Neurodegenerative Disorder, Jan 54

Neuro-degenerative disorder
Surat Tanprawate, MD, MSc(Lond.), FRCP(T) Division of Neurology, Department of Medicine Chiang Mai university
Friday, July 8, 2011
Etymology
Neuro-degenerative disorder
NeuroAncient Greek: -(neuro-), from (neuron,sinew, tendon, cord).
DeLatin: down from, off, away from,"
Generate
c.1500: "to beget, produce"
Thus, in the strict sense of the word, neurodegeneration corresponds to any pathological condition primarily affecting neurons
Przedborski S,Vila M, Jackson-Lewis V. J. Clin Invest.111:3-10
By Denition
represent a large group of neurological disorders with heterogenous clinical and pathological expressions affecting specic subsets of neurons in specic functional anatomic systems; they arise for unknown reasons and progress in a relentless manner.
Przedborski S,Vila M, Jackson-Lewis V. J. Clin Invest.111:3-10
Neurodegenerative diseases
Classication of Neurodegenerative disorder
based on clinical features based on topography of the

predominant lesion
combination
Cerebral cortex
Basal ganglia
Cerebellum
Brain stem
Spinal cord
Classication and sub-classication of Neurodegenerative disorder

Cerebral cortex
dementia(ex. Alzheimers disease) vs non-dementia
Basal ganglia: based on phenomenology of movement

hypokinetic (ex. Parkinsons disease) vs hyperkinetic movement (ex. Huntingtons disease)
Cerebellar system: based on neuropathological subtype ex. pontocerebellar atrophy (affect to several cerebellar and brain stem structure
Brain stem Spinal cord
Motor neuron disease(MND)
Common neurodegenerative disorder
Alzheimers disease(AD) Parkinsons disease(PD) Huntingtons disease(HD) Amyotrophic lateral sclerosis(ALS)


Historical note Denition Epidemiology Pathologic basis of disease: etiology, pathogenesis, pathology, pathophysiology Clinical manifestation Diagnostic studies Diagnosis Differential diagnosis Treatment Prognosis
Disease oriented knowledge
Alzheimers disease
Alois Alzheimer (1964-1915)

German psychiatrist and neuropathologist
Auguste Deter, 1901

Alois Alzheimer and Auguste Deter
In 1901, Alzheimer observed a patient at the Frankfurt Asylum named Auguste Deter
The 51-year-old patient had strange behavioral symptoms, including a loss of short-term memory.
In April 1906, Mrs. Deter died and Alzheimer identied amyloid plaques and neurobrillary tangles from Augustes brain A speech given on 3 November 1906 would be the rst time the pathology and the clinical symptoms of presenile dementia would be presented together.
Epidemiology
The most common degenerative disorder
of the brain
Male = female The prevalence by age over 65 years: 10% by age 85 in the range of 30%-40%
DeKosky ST, Kaufer DI et al. Neurology in Clinical Practice. 5 ed. 2008
Risk of Alzheimers disease

Age: prevalence doubles with every decade after age 60 Family History Risk is higher for relatives of affected individual; even higher for early-onset AD(<60) Gender: female Head trauma High cholesterol Lack of mental stimulation
Pathologic basis of the disease
Etiology Pathology, pathogenesis,

pathophysiology
Pathophysiology
Structural change Gross: brain atrophy esp. hippocampi and
temporal lobe
Histopathology: senile plaques
(argyrophilic with central amyloid core), neurobrillary tangles
Neurotransmitter change Depletion of acetylcholine (ACh)

Neuropathologic Changes Characteristic of AD

Normal AD
AP
NFT
AP=amyloid plaques; NFT=neurobrillary tangles

Major cholinergic change in AD

Depletion of acetylcholine (ACh): especially in moderate to severe disease stages Decline in choline acetyltransferase (ChAT) activity Loss of cholinergic neurons Loss of muscarinic (M2) receptors Loss of nicotinic receptors (nAChR) Decrease AChE Increase Butylcholinesterase (BuChE)
Flynn et al, 1995; Perry et al, 1978; Rodriguez-Puertas et al, 1997; Whitehouse et al, 1982.
Pathophysiology
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Genetic defects and risk factors associated with AD

NOTIATION CHROMOSOME GENE Amyloid precursor protein GENETICS AGE CLINICAL FEATURES Rare but clinically simulates sporadic AD As above
APP
21
AD
Early
PS1
14
Presenilin 1
AD
Early
PS2
Presenilin 2
AD
Early
As above
These variants modify susceptibility to typical AD
ApoE
19
Apolipoprotein E
Haplotype
Late
UBQLN1
Ubiquilin 1 Amyloid precursor protein
SNP
Late
Familial only
Alzheimer change is almost universal in Down syndrome
Trisomy 21
21
Triploidy
Middle age
http://www.motherhealthcare.com/AD_2003.jpg
Alzheimers disease Diagnosis
Alzheimers disease
Clinical manifestation

Progressive, degenerative CNS disorder Characterized by memory impairment plus one or more additional cognitive disturbances Gradual decline in three key symptom domains
Activities of daily living (ADL), Behavior and personality and Cognition
Most common cause of dementia in people aged 65 and over
Dementia diagnosis: DSM IV criteria

The development of multiple cognitive decit that include memory impairment and at least one of the following

Aphasia, Apraxia, Agnosia, Disturbance of executive function
The cognition decit must meet the following criteria Be sufciently severe to cause impairment in occupational or social functioning Represent a decline from a previous from a previous higher level of functioning
Diagnosis should not be diagnosed if the cognitive decit occur exclusively during the course of delirium. However, a dementia and a delirium both may be diagnosed if the dementia is present at times when the delirium is not present Dementia may be related etiologically to a general medical condition, to the persisting effects of substance abuse(including toxin exposure), or to a combine of these factor
NINCDS-ADRDA Criteria for diagnosis AD

DEMENTIA established by clinical examination; conrmed by cognitive screening test(MMSE) Decit of TWO or MORE area of cognitive function Progressive worsening of memory and other cognitive function No disturbance of consciousness Onset between ages 40 and 90, most often after age 65 Absence of systemic disorders or others brain diseases that could account for the decits and progression
Neurology, Vol. 34, pp 939-944
Diagnostic studies
MRI/CT brain
generalized brain atrophy medial temporal lobes reveals a disproportionate atrophy of the hippocampi
http://www.elements4health.com/mri-scans-accurately-diagnose-alzheimers-disease.html
Differential Diagnosis
Reversible dementia, and nonneurodegenerative dementia
nutritional deciency (thiamine), drug intoxication(sedative), metabolic disorder (hypothyroid, hepatic/uremic encephalopathy), neurosyphilis, hydrocephalus, vascular dementia, dementia of AIDS, paraneoplastic syndrome Diffuse Lewy Bodies dementia(DLB), Frontotemporal lobar degeneration(FTLD)
Other neurodegenerative dementia
Treatment
Supportive care Acetylcholine esterase inhibitor N-methyl-D-aspartate(NMDA)
glutaminergic antagonist
Symptomatic treatment
Parkinsons disease
James Parkinson, London (1755 1824)
An Essay on the Shaking Palsy(1817)

Shaking Palsy(Paralysis agitans)
He identified 6 cases, 3 of whom he personally examined; 3 he observed on the streets of London

J Neuropsychiatry Clin Neurosci 2002;14:22336
Parkinsonism
clinical syndrome of bradykinesia, resting tremor,

cogwheel rigidity, and postural instability Parkinsons disease
clinical syndrome of asymmetrical parkinsonism,
usually with rest tremor, in association with the specic pathological ndings of depigmentation of the SN as a result of loss of melanin-laden dopaminergic neurons containing eosinophilic cytoplasmic inclusions(Lewy bodies)
Epidemiology
Community based series prevalence 360 per 100,000 and an
disease before age 30 years is rare incidence of 18 per 100,000 per year
PD is an age-related disease gradually increase after age 50 years, and Female: Male=1:1
de Lau and Breteler. Lancet Neurol 2006; 5: 525-535
Pathologic basis
Etiology Pathology, pathogenesis,

pathophysiology
Pathophysiology
Structural change
Loss of pigmented neurons in the SNc and other pigmented neuron Histopathology: Lewy bodies Depletion of dopamine containing cells in the substantia nigra leads to decreased dopamine n the striatal
Neurotransmitter change
Pathology
Gross: loss of pigmented cell in substantial nigra(SN) and other pigmented nuclei(locus ceruleus (LC), dorsal motor nucleus of the vagus)
http://www.babraham.ac.uk/images/research/SAS/emson/g1.jpg
http://www.uhmc.sunysb.edu/pathology/neuropath
Pathology
Normal substantia nigra
Surviving neuron contains a Lewy body

Extensive loss of pigmented neurons
Classication of Parkinsonism
Primary or idiopathic parkinsonism Parkinsons disease Secondary parkinsonism hydrocephalus, vascular parkinsonism, encephalitis Parkinson plus syndrome Progressive supranuclear palsy(PSP), corticobasal Hereditary parkinsonism Wilsons disease, Dopa-responseive dystonia,
Huntingtons disease(HD)
degeneration(CBD), multiple system atrophy(MSA)
United Kingdom Parkinson's Disease Society(UKPDS) Brain Bank Diagnostic Criteria for PD
Step 1: Diagnosis of Parkinsonism Step 2: Features tending to exclude Parkinsons disease as the cause of Parkinsonism Step 3: Features that support a diagnosis of Parkinsons disease (three or more required for diagnosis of denite Parkinsons disease)
Diagnostic accuracy to 82%
Hughes AJ, Daniel SE, Kilford L, Lees AJ. JNNP 1992 Mar;55(3):181-4
Step 1: Diagnosis of Parkinsonism

Bradykinesia and at least one of the
following:
Muscular rigidity 46 Hz resting tremor Postural instability not caused by primary

visual, vestibular, cerebellar or proprioceptive dysfunction
Step 2: Features tending to exclude Parkinsons disease as the cause of Parkinsonism
History of repeated strokes with stepwise progression of parkinsonian features History of repeated head injury History of denite encephalitis Neuroleptic treatment at onset of symptoms >1 affected relatives Sustained remission Strictly unilateral features after 3 years
Supranuclear gaze palsy Cerebellar signs Early severe autonomic involvement Early severe dementia with disturbances of memory, language and praxis Babinski's sign Presence of a cerebral tumour or communicating hydrocephalus on computed tomography scan Negative response to large doses of levodopa (if malabsorption excluded) MPTP exposure
Step 3: Features that support a diagnosis of PD (three or more required)

Unilateral onset Rest tremor present Progressive disorder Persistent asymmetry affecting the side of onset most Excellent (70100%) response to levodopa Severe levodopa-induced chorea Levodopa response for 5 years Clinical course of 10 years
Diagnostic studies
MRI/CT brain: using for exclude

other cause of parkinsonism normal
In PD, the MRI brain usually reveals
Differential diagnosis
Christine CW, Aminoff MJ, Am J Med. 2004;117: 412419.

Treatment
Levodopa MAO inhibitor Dopamine agonist Anti-cholinergic drug Surgical treatment Deep brain stimulation
Huntingtons disease
Historical Note
George Huntington,
American physician 1872
Hereditary form of chorea report. The Medical and Surgical Reporter in the April 13, 1872
Huntingtons Disease Dened

An inherited disease of the central
nervous system characterized by progressive dementia and involuntary choreic movements, resulting from degeneration of the caudate and putamen nuclei.
Perlman & Konrad Schulze-Delrieu
Huntingtons Disease
It is an inherited, autosomal dominant
disorder, which means that half the children of a parent with the HD gene also will develop the disease. also may begin during childhood.
The typical age of onset is middle age, but it
Epidemiology
Prevalence of HD vary depending on the The disease is reported in all races
geographical area, but the best estimate is 10 per 100,000
Etiology and pathophysiology
HD is a dominantly inherited condition caused by an unstable expanded CAG trinucleotide repeat in exon 1 of the HD gene
Pathology
neuronal loss in the
caudate and putamen diffuse brain atrophy
Normal
HD
Clinical symptoms
Usually develops at age 35 45
(+ or 17
years) 10% in children Men and women equally Younger people with Huntington's disease often have more severe case, and symptoms may progress more quickly Gradual loss of motor coordination and mental function
Type of symptoms
Movement Cognitive Psychiatric

Movement
usually begin with clumsiness and dgetiness that

evolves into chorea
bradykinesia and motor impersistence may occur

Movement
usually begin with clumsiness and dgetiness that

evolves into chorea
bradykinesia and motor impersistence may occur

Cognitive

As Huntington's disease progresses, the ability to concentrate becomes more difcult May have difculty driving, keeping track of things, making decisions, answering questions, and may lose the ability to recognize familiar objects. Over time judgment, memory, and other cognitive functions begin to deteriorate into dementia
Psychiatric
Early psychiatric symptoms of Huntington's
disease are subtle, varied, and easily overlooked or misinterpreted
Depression is the most common psychiatric

symptom and often develops early in the course of the disease. Signs of depression include: - Hostility/irritability, Inability to take pleasure in life (anhedonia), Lack of energy
Diagnostic studies
MRI/CT brain: caudate atrophy, cortical
atrophy
Genetic study
Treatment
No treatment is yet proven to favorably
inuence disease progression
Symptomatic treatment neuroleptic, antidopaminergic,

amantadine, SSRI
Amyotrophic Lateral Sclerosis

Lou Gehrig, American baseball player , suffered from ALS

ALS (Classic form) is also known as motor neurone disease (MND), Charcots disease, and Lou Gehrig disease.
Amyotrophic Lateral Sclerosis Amyotrophic refers to the muscle

Lateral sclerosis refers to the
hardness to palpation of the lateral columns of the spinal cord in autopsy specimens, where gliosis follows degeneration of the corticospinal tracts.
atrophy, weakness, and fasciculation that signify disease of the lower motor neurons.
Motor Neurons Selectively Affected in ALS.
Classic form of ALS

The classic form of sporadic ALS usually Ventilatory failure results in death, on
starts as dysfunction or weakness in one part of the body and spreads gradually within that part and then to the rest of the body. average, 3 years after the onset of focal weakness.
Subtype of Motor Neuron Disease(MND)

Progressive muscular atrophy(PMA)
involve only lower motor neuron
Primary lateral sclerosis involve only upper motor neuron
Spinal muscular atrophy(SMA) familial and involve lower motor neuron
Progressive bulbar palsy (PBP) the disease is restricted to bulbar muscles
Etiology
Insufcient evidence May be.... viral infection activation of immune system exogenous toxins hormonal disturbance
Pathogenesis of sporadic ALS

Glutamate excitotoxicity and free radical
injury
Immunological and inammatory

abnormalities dysfunction
Neurolament and microtubular SOD1 gene mutation

Symptoms
Muscle weakness without sensory loss Combined signs/symptoms of UMN+LMN UMN sign spasticity, hyperreexia, Hoffmans sign LMN sign Muscle atrophy, muscle fasciculation
Diagnostic studies
MRI/CT brain or spinal cord: exclude other
mimicker condition
Nerve conduction study: normal Electromyography(EMG): conrm
widespread denervation by testing at least 3 limbs
Treatment
Riluzole Supportive care
Conclusion
Neuro-degenerative disorder: denition Common neuro-degenerative disorder:
AD, PD, HD, ALS
The disease can not be cured, so
supportive and symptomatic treatment are the key
Thank You for Your Attention

Neurodegenerative Disorder, Jan 54

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Neuro-degenerative disorder

Friday, July 8, 2011

DeLatin: down from, off, away from,"

Classication of Neurodegenerative disorder

based on clinical features based on topography of the

Classication and sub-classication of Neurodegenerative disorder

dementia(ex. Alzheimers disease) vs non-dementia

Basal ganglia: based on phenomenology of movement

Brain stem Spinal cord

Motor neuron disease(MND)

Common neurodegenerative disorder

Alzheimers disease(AD) Parkinsons disease(PD) Huntingtons disease(HD) Amyotrophic lateral sclerosis(ALS)

Disease oriented knowledge

Alois Alzheimer (1964-1915)

Auguste Deter, 1901

Alois Alzheimer and Auguste Deter

Friday, July 8, 2011

Risk of Alzheimers disease

Pathologic basis of the disease

Etiology Pathology, pathogenesis,

Friday, July 8, 2011

Histopathology: senile plaques

(argyrophilic with central amyloid core), neurobrillary tangles

Neurotransmitter change Depletion of acetylcholine (ACh)

Neuropathologic Changes Characteristic of AD

AP=amyloid plaques; NFT=neurobrillary tangles

Major cholinergic change in AD

Friday, July 8, 2011

Friday, July 8, 2011

Genetic defects and risk factors associated with AD

Ubiquilin 1 Amyloid precursor protein

Friday, July 8, 2011

Alzheimers disease Diagnosis

Friday, July 8, 2011

Activities of daily living (ADL), Behavior and personality and Cognition

Most common cause of dementia in people aged 65 and over

Dementia diagnosis: DSM IV criteria

Aphasia, Apraxia, Agnosia, Disturbance of executive function

NINCDS-ADRDA Criteria for diagnosis AD

Other neurodegenerative dementia

Friday, July 8, 2011

James Parkinson, London (1755 1824)

An Essay on the Shaking Palsy(1817)

He identified 6 cases, 3 of whom he personally examined; 3 he observed on the streets of London

clinical syndrome of bradykinesia, resting tremor,

clinical syndrome of asymmetrical parkinsonism,

Friday, July 8, 2011

Etiology Pathology, pathogenesis,

Friday, July 8, 2011

Friday, July 8, 2011

Surviving neuron contains a Lewy body

degeneration(CBD), multiple system atrophy(MSA)

Friday, July 8, 2011

Step 1: Diagnosis of Parkinsonism

Muscular rigidity 46 Hz resting tremor Postural instability not caused by primary

Friday, July 8, 2011

Friday, July 8, 2011

Friday, July 8, 2011

Step 2: Features tending to exclude Parkinsons disease as the cause of Parkinsonism

Friday, July 8, 2011

Step 3: Features that support a diagnosis of PD (three or more required)

MRI/CT brain: using for exclude

In PD, the MRI brain usually reveals

Friday, July 8, 2011