PARKINSONS DISEASE PATHOGENESIS A DEEP INSIGHT BY VISHNU

PARKINSON’S DISEASE PATHOGENESIS : A DEEP INSIGHT BY: VISHNU. R. NAIR, 4 TH YEAR PHARM. D, NATIONAL COLLEGE OF PHARMACY (NCP)

GENERAL INTRODUCTION : • Defined as “CHRONIC, PROGRESSIVE DISEASE of NERVOUS SYSTEM, characterized by cardinal features of RIGIDITY, BRADYKINESIA, TREMOR and POSTURAL INSTABILITY” • First described by a London Physician, Dr. James Parkinson, on 1817, in his work : “ AN ESSAY ON THE SHAKING PALSY”………

EPIDEMIOLOGICAL STATISTICS : • Affects approx. 1% of individuals > 60 yrs. of age • Incidence is estimated at 4. 5 -21 cases/ 1, 000 population/ year • Incidence and prevalence increases with age • Average of onset is approx. 60 years • 1. 5 times more common in men than in women • SEVERE HEAD INJURY & PESTICIDE EXPOSURE increases risk for PD • Smoking and caffeine consumption reduces risk for PD……………….

CAUSES / ETIOLOGY OF PARKINSONISM : 1. CORTICOBASAL DEGENERATION (CBD): - Rare type of PD, that affects mental processes, personality and behaviour - Causes Parkinson-like symptoms - Tends to affect one side of the body more than the other - Can cause “ALIEN LIMB SYNDROME” , in which the person’s arms/ legs may seem to move independently - Shows similarities with PROGRESSIVE SUPRANUCLEAR PALSY (PSP)

2. DEMENTIA WITH LEWY BODIES (DLB): - Possesses features of both PD and AD - Since DLB shares certain symptoms of dementia (memory loss, varying attention and alertness) this is often confused with AD - People with DLB Develop Parkinson-type symptoms like TREMOR, SLOW MOVEMENT, STIFFNESS, and RISK OF FALLS - LEWY BODIES: a. “Intracytoplasmic eosinophilic inclusions, found with halos” b. Contain polymerized ALPHA-SYNUCLEIN Thus PD is a SYNUCLEINOPATHY……

3. DRUG-INDUCED PARKINSONISM: - A number of people develop PD after taking certain medications - Such medications include: A. CLOZAPINE (CLOZARIL) B. QUETIAPINE (SEROQUEL) C. OLANZAPINE (ZYPREXA) D. RISPERIDONE (RISPERDAL) E. PROCHLORPERAZINE (STEMETIL) F. METOCLOPRAMIDE (MAXALON) G. CINNARIZINE (STUGERON) H. FLUNARIZINE (SIBELIUM)………. .

4. VASCULAR (ARTERISCLEROTIC) PARKINSONISM: - Several small strokes in the part of the brain that receives information about positions and movement usually trigger PARKINSON-TYPE SYMPTOMS like RIGIDITY, SLOWNESS, WALKING WITH SHORT SHUFFLING STEPS, SPEECH & MEMORY / THINKING PROBLEMS - Vascular Parkinsonism can be difficult to distinguish from PD - Affects legs more than upper part of the body 5. GENETIC CAUSES : - Mutation of the following loci are validated causes of FAMILIAL PD: a. SNCA b. LRRK 2 c. PRKN d. DJ 1 e. PINK 1 f. ATP 13 A 2

- Genetic causes in PD are very important when the disease begins at/ before 50 years of age 6. ENVIRONMENTAL CAUSES : - Include: A. LIVING IN A RURAL ENVIRONMENT B. WELL WATER CONSUMPTION C. PROXIMITY TO INDUTRIAL PLANTS/ QUARRIES D. PESTICIDE EXPOSURE (increases risk by 80%) E. FUNGICIDE EXPOSURE (Maneb/ Mancozeb) F. WEED KILLER EXPOSURE (PARAQUAT) G. MANGANESE H. METHANOL

- MPTP (1 -methyl, 4 -phenyl, 1, 2, 3, 6, -tetrahydropyridine) crosses BBB Oxidized to 1 -methyl-4 -phenyl-pyridinium (MPP+) by MAO-B Accumulates in mitochondria interferes with brain function 7. OXIDATION HYPOTHESIS : - According to this hypothesis : “ FREE RADICAL DAMAGE , RESULTING FROM DOPAMINE OXIDATIVE METABOLISM, PLAYS A ROLE IN DEVELOPMENT OR PROGRESSION OF PARKINSONISM” - In normal cases DA Oxidized by MAO to H 202 Cleared rapidly by GLUTATHIONE - If there is lacking of GLUTATHIONE H 202 forms highly reactive OH- radicals causes LIPID PEROXIDATION & CELL DAMAGE……. .

NORMAL PHYSIOLOGY & PATHOPHYSIOLOGY 1. NORMAL PHYSIOLOGY : - BASAL GANGLIA id associated with: I. NUCLEUS CAUDATUS II. THALAMUS III. NUCLEUS RUBER IV. SUBSTANTIA NIGRA V. NUCLEUS SUBTHALAMUS VI. GLOBUS PALLIDUS VII. PUTAMEN - Main input structure of BASAL GANGLIA is STRIATUM - INPUT Received from all parts of cerebral cortex & substantia nigra pars compacta

- OUTPUT By GLOBUS PALLIDUS and SUBSTANTIA NIGRA pars reticulate - OUTPUT transmitted towards thalamus goes back to the cortex - Functions of BASAL GANGLIA: a. Role in planning and programming of movement , by selecting and inhibiting specific motor synergies b. Regulation of cognitive processes (especially caudate nucleus) c. Awareness of body orientation in space d. Ability to adapt to behaviour as task requirements change e. Motivation

2. PATHOPHYSIOLOGY: - ANTIPSYCHOTICS, ENCEPHALITIS / OTHER CAUSES Affects substantia nigra destruction of DA producing neurons within basal ganglia occurs reduced amount of available striatal DA - Reduced levels of DA reduces inhibitory effects on ACETYLCHOLINE Increases Ach levels increases EXCITATTORY EFFECTS of Ach – imbalance between INHIBITORY & EXCITATORY effects PD occurs Patient finds difficulty in controlling and initiating voluntary movements 3. CHIEF PATHOLOGICAL FEATURES OF PD: - Degeneration of DA neurons that produce DA - Loss of MELANIN containing neurons produce characteristic changes in depigmentation - Formation of LEWY BODIES - Loss of DA results in akinesia , rigidity and bradykinesia

CLINICAL PRESENTATION : • RIGIDITY • BRADYKINESIA • TREMOR • POSTURAL INSTABILITY • MOTOR ABNORMALITIES • GAIT • SENSATION • SPEECH, VOICE AND SWALLOWING MANIFESTATIONS • COGNITIVE FUNCTION AND BEHAVIOUR • ANS SYMPTOMS • CARDIOPULMONARY MANIFESTATIONS

1. RIGIDITY: - Clinical hallmark of PD - Defined as “INCREASED RESISTANCE TO PASSIVVE MOTION” - Felt uniformly in agonist, and antagonist muscles in both directions - Consists of 2 types: A. COG-WHEEL RIGIDITY: JJerky resistance to passive movement JMuscles alternatively tense and relax B. LEAD PIPE RIGIDITY: JNo fluctuations JIncreased sustained resistance to passive movements - Prolonged rigidity reduces ROM Causes POSTURAL DEFORMITY….

2. BRADYKINESIA : - “Slowness and difficulty in maintaining movements” - Movements are typically reduced in speed, range and amplitude - Movements can be influenced by rigidity and depression - Most disabling symptom of PD 3. TREMOR: - “Involuntary oscillation of body part, occurring at a slow frequency of 4 -6 Hz” - PARKINSONIAN TREMOR Present at rest and disappears with voluntary movements - Also known as “RESTING TREMOR” - PILL ROLLING TREMOR occurs at hand - RESTING TUMORS may also be seen in forearm, jaw/ tongue

- Lower limb tremors are common when the patient lies SUPINE - POSTURAL TREMOR Occurs in head & trunk , when patient tries to maintain upright position against gravity - Completely diminish during sleep 4. POSTURAL INSTABILITY: - Narrowing of base of support - Increased difficulty during dynamic activities like walking, running, and functional reach - Contributing factors include: A. RIGIDITY B. REDUCED MUSCLE TORQUE PRODUCTION C. LOSS OF ROM D. WEAKNESS

- Extensor muscles of trunk show greater weakness than flexor muscles causes a flexed , stooped posture , with increased flexion of neck, trunk, hips and knees 5. MOTOR ABNORMALITIES: - “START HESITATION” : Common, especially on PD progression - “MICROGRAPHIA” : Abnormally small handwriting, that is difficult to read - FREEZING EPISODES - “HYPOMIMIA” : Reduced face expressiveness (masked face) - Mental fatigue - Loss of motivation - Learning deficits

6. GAIT: - Abnormal stooped posture , characterized by a progressive reduction in speed, with shortening of strides - Gait is of 2 types: A. ANTEROPULSIVE GAIT (FORWARD GAIT) B. RETROPULSIVE GAIT (BACKWARD GAIT) - Some patients can stop only when they come in contact with an object/wall - Also associated with toe walking and postural instability………………. .

7. SENSATION : - No primary sensory losses - Paresthesias - Pain - Numbness - Tingling - Coldness - Caused by faulty posture, muscle rigidity - AKATHISIA : “Sense of inner restlessness and need to move”…. .

8. SPEECH, VOICE & SWALLOWING MANIFESTATIONS: - DYSPHAGIA: a. “Impaired swallowing, due to rigidity, reduced mobility, and restricted ROMs” b. Leads to choking, aspiration pneumonia, impaired nutrition, with significant weight loss - Fatigue and exhaustion - SIALORRHOEA : a. Excessive drooling b. Increases salivary production and reduced swallowing - HYPOKINETIC DYSARTHRIA : a. Reduced voice volume b. Monotone/ monopitch speech c. Uncontrolled speech rate d. Hoarse, breathy and harsh speech

- Reduced mobility - Uncontrolled rate of movement of muscles controlling respiration, phonation, resonation, and articulation 9. COGNITIVE FUNCTION AND BEHAVIOUR: - DEMENTIA: a. Occurs in 20 -40% PD patients b. Loss of functions like planning, reasoning, thinking, judgement, memory and verbal fluency - BRADYPHRENIA : a. Disorder of intellectual function b. Slowing of thought and information processing - Problems in selective and shifting attention - Depression….

10. ANS MANIFESTATIONS: - DYSAUTONOMIA - THERMOREGULATORY DYSFUNCTION: a. Increased sweating b. Abnormal sensations of warmth and coldness - SEBORRHEIC DERMATITIS - Abnormally slow pupillary responses to light and pain - GI DYSFUNCTION: a. Poor motility b. Alteration in appetite c. Sialorrhoea d. Weight loss e. Constipation

- URINARY BLADDER DYSFUNCTION: a. Urinary frequency b. Urinary urgency c. Nocturia - SEXUAL DYSFUNCTION 11. CARDIOPULMONARY MANIFESTATIONS: - Orthostatic hypotension - Reduced resting BP - Reduced cardiovascular reflexes - Arrhythmias - Airway obstruction - Lung dysfunction - Reduced chest expansion - Venous pooling in lower extremities (due to reduced mobility and prolonged sitting)…………………

STAGES OF PARKINSON’S DISEASE : - According to “Hoehn and Yahr Classification of Disability” there are 5 stages of PD: A. STAGE I (MILD/EARLY DISEASE) : - Only 1 side of body is affected - Minimal/ no functional impairment B. STAGE II : - Both sides of body equally affected - Normal posture and balance C. STAGE III (MODERATE DISEASE): - Both sides of body affected - Mild imbalance when standing/ walking

D. STAGE IV (ADVANCED DISEASE ): - Both sides of body affected - Disabling inability while standing/ walking - Patient requires substantial help - Can’t live alone E. STAGE V: - Severe/ last stage of disease - Patient is restricted to bed/wheelchair, unless aided…………. .

DIAGNOSIS OF PARKINSON’S DISEASE : Diagnostic principles for PD include: A. RADIOLOGICAL STUDIES : Include: I. MRI SCAN : - Useful to exclude STROKES, TUMORS, MULTI-INFARCT STATES, HYDROCEPHALUS & LESIONS OF WILSON’S DISEASE - Used in people who : i. Lack tremor ii. Have acute/ stepwise progression of the disease/ disability iii. Less than 55 years of age

II. PET SCAN : - Useful diagnostic imaging technique - More expensive - Not readily available as SPECT - Mainly used in research III. SPECT SCAN : - In this scan different RADIOLIGANDS are used permit imaging of different components/ abnormalities within brain - Used to identify loss of DA- producing cells in brain that leads to PD - Also helps to distinguish PD from PARKINSON LIKE CONDITIONS (eg: Essential Tremor) IV. CT-SCAN : - In this scan X-rays are passed through body from different angles provides crosssection of brain used to rule out VASCULAR DISEASE & TUMORS as PD causes…. .

B. HISTOLOGICAL STUDIES: Histological studies include: - DEGENERATION of neurons containing NEUROMELANIN, especially in SUBSTANTIA NIGRA - Presence of LEWY BODIES C. LUMBAR PUNCTURE : - Considered if signs of NORMAL PRESSURE HYDROCEPHALUS(NPH) are observed (incontinence, ataxia, dementia ) - Usually if 20 ml. of CSF removed signs improve…………………. .

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