motor aspects of PD such as falls may also be intricately linked to specific NMSs of PD such as cognition. • PIGD & ART may be more prone to mood disorders. • Non-tremor-dominant PD represents a more advanced and diffuse neurodegeneration than tremor-dominant PD, encompassing dopaminergic and nondopaminergic as well as synuclein and nonsynuclein (Abeta) pathologies. • NMS as biomarker for disease progression. Patients with the diffuse/malignant phenotype were more likely to have mild cognitive impairment, orthostatic hypotension, and RBD at baseline (Fereshtehnejad et al 2015)/ Marras & Chaudhuri MDJ 2016 Marras & Chaudhuri
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