Download - Parkinsonism & Alzheimer's disease
History & epidemiology
Anatomy & physiology
Pathology of Parkinsonism
Clinical features & diagnosis of Parkinsonism
Management of Parkinsonism
Pathology of Alzheimer’s disease
Clinical Feature & Diagnosis of Alzheimer’s
- Introduction and Conclusion
Management Of Alzheimer’s Disease
Neurodegenerative diseases
Parkinson’s DiseaseAlzheimer’s DiseaseHuntington’s DiseaseAmyotrophic lateral sclerosis (ALS)Spinocerebellar Ataxia
PARKINSON’S DISEASENeurodegenerative disorder which effects the extrapyramidal system
ALZHEIMER’S DISEASE
Neurodegenerative disease affecting the cerebral cortex & hippocampus
Case Presentation
Surendra Kshetri
Began to experience tremors and stiffness of his left arm while he walked
Changes in his posture and unusual movements of his left arm.
Sleep disturbances Gait problems- stooped posture Symptoms gradually worsened with time
Case 1Mr Poudel, 65 years old man, a retired university professor……
Case 2Mrs Ellis Grey, 76 years old woman
Lived alone for several years Brought to the neurological department,
MTH by her daughter, memory impairment General and neurological examinations-
normal Speech – highly anomic , paraphasic Unable to provide birth month, year, current
year Cognitive domain – below average
HISTORY & EPIDEMIOLOGY
History of Parkinson’s Disease
First clear medical description: James
Parkinson in An Essay on the Shaking Palsy (1817)
Jean-Martin Charcot- Influential in refining and expanding this
early description & in disseminating information internationally
Named the disorder as Parkinson’s disease
William Gowers- Slight male predominance of the disorder, joint deformities typical of the disease.
Richer and Meige Babinski - Babinski sign Brissaud Greenfield and Bosanquet- Clear delineation of
the brain stem lesions
Epidemiology of Parkinson’s disease
Prevalence Crude prevalence -15 per 100,000 population
(China) to 657 (Argentina)
Incidence Crude annual incidence rates- 1.5 per 100,000
population (China) in 1986 to 14.8 (Finland) through 1968 to 1970.
Gender differences Slightly more common in men than in women Male to female ratio- 1.2:1 to 1.5:1
Geographic distribution Crude prevalence
• China - 15 per 100,000 • India - 328 per 100,000 • Mississippi, USA - 131 per 100,000 • Argentina - 657 per 100,000
Ethnic distribution
White people in Europe and North America have a higher prevalence, around 100 to 350 per 100,000 population.
Asians in Japan & China and Africans have lower rates, around one-fifth to one-tenth of those in whites.
Age Distribution
Less common before 50 years of age & increases steadily with age thereafter up to the ninth decade.
~1 in every 200 persons aged 60–69 had PD in the United States (US) and Western Europe.
For people in their 70’s, this increased to ~1 person with PD in every 100 people,
For people in their 80’s, ~1 in every 35 had PD
History of Alzheimer's disease
Ancient Greek and Roman
philosophers and physicians associated old age with increasing dementia.
Alois Alzheimer- Identified the first case of what became known as Alzheimer's disease
Emil Kraepelin- First described as a distinctive disease
Epidemiology of Alzheimer’s disease
Prevalance: Globally estimated number:
• 2013 - 44 million. • By 2030 - 76 million • By 2050 - 135 million
In the Asia Pacific Region, will increase from 23 million in 2015 to almost 71 million by 2050.
By 2050 more than half of the people with dementia worldwide (135 million) will live in this region.
Incidence
“Every four seconds, a new case of dementia occurs somewhere in the world.”
Cohort longitudinal studies provide rates between 10 and 15 per thousand.
Advancing age -primary risk factor Women- higher risk of developing AD particularly
in the population older than 85
Basal Ganglia
GRAY MATTER(COLLECTION)
•CORPOUS STRATUM•AMYGDALOID •CLAUSTRUM•SUBTHALAMIC NUCLEI•SUBSTANTIA NIGRA
Corpus striatum
Lentiformnucleus
putamen
Globus pallidus
Caudatenucleus
caudate
putamen
Globus pallidus
Cognition(caudate circuit) eg:A person seeing a lion approach ????
Executes Learned Patterns of Motor Activity
FUNCTIONS
eg:writing of letters of the alphabet. hammering nails, shooting a basketball through a hoop,
Control of movement
Nigrostriatal
pathway
Indirectpathway
Direct Pathway
Planning of movement
GlobuspallidusInternal
&substantianigra parsreticulata
Globuspallidusexternal
Striatum
Cortex
Subthalamic nucleus
Thalamus
Motor Cortex
BasalGanglia
Direct Pathway(decreases inhibition of thalam
us)
Functional organization of the Basal Ganglia
Excitatory
Inhibitory
Indire
ctpa
thway
Direct
pathway
Indi
rect
Pat
hway
(incr
ease
s in
hibi
tion
of th
alam
us)
Substantianigra parscompacta
D1D2
PATHOLOGY OF PARKINSON’S DISEASE
Parkinsonism is a clinical syndrome characterized by motor symptoms like bradykinesia,tremor and rigidity.
Classification of the Parkinsonism Primary parkinsonism (Parkinson’s disease)
• Sporadic• Genetic
Secondary parkinsonism (environmental etiology)• Drugs (Antipsychotic medications, Reserpine,
Tetrabenazine)• Postencephalitic• Toxins: MPTP, cyanide• Heavy metal (iron, manganese)• Vascular• Brain tumors• Head trauma• Normal-pressure hydrocephalus
Parkinsonism-plus syndromes• Progressive supranuclear palsy• Multiple system atrophy• Cortical-basal ganglionic degeneration• Progressive pallidal atrophy• Diffuse Lewy body disease (DLBD
Etiology
Idiopathic Genetic
Parkinson’s disease
Results due to reduction in the striatal dopamine content due to damage of nigrostriatal pathway.
Idiopathic
Ageing Usual occurrence in late middle age,
and increases in its prevalence at older ages
Loss of striatal dopamine and dopamine of cells in the SN with age
Genetic factors
PD may be multifactorial in etiology with genetic contributions
The younger the age of symptom onset, the more likely genetic factors play a dominant role
At least ten single gene mutations identified
Mutations in gene coding Alpha synuclein and LRRK2 (leucine rich repeat kinase 2) - Autosomal dominant PD
Mutations in gene coding Parkin,DJ-1and PINK1- Autosomal recessive PD
Pathogenesis Three major mechanisms in dopaminergic neuron
loss
Mitochondrial dysfunction
Oxidative and nitrosative stress
Ubiquitin proteosome system dysfunction
Morphology Macroscopic:
Pallor or depigmentation of neurons in substantia nigra and locus ceruleus
Microscopic
Loss of pigmented ,catecholaminergic neurons Intraneuronal Lewy bodies within the
pigmented neurons of the substantia nigra. Lewy bodies are cytoplasmic eosinophilic round
to elongated inclusions that often have a dense core sourrounded by halo.
Lewy bodies are composed of Alpha –synuclein
NORMAL PARKINSONS DISEASE
Clinical Features & Diagnosis of Parkinsonism
Motor symptomsNon-motor symptoms
Motor symptoms
Characterized by Four cardinal features : Bradykinesia (or Hypokinesia ) Tremor at rest Rigidity Postural instability
Bradykinesia
Slowness of movements with a progressive loss of amplitude or speed.
Difficulty with planning, initiation and execution of movements.
Clinical Manifestations of Bradykinesia Difficulties with tasks requiring fine motor control: Loss of spontaneous movements and gesturing Hypomimia (decreased facial expression)
MASK LIKE FACE Decreased spontaneous blinking Hypophonia Micrographia Sialorrhoea
Why Bradykinesia in Parkinsonism??
“Driving while stepping on the brakes”
Rest Tremor
Tremor : Rhythmical & involuntary shaking, trembling or quivering movements of the muscles.
Rest tremor ( 4 - 6 Hertz) : Maximal when the limb is at rest Disappears with voluntary movement and sleep
Alternating contraction of agonist and antagonist muscles at a rapid pace
Usually Unilateral at onset
Involves the hands, lips, chin, jaw and legs . “Pill-rolling” Tremor:
Rigidity Increased muscle tone felt during examination by
passive movement Both the agonist and antagonist muscles are
involved Rigidity :
Cogwheel rigidity Lead-pipe rigidity
Postural instability Stooped Posture UNIVERSAL FLEXION :
Extreme neck flexion , Extreme anterior truncal flexion (camptocormia) &
Flexion of elbows and knees.
Festinating / Shuffling Gait:i) Difficulty to initiate walkingii) Shortened strideiii) Reduced arm swingiv) Rapid small steps (shuffling)
RUNNING AFTER THE CENTRE OF GRAVITY
Freezing phenomenon
Non-motor symptoms Neuropsychiatric
Depression & Anxiety disorders Apathy
Autonomic disturbance (dysautonomia) Urinary dysfunction Constipation
Sensory symptoms
pain Restless legs syndrome Olfactory dysfunction
Sleep disturbances REM behavior disorder excessive day time drowsiness
Cognitive impairment Dementia : In >80% of patients after 20 years of
disease
Diagnosis of Parkinsonism
Diagnosis is primarily clinical, based on history and examination
Confirmatory diagnosis : Histological demonstration of the intraneuronal Lewy bodies on autopsy
CT scan & MRI exclude other causes.
Examination of signs Bradykinesia :
Ask patient to do repetitive movements as quickly and as possible
• opening and closing the hand• tapping thumb and index fingers• or tapping the foot on the ground
Rest tremor: Differentiate from the intentional tremor seen in
cerebellar disease Best observed while the patient is focused on a
particular mental task.
Rigidity: Increased resistance to passive movements
Postural stability The “Pull test” is performed in order to assess
postural stability
UK Parkinson’s Disease Society Brain Bank’s clinical criteria for the diagnosis of probable Parkinson’s disease
Step 1 Bradykinesia At least one of the following criteria:
• Rigidity• Rest tremor (4–6 Hz )• Postural instability (not caused by primary
visual, vestibular, cerebellar or proprioceptive dysfunction)
Step 2 Exclude other causes of parkinsonism
Step 3 At least three of the following supportive
(prospective) criteria:• Unilateral onset• Rest tremor• Progressive disorder• Persistent asymmetry• Severe levodopa induced chorea (dyskinesia)• Clinical course of 10 years or more
Management of Parkinsonism
No definite cureRelief of cardinal signs- rigidity, tremor , &
akinesiaCorrection of mood changesTreatment of other symptoms such as
depression,sleep disturbance .Treatment of cause when possible
Management
General Measures
Drug Therapy Surgery
1.General Measures
Physiotherapy
Speech therapy
Dietary controls
Physiotherapy
Helps to reduce rigidity Corrects abnormal posture Improves walking , turning
& balance
Speech therapy
Helpful in patients where dysarthria and dysphonia interferes communication
Dietary controls
Include high-fiber diet Choose foods low in saturated
fat and cholesterol. Avoid high protein diet
Drug Therapy
Does not prevent disease progression but improves quality of lifeDrug therapy
Dopaminergic
activity
Cholinergic activity
Classification of drugs
Drugs affecting Dopaminergic system
Dopamine precursors: Levodopa Peripheral decarboxylase inhibitors: Carbidopa MAO-B Inhibitors: Selegiline COMT Inhibitors: Tolcapone Dopamine releasing drugs: Amantadine Dopamine receptor agonists: Bromocriptine
Drugs affecting Cholinergic system
Central anticholinergic: Trihexyphenidyl Antihistaminics: Promethazine
Levodopa
‘Gold-standard' treatment for Parkinson's.. Therapautic benefit is nearly complete in early stages
but declines as disease advances1-2% cross BBBImproves cardinal signs- tremor, rigidity and akinesia.
Side EffectsAt the initiation of therapy
Nausea, vomiting, hypotension, cardiac arrhythmias, angina, taste alteration.
Long-term complications Dyskinesias Behavioural effects: hallucination, psychosis On –off effect Wearing-off effect
LEVODOPA + CARBIDOPA
Surgery
Deep Brain Stimulation
Thalamotomy
Pallidotomy
Neural Transplantation
Treatment approaches to newly diagnosed PD
ALZHEIMER’S DISEASE
ALZHEIMER’S DISEASE Neurodegenerative disorder Most common form of dementia in the elderly
Aβ Peptide
AETIOLOGY Old age, Family history
Diabetes Mellitus Hypertension, Elevated cholesterol, Low levels
of exercise
Genetic mutation (chromosome 21/14/1/19)
Sequential cleavage by β-secretase and ɣ-secretase
Formation of Aβ peptide (Aβ40 / Aβ42)
Aβ peptide is prone to aggregation•Initially to oligomers•Then to large aggregates and fibrils
PATHOGENESIS
Aβ peptide deposition
Direct Neurotoxicity Synaptic Dysfunction Inflammatory
Response
•Blocks long term potentiation•Changes membrane properties
(by microglia and astrocytes) •secretion of mediators•oxidative injury•alterations in Tau phosphorylation
Biochemically,•Decrease in cortical levels of Ach, choline acetyltransferase•Decrease in cholinergic receptors•Also NA and serotonin depletion
MORPHOLOGYGROSS Cortical atrophy
Widening of cerebral sulci Compensatory ventricular enlargement
MORPHOLOGY
MICROSCOPIC Senile (neuritic) plaque:
Spherical collection dilated, tortuous,
neuritic processes Amyloid core with Aβ peptides Microglia and Astrocytes at periphery Visualized with silver stain,Congo red Hippocampus, amygdala & neocortex
Diffuse Plaques
MORPHOLOGY Neurofibrillary Tangles
Bundles of filaments in cytoplasm of neurons Common in cortical neurons ,hippocampus . Ultrastructurally, composed of paired
and some straight filaments
Hyperphosphorylated tau proteins, MAP2
Cerebral Amyloid Angiopathy Neuritic plaques in the walls
of small blood vessels in the brain Granulovacuolar degeneration
Small, clear intraneuronal cytoplasmic
vacuoles
Hirano bodies Elongated, glassy, eosinophilic bodies Major component- actin
CLINICAL FEATURES AND DIAGNOSIS OF
ALZHEIMER’S DISEASE
DEFINITION
It is a chronic neurodegenerative disease that usually starts slowly and gets worse over time.
It most often begins in people over 65 years of age, although 4% to 5% of cases are early-onset Alzheimer's which begin before this.
The average life expectancy following diagnosis is three to nine years.
The most common cause of death of people with Alzheimer’s Disease is Aspiration Pneumonia.
AREAS AFFECTED
STAGES OF PROGRESSION
Some experts use a simple three-phase model (early, moderate and late)
The most common system, developed by Dr. Barry Reisberg of New York University, breaks the progression of Alzheimer’s disease into seven stages
THE 7 – STAGE SYSTEM Stage 1: No ImpairmentMemory problems or other symptoms of dementia are absent
Stage 2: Very Mild Decline
Minor memory problems or lose things around the houseNormal-aged forgetfulness is probably the most satisfactory terminology
Stage 3: Mild DeclineRepeat statements and questions over and overOccasionally misplace possessionsDifficulty in remembering names of people and everyday objects
Stage 4: Moderate DeclineHave difficulty with simple arithmeticForget details about life historiesHave poor short term memory
Stage 5: Moderately Severe Decline
Increasing confusion and disorientation Memory problems will get worseDifficulty in dressing properlyDelusionsObsessive, repetitive or impulsive behaviorProblems with speech or language
Stage 6: Severe DeclineMajor personality changesProblems with eyesightDifficulty changing position or moving around without assistanceLoss of bowel and bladder controlWandering
Stage 7: Very Severe Decline
Need assistance with all activities of daily livingLose their ability to swallowGradual loss of speechStart to neglect their personal hygiene
DIAGNOSIS
IMPORTANCE OF EARLY DIAGNOSIS A better chance of benefiting from treatment
More time to plan for the future
Increased chances of participating in clinical drug trials
An opportunity to participate in decisions about care, transportation, living options, financial and legal matters
Benefit from care and support services, making it easier for them and their family
CONDITIONS THAT MIMIC EARLY
ALZHEIMER’S DISEASE Central nervous system and other degenerative
disorders
Metabolic ailments
Substance-induced conditions
Psychological factors
Infections
There is no specific test to prove that a person has Alzheimer’s
A diagnosis is made through a complete assessment that considers all possible causes
1. Medical History2. Physical Exam3. Neurological Exam4. Mental Status Tests5. Brain Imaging
MENTAL STATUS TESTS Mini-mental state exam (MMSE) During the MMSE, a health professional asks the patient series of questions designed to test a range of everyday mental skills.
Mini-cog During the mini-cog, a person is asked to complete two tasks: Remember and repeat the names of three common objects
after a few minutes Draw the face of a clock showing all 12 numbers in the right
places and a time specified by the examiner The results of this brief test can help a physician determine if
further evaluation is needed.
BRAIN IMAGING
Structural imaging with MRI or CT.
Primarily done to rule out other conditions that may cause symptoms similar to Alzheimer's
FUTURE OF DIAGNOSIS
Scientists are investigating a number of disease markers and diagnostic tests, such as genes, disease-related proteins and imaging procedures, which may accurately and reliably indicate whether you have Alzheimer's disease and how much the disease has progressed.
However, more research on these tests is necessary.
MANAGEMENT OF ALZHEIMER’S DISEASE
There is no known cure for Alzheimer's disease - the death of brain cells in the dementia cannot be halted or reversed
Management of Alzheimer’s Disease
PHARMACOLOGICAL
NON PHARMACOLOGICAL
Managecognitive symptoms
Manage secondary symptoms
Modification&Support
patient/family
Increased quality
of life for
patient
1.
2.
3.
Pharmacologic Options Cognitive enhancers
2 classes
• Donepezil• Galantamine• Rivastigmine• Tacrine [not used due to frequent side
effects and Hepatotoxicity]
Cholinesterase inhibitors
(ChEIs)
• MemantineNMDA-
receptor antagonist
Mechanism of action: Cholinesterase inhibitors
Blocks acetylcholinesterase in Brain
Increase in Ach level in Brain
Increased communication between the nerve cells that use acetylcholine as a chemical messenger
Improve the symptoms of Alzheimer's disease
Mechanism of action : Memantine
Blocks Glutamate ;released in excessive amounts when brain cells are damaged by Alzheimer's disease
Better tolerated than ChEIs Used either to replace or
supplement ChEIs
Cholinesterase inhibitors(Donepezil, Galantamine, Rivastigmine)
NMDA-receptor antagonist(Memantine)
• Nausea• Vomiting• Diarrhea• Weight loss• Loss of appetite• Muscle weakness• Vivid dreams/nightmares
(donepezil)
• Dizziness• Headache• Constipation• Confusion
.
Common Side Effects
Treatment
Agent Starting Dose
Titration Schedule
Metabolism
Donepezil 5 mg OD by 5 mg every 4 weeks
hepatic
Galantamine 4 mg BD by 4 mg every 4 weeks
hepatic
Rivastigmine 1.5 mg BD by 1.5 mg e every 4 4 weeks
Non hepatic
Memantine 5 mg OD by 5 mg e every weeks
Non hepatic
• Mild/Moderate AD: Cholinesterase inhibitors Moderate/Severe
• Memantine
Managing Secondary symptoms
Mood stabilizers[anticonvulsant] may be effective in some patients Carbamazepine
Antidepressants are generally well tolerated in persons with dementia like Citalopram Fluoxetine
The antipsychotics, especially the second generation agents, are
the most commonly prescribed medications like Aripiprazole Olanzapine
NON PHARMACOLOGIC
•Life style and Diet•Regular appointments•Communication with family, caregivers•Environmental modification•Attention to safety
Advice & Life style A caregiver; to meet their
requirements. Remove excess furniture so
they can get around more easily.
Install handrails on the stairs and in the bathroom.
A 30 minute walk each day Reduce the number of mirrors:
They may find images in mirrors confusing or frightening.
Diet
Omega 3 Fatty Acids ; help to improve cognitive abilities,
Nutritious diet is also important with high calorie drinks like milkshakes.
The patient should not drink caffeine or alcoholic beverages.
New Treatment For A.D (Under trial)
By Purdue University researcher, The molecule, called a beta-secretase inhibitor,
prevents amyloid plaque formation in the brain
This plaque formation creates fibrous clumps of toxic proteins that are believed to cause the devastating symptoms of Alzheimer's.
2. NIC5-15, by Mount Sinai School of Medicine
effective treatment to stabilize cognitive performance
CONCLUSION!
REVIEW AND
PARKINSONISM
CASE 1 Mr Poudel, 65 years old
man Difficulty in walking and
speaking , tremor in left hand and leg
Sleep disturbances
Rx: Levodopa 250 mg+ carbidopa 25mg
Medication reduced his symptoms but did not stop the disease from getting worst.
His loss of mobility and speech impairment limited his social interactions.
He and his wife also have had to give up many of their retirement travel plans.
ALZHEIMER’S
Case2
Mrs Ellis Grey, 76 years old woman
Anomic and paraphasic speech
Cognitive domain was below average
On neurological examination Unable to focus on the nurse’s questions. Knew her own identity, unsure of her exact
location and current date Mild cognitive impairment Mild anomic aphasia
No thyroid disease & vitamin deficiencies MRI
Diffuse & posteriorly predominant hippocampal and cortical atrophy
RX :Tab DonepezilMental excercises
Alzheimer’s Disease