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Neuro-degenerative
disorder
Surat Tanprawate, MD, MSc(Lond.), FRCP(T)Division of Neurology, Department of Medicine
Chiang Mai university
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GenerateDe-Neuro-
Etymology
Neuro-degenerative disorder
Ancient Greek:
νευρο- (neuro-),
from νεῦρον
(neuron, “sinew,tendon, cord”).
Latin:“down from,off, away from,"
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
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By Definition
Neurodegenerative diseases represent a large group of neurological
disorders with heterogenous clinical andpathological expressions affecting specificsubsets of neurons in specific functional
anatomic systems; they arise for unknownreasons and progress in a relentless manner.
Przedborski S, Vila M, Jackson-Lewis V. J. Clin Invest .111:3-10
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Classification of
Neurodegenerative disorder
• based on clinical features
• based on topography of thepredominant lesion
• combination
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Cerebral cortex
Basal ganglia
Cerebellum
Brain stem
Spinal cord
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Classification and sub-classification of Neurodegenerative disorder
• Cerebral cortex
• dementia(ex. Alzheimer’s disease) vs non-dementia
• Basal ganglia: based on phenomenology of movement
• hypokinetic (ex. Parkinson’s disease) vshyperkinetic movement (ex. Huntington’s disease)
• Cerebellar system: based on neuropathological subtype
• ex. pontocerebellar atrophy (affect to severalcerebellar and brain stem structure
• Brain stem
• Spinal cord
Motor neuron disease(MND)
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Common neurodegenerative
disorder
• Alzheimer’s disease(AD)
• Parkinson’s disease(PD)
• Huntington’s disease(HD)
• Amyotrophic lateral sclerosis(ALS)
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Disease
orientedknowledge
• Historical note
• Definition
• Epidemiology
• Pathologic basis of disease:etiology, pathogenesis,pathology, pathophysiology
• Clinical manifestation
• Diagnostic studies
•Diagnosis
• Differential diagnosis
• Treatment
• PrognosisFriday, July 8, 2011
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Alzheimer’sdisease
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Alois Alzheimer (1964-1915)
German psychiatrist and neuropathologist
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Auguste Deter, 1901
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Alois Alzheimer and Auguste Deter
• The 51-year-old patienthad strange behavioralsymptoms, including a loss
of short-term memory.
• In April 1906, Mrs. Deter died andAlzheimer identified amyloid plaques and neurofibrillary tangles from Auguste’s brain
• A speech given on 3 November1906 would be the first time thepathology and the clinicalsymptoms of presenile dementiawould be presented together.
In 1901, Alzheimer observed a patientat the Frankfurt Asylum named
Auguste Deter
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Epidemiology
• The most common degenerative disorderof 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
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Risk of Alzheimer’s
disease• Age: prevalence doubles with every decade after age 60
• Family History
• Risk is higher for relatives of affected individual; evenhigher for early-onset AD(<60)
• Gender: female
• Head trauma
• High cholesterol
• Lack of mental stimulation
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Pathologic basis of
the disease
• Etiology
• Pathology, pathogenesis,
pathophysiology
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Pathophysiology
• Structural change
• Gross: brain atrophy esp. hippocampi and
temporal lobe
• Histopathology: senile plaques(argyrophilic with central amyloid core),
neurofibrillary tangles
• Neurotransmitter change
• Depletion of acetylcholine (ACh)
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Neuropathologic Changes
Characteristic of AD
ADNormal
NFTAP
AP=amyloid plaques; NFT=neurofibrillary tangles
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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.
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Pathophysiology
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Genetic defects and risk factors
associated with AD
NOTIATION CHROMOSOME GENE GENETICS AGECLINICALFEATURES
APP 21Amyloid
precursor proteinAD Early
Rare but clinicallysimulates sporadic
AD
PS1 14 Presenilin 1 AD Early As above
PS2 1 Presenilin 2 AD Early As above
ApoE 19 Apolipoprotein E Haplotype Late
These variants modify
susceptibility totypical AD
UBQLN1 9 Ubiquilin 1 SNP Late Familial only
Trisomy 21 21Amyloid
precursor proteinTriploidy Middle age
Alzheimer change isalmost universal in
Down syndrome
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http://www.motherhealthcare.com/AD_2003.jpg
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Alzheimer’s diseaseDiagnosis
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Alzheimer’s disease
Clinical manifestation• Progressive, degenerative CNS disorder
• Characterized by memory impairment plus oneor more additional cognitive disturbances
• Gradual decline in three key symptom domains
• Activities of daily living (ADL), Behavior andpersonality and Cognition
• Most common cause of dementia in peopleaged 65 and over
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Dementia diagnosis: DSM IV criteria
• The development of multiple cognitive deficit that include memory
impairment and at least one of the following
• Aphasia, Apraxia, Agnosia, Disturbance of executive function
• The cognition deficit must meet the following criteria
• Be sufficiently 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 deficit occur exclusively
during the course of delirium. However, a dementia and a delirium both maybe diagnosed if the dementia is present at times when the delirium is notpresent
• Dementia may be related etiologically to a general medical condition, to thepersisting effects of substance abuse(including toxin exposure), or to a
combine of these factor
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NINCDS-ADRDA Criteria for diagnosis AD
• DEMENTIA established by clinical examination;confirmed by cognitive screening test(MMSE)
•Deficit of TWO or MORE area of cognitive function
• Progressive worsening of memory and other cognitivefunction
• No disturbance of consciousness
• Onset between ages 40 and 90, most often after age 65
• Absence of systemic disorders or others brain diseasesthat could account for the deficits and progression
Neurology, Vol. 34, pp 939-944
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Diagnostic studies
• MRI/CT brain
• generalized brain
atrophy
• medial temporallobes reveals a
disproportionateatrophy of thehippocampi
http://www.elements4health.com/mri-scans-accurately-diagnose-alzheimers-disease.html
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Differential Diagnosis
Reversible dementia, and non-neurodegenerative dementia
• nutritional deficiency (thiamine), drug
intoxication(sedative), metabolic disorder(hypothyroid, hepatic/uremic encephalopathy),neurosyphilis, hydrocephalus, vasculardementia, dementia of AIDS, paraneoplasticsyndrome
Other neurodegenerative dementia
• Diffuse Lewy Bodies dementia(DLB),Frontotemporal lobar degeneration(FTLD)
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Treatment
• Supportive care
• Acetylcholine esterase inhibitor
• N-methyl-D-aspartate(NMDA)glutaminergic antagonist
• Symptomatic treatment
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Parkinson’sdisease
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James Parkinson, London
(1755 – 1824)
An Essay on the Shaking Palsy(1817)
Shaking Palsy(Paralysis agitans)
He identified 6 cases, 3 of whom hepersonally examined; 3 he observedon the streets of London
J Neuropsychiatry Clin Neurosci 2002;14:223–36
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Parkinsonism
• clinical syndrome of bradykinesia, resting tremor,cogwheel rigidity, and postural instability
Parkinson’s disease
• clinical syndrome of asymmetrical parkinsonism,usually with rest tremor, in association with thespecific pathological findings of depigmentation of
the SN as a result of loss of melanin-ladendopaminergic neurons containing eosinophiliccytoplasmic inclusions(Lewy bodies)
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Epidemiology
• Community based series
• prevalence 360 per 100,000 and an
incidence of 18 per 100,000 per year
• PD is an age-related disease
• gradually increase after age 50 years, anddisease before age 30 years is rare
• Female: Male=1:1
de Lau and Breteler. Lancet Neurol 2006; 5: 525-535
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Pathologic basis
•Etiology
• Pathology, pathogenesis,
pathophysiology
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Pathophysiology
• Structural change
• Loss of pigmented neurons in the SNc and
other pigmented neuron
• Histopathology: Lewy bodies
• Neurotransmitter change
• Depletion of dopamine containing cells inthe substantia nigra leads to decreaseddopamine n the striatal
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Pathology
• Gross: loss of pigmented cell insubstantial nigra(SN) and otherpigmented nuclei(locus ceruleus(LC), dorsal motor nucleus of thevagus)
http://www.uhmc.sunysb.edu/pathology/neuropathhttp://www.babraham.ac.uk/images/research/SAS/emson/fig1.jpg
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Pathology
Normal substantia nigra
Extensive loss of pigmented neurons
Surviving neuron contains a Lewy body
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Classification of Parkinsonism
• Primary or idiopathic parkinsonism
• Parkinson’s disease
• Secondary parkinsonism
• hydrocephalus, vascular parkinsonism, encephalitis
• Parkinson plus syndrome
• Progressive supranuclear palsy(PSP), corticobasal
degeneration(CBD), multiple system atrophy(MSA)
• Hereditary parkinsonism
• Wilson’s disease, Dopa-responseive dystonia,Huntington’s disease(HD)
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'
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United Kingdom Parkinson's DiseaseSociety(UKPDS) Brain Bank Diagnostic
Criteria for PD
• Step 1: Diagnosis of Parkinsonism
•Step 2: Features tending to excludeParkinson’s disease as the cause of Parkinsonism
• Step 3: Features that support a diagnosis of
Parkinson’s disease (three or more requiredfor diagnosis of definite Parkinson’s disease)
Hughes AJ, Daniel SE, Kilford L, Lees AJ. JNNP 1992 Mar;55(3):181-4
Diagnostic
accuracy to 82%
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Step 1: Diagnosis of
Parkinsonism• Bradykinesia and at least one of the
following:
• Muscular rigidity
• 4–6 Hz resting tremor
•Postural instability not caused by primaryvisual, vestibular, cerebellar orproprioceptive dysfunction
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St 2 F di l d P ki ’
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Step 2: Features tending to exclude Parkinson’sdisease as the cause of Parkinsonism
• History of repeated strokeswith stepwise progression of parkinsonian features
• History of repeated headinjury
• History of definite encephalitis
• Neuroleptic treatment atonset of symptoms
• >1 affected relatives
• Sustained remission
• Strictly unilateral features after3 years
• Supranuclear gaze palsy
• Cerebellar signs
• Early severe autonomic involvement
• Early severe dementia with
disturbances of memory, languageand praxis
• Babinski's sign
• Presence of a cerebral tumour or
communicating hydrocephalus oncomputed tomography scan
• Negative response to large doses of levodopa (if malabsorptionexcluded)
• MPTP exposure
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Step 3: Features that support a diagnosisof PD (three or more required)
• Unilateral onset
• Rest tremor present
• Progressive disorder
• Persistent asymmetry affecting the side of onset most
• Excellent (70–100%) response to levodopa
• Severe levodopa-induced chorea
• Levodopa response for 5 years
• Clinical course of 10 years
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Diagnostic studies
•MRI/CT brain: using for excludeother cause of parkinsonism
• In PD, the MRI brain usually reveals
normal
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Diff ti l di i
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Christine CW, Aminoff MJ, Am J Med . 2004;117: 412–419.
Differential diagnosis
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Treatment
• Levodopa
• MAO inhibitor
• Dopamine agonist
• Anti-cholinergic drug
• Surgical treatment
• Deep brain stimulation
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Huntington’sdisease
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Hereditary form of chorea report. The Medical and
Surgical Reporter in the April 13, 1872
George Huntington,American physician 1872
Historical Note
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H i ’
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Huntington’s
Disease De ned• An inherited disease of the central
nervous system characterized byprogressive dementia and involuntarychoreic movements, resulting from
degeneration of the caudate andputamen nuclei.
Perlman & Konrad Schulze-Delrieu
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H i ’
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Huntington’s
Disease• It is an inherited, autosomal dominant
disorder, which means that half the childrenof a parent with the HD gene also willdevelop the disease.
•The typical age of onset is middle age, but italso may begin during childhood.
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Epidemiology
• Prevalence of HD vary depending on thegeographical area, but the best estimate is10 per 100,000
•The disease is reported in all races
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Etiology and
pathophysiology
HD is a dominantly inherited condition caused by an unstableexpanded CAG trinucleotide repeat in exon 1 of the HD gene
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Pathology
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Normal HD
Pathology
•neuronal loss in thecaudate andputamen
•diffuse brainatrophy
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Clinical symptoms
• Usually develops at age 35 – 45 (+ or – 17years)
• 10% in children
• Men and women equally
• Younger people with Huntington's diseaseoften have more severe case, and
symptoms may progress more quickly
• Gradual loss of motor coordination andmental function
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Type of symptoms
•Movement•Cognitive
•Psychiatric
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M t
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Movement
• usually begin with clumsiness and fidgetiness thatevolves into chorea
• bradykinesia and motor impersistence may occur
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Movement
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Movement
• usually begin with clumsiness and fidgetiness thatevolves into chorea
• bradykinesia and motor impersistence may occur
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Cognitive
• As Huntington's disease progresses, the abilityto concentrate becomes more difficult
• May have difficulty driving, keeping track of things, making decisions, answering questions,and may lose the ability to recognize familiarobjects.
• Over time judgment, memory, and othercognitive functions begin to deteriorate intodementia
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Psychiatric
• Early psychiatric symptoms of Huntington'sdisease are subtle, varied, and easilyoverlooked or misinterpreted
• Depression is the most common psychiatricsymptom and often develops early in thecourse of the disease. Signs of depression
include:- Hostility/irritability, Inability to takepleasure in life (anhedonia), Lack of energy
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Diagnostic studies
• MRI/CT brain: caudate atrophy, corticalatrophy
• Genetic study
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Treatment
• No treatment is yet proven to favorably
influence disease progression
• Symptomatic treatment
• neuroleptic, antidopaminergic,
amantadine, SSRI
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AmyotrophicLateralSclerosis
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Lou Gehrig, American baseball player , suffered from ALS
ALS (Classic form) is also known as motor neurone disease
(MND), Charcot’s disease, and Lou Gehrig disease.Friday, July 8, 2011
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Amyotrophic Lateral
Sclerosis• “ Amyotrophic” refers to the muscle
atrophy, weakness, and fasciculation thatsignify disease of the lower motor neurons.
• “Lateral sclerosis” refers to thehardness to palpation of the lateralcolumns of the spinal cord in autopsyspecimens, where gliosis followsdegeneration of the corticospinal tracts.
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Motor Neurons Selectively Affected in ALS.
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y
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Classic form of ALS
• The classic form of sporadic ALS usuallystarts as dysfunction or weakness in one
part of the body and spreads graduallywithin that part and then to the rest of the body.
• Ventilatory failure results in death, onaverage, 3 years after the onset of focalweakness.
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Subtype of Motor Neuron
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Subtype of Motor NeuronDisease(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
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Etiology
• Insufficient evidence
• May be....
• viral infection
• activation of immune system
• exogenous toxins
• hormonal disturbance
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Pathogenesis of sporadic
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Pathogenesis of sporadic
ALS• Glutamate excitotoxicity and free radical
injury
• Immunological and inflammatoryabnormalities
• Neurofilament and microtubular
dysfunction
• SOD1 gene mutation
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Symptoms
• Muscle weakness without sensory loss
• Combined signs/symptoms of UMN+LMN
• UMN sign
• spasticity, hyperreflexia, Hoffman’s sign
• LMN sign
• Muscle atrophy, muscle fasciculation
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Diagnostic studies
• MRI/CT brain or spinal cord: exclude othermimicker condition
• Nerve conduction study: normal
• Electromyography(EMG): confirm
widespread denervation by testing at least3 limbs
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Treatment
• Riluzole
• Supportive care
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Conclusion
• Neuro-degenerative disorder: definition
• Common neuro-degenerative disorder:AD, PD, HD, ALS
• The disease can not be cured, so
supportive and symptomatic treatment arethe key
Friday, July 8, 2011
8/7/2019 Neurodegenerative Disorder, Jan 54
http://slidepdf.com/reader/full/neurodegenerative-disorder-jan-54 75/75
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