Neurodegenerative Disorder, Jan 54

8/7/2019 Neurodegenerative Disorder, Jan 54

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Neuro-degenerative

disorder

Surat Tanprawate, MD, MSc(Lond.), FRCP(T)Division of Neurology, Department of Medicine

Chiang Mai university

Friday, July 8, 2011



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


http://en.wiktionary.org/wiki/neuron

http://en.wiktionary.org/wiki/neuron

http://en.wiktionary.org/wiki/%CE%BD%CE%B5%E1%BF%A6%CF%81%CE%BF%CE%BD

http://en.wiktionary.org/wiki/%CE%BD%CE%B5%E1%BF%A6%CF%81%CE%BF%CE%BD

http://en.wiktionary.org/w/index.php?title=%CE%BD%CE%B5%CF%85%CF%81%CE%BF-&action=edit&redlink=1

http://en.wiktionary.org/w/index.php?title=%CE%BD%CE%B5%CF%85%CF%81%CE%BF-&action=edit&redlink=1

http://en.wikipedia.org/wiki/Ancient_Greek_language

http://en.wikipedia.org/wiki/Ancient_Greek_language



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




Classification of

Neurodegenerative disorder

• based on clinical features

• based on topography of thepredominant lesion

• combination




Cerebral cortex

Basal ganglia

Cerebellum

Brain stem

Spinal cord




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)




Common neurodegenerative

disorder

• Alzheimer’s disease(AD)

• Parkinson’s disease(PD)

• Huntington’s disease(HD)

• Amyotrophic lateral sclerosis(ALS)




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



Alzheimer’sdisease




Alois Alzheimer (1964-1915)

German psychiatrist and neuropathologist




Auguste Deter, 1901




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


http://en.wikipedia.org/wiki/Neurofibrillary_tangles

http://en.wikipedia.org/wiki/Neurofibrillary_tangles

http://en.wikipedia.org/wiki/Amyloid

http://en.wikipedia.org/wiki/Amyloid



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




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




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),

neurofibrillary tangles

• Neurotransmitter change

• Depletion of acetylcholine (ACh)




Neuropathologic Changes

Characteristic of AD

ADNormal

NFTAP

AP=amyloid plaques; NFT=neurofibrillary 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.



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Pathophysiology




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




http://www.motherhealthcare.com/AD_2003.jpg






Alzheimer’s diseaseDiagnosis




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




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




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




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






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)




Treatment

• Supportive care

• Acetylcholine esterase inhibitor

• N-methyl-D-aspartate(NMDA)glutaminergic antagonist

• Symptomatic treatment




Parkinson’sdisease




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




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)




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




Pathologic basis

•Etiology

• Pathology, pathogenesis,

pathophysiology




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




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


http://www.babraham.ac.uk/images/research/SAS/emson/fig1.jpg



http://www.uhmc.sunysb.edu/pathology/neuropath

http://www.uhmc.sunysb.edu/pathology/neuropath



Pathology

Normal substantia nigra

Extensive loss of pigmented neurons

Surviving neuron contains a Lewy body




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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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%




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








St 2 F di l d P ki ’



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




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




Diagnostic studies

•MRI/CT brain: using for excludeother cause of parkinsonism

• In PD, the MRI brain usually reveals

normal


Diff ti l di i



Christine CW, Aminoff MJ, Am J Med . 2004;117: 412–419.

Differential diagnosis




Treatment

• Levodopa

• MAO inhibitor

• Dopamine agonist

• Anti-cholinergic drug

• Surgical treatment

• Deep brain stimulation




Huntington’sdisease




Hereditary form of chorea report. The Medical and

Surgical Reporter in the April 13, 1872

George Huntington,American physician 1872

Historical Note


H i ’



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


H i ’



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.




Epidemiology

• Prevalence of HD vary depending on thegeographical area, but the best estimate is10 per 100,000

•The disease is reported in all races




Etiology and

pathophysiology

HD is a dominantly inherited condition caused by an unstableexpanded CAG trinucleotide repeat in exon 1 of the HD gene


Pathology



Normal HD

Pathology

•neuronal loss in thecaudate andputamen

•diffuse brainatrophy




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




Type of symptoms

•Movement•Cognitive

•Psychiatric


M t



Movement

• usually begin with clumsiness and fidgetiness thatevolves into chorea

• bradykinesia and motor impersistence may occur


Movement



Movement

• usually begin with clumsiness and fidgetiness thatevolves into chorea

• bradykinesia and motor impersistence may occur




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




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




Diagnostic studies

• MRI/CT brain: caudate atrophy, corticalatrophy

• Genetic study




Treatment

• No treatment is yet proven to favorably

influence disease progression

• Symptomatic treatment

• neuroleptic, antidopaminergic,

amantadine, SSRI




AmyotrophicLateralSclerosis




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



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.


Motor Neurons Selectively Affected in ALS.



y




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.


Subtype of Motor Neuron



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




Etiology

• Insufficient evidence

• May be....

• viral infection

• activation of immune system

• exogenous toxins

• hormonal disturbance


Pathogenesis of sporadic



Pathogenesis of sporadic

ALS• Glutamate excitotoxicity and free radical

injury

• Immunological and inflammatoryabnormalities

• Neurofilament and microtubular

dysfunction

• SOD1 gene mutation




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




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




Treatment

• Riluzole

• Supportive care




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




Thank You for Your Attention

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Neurodegenerative Disorder, Jan 54