DEGENERATIVE AND DEMYELINATING DISEASES OF  Misfolded A-synuclein – part of the

THE BRAIN abnormal protein aggregate found in

Reynold A. Wong, MD, FPNA Lewy bodies
 Synucleinopathies
NEURODEGENERATIVE DISEASES  Parkinson’s disease
 Degeneration  Dementia with lewy body (DLB)
 Gowers (1902) – abiotrophy  LB variant of AD
 Lack of vital endurance  Multiple system atrophy (MSA) –
 Premature death OPCA, SND, SDS
 “Aging and NDD share similar  Neurodegeneration with brain iron
processes” accumulation type 1 (Hallervorden-
 Many NDD causes considered Spatz disease)
 Idiopathic
 Inherited à familial Etiology
 Apoptosis  Factors
 Genetically programmed cell death  Genetic predisposition
 Deletion of individual cells by  Environmental toxins
fragmentation into membrane-bound  Oxidative stress
particles which are phagocytized  Aging
 Elicits no inflammatory response into
adjacent cells and tissues General Clinical Features
 Induced by injury to cellular DNA (i.e.  Insidious onset
irradiation and cytotoxic agents)  Progressive, relentless clinical course
 Suppressed by naturally occurring  Selective involvement of the neuronal systems
factors (i.e. protein kinase)  Symmetrical occurrence or involvement
(unilateral in early presentation)
Basic Mechanism
 Degeneration versus Apoptosis Diagnostics
Apoptosis Degeneration  CSF – minimal change, little cellular reaction
Characteristic gradual More rapid neuronal  Brain imaging – Tissue loss, no reaction or
neuron loss not preceded breakdown/loss, enhancement
by accumulation of associated with deposition
of degenerative products
degenerative products SYNDROMES OF DEMENTIA
and associated with sparse Evokes phagocytosis and  Primary Progressive
gliosis gliosis  Alzheimer disease
 LB dementia
 Picks disease
Degenerative Products
Tau and Tauopathies
 Tau
 Neuronal microtubule stabilizing
protein
 Contributes to axonal transport,
growth and morphology
 Misregulation and deposition results in
neuronal cell death (i.e. Fronto-
temporal dementia and Parkinsonism)
Alpha synuclein and Synucleinopathies
 Progressive dementias with other neurological
 Alpha synuclein
abnormality
 Tubular filamentous non-soluble
 Huntington’s disease
protein
 Cortico-striato-spinal degeneration
 Important role in maintenance of
 Dementia-Parkinson-ALS complex of
synaptic pool
Guam
 Cortico-basal ganglionic degeneration

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  Dentato-rubro-pallido-Luysian
degeneration
SYNDROMES OF MOVEMENT DISORDERS
 Parkinson’s disease
 Striato-nigral degeneration
 Progressive supranuclear palsy (PSP)
 Dystonia musculorum deformans
 Guilles dela Tourette
 Hallervorden Spatz disease
 Acanthosis chorea
SYNDROMES OF PROGRESSIVE ATAXIA
 Predominantly spinal
 Friedrich ataxia
 Non-Friedrich ataxia
 Pure cerebellar
 Complicated cerebellar
 OPCA (MSA)
 Gerstmann-Straussler-Sheinker disease
 Machado Joseph disease
 Paraneoplastic and alcohol related ataxia
SYNDROMES OF PROGRESSIVE WEAKNESS AND
ATROPHY
 Without sensory changes
 Progressive SMA
 ALS
 Progressive bulbar palsy
 Primary lateral sclerosis
 Hereditary progressive atrophy and
spastic paraplegia
 With sensory changes
 HSN
 HSMN
o Charcot Marie Tooth disease
o Dejerine Sottas Disease
o Refsums disease
ALZHEIMER’S DISEASE
 Epidemiology
 Worldwide: 5-10% of people over 65
years old are affected
 Double every 5 years over 65 years old
 50% in over 80 years old
 2 most significant findings
 Neuritic plaques
 NFT
 Amyloid beta protein
 Central role for A-beta peptide in AD
 Amyloid plaques primarily composed of A-beta
peptides produced by cleavage of amyloid
precursor protein
 Mutations in APP lead to overproduction of
insoluble amyloid peptide and its deposition in
neuritic plaques
 ApoE
 Protein found with beta amyloid in
neuritic plaques
 Genotype is most important genetic risk
factor for AD
 Neurofibrillary Tangles
 Beta-amyloid Plaques

SYNDROMES OF PROGRESSIVE BLINDNESS OR

OPHTHALMOPLEGIA
 Leber’s optic atrophy  Genetics
 Retinitis pigmentosa  Occur more among relatives
 Kayrne-Sayre disease  Inherited pattern exists in <10% of
cases
Dementia Causes  40% inherited as AD
 Alzheimers disease
 APP gene in Chrom 21 implicated
 Frontotemporal dementia
 Seen in Down syndrome patients who
 Vascular dementia
survive above 40 years old
 Parkinsons with dementia
 Some families with early-onset AD
 Lewy body dementia
 Mutation in presenilin-1 gene Chrom
 Progressive supranuclear palsy
14
 Normal pressure hydrocephalus
 ApoE gene in Chrom 19
 Creutzfeldt-Jacob disease
 Risk factors
 Huntington’s disease
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  Age
 ApoE
 Chronic hypertension
 Head injury – 3x increased risk
 Diagnostics
 EEG
o Normal
 SPECT
o Symmetrical reduction in gray
matter
 PET
o Bilateral reduction of oxygen
utilization and glucose uptake
in parietal and temporal lobes
(early stage), frontal lobe (later
stage)
 CT scan
o Cortical atrophy, not strong  Balloon neuron in Pick’s disease
o Ventricular size – provided
better correlation
 MRI
o Provides little additional
information than CT scan
 Treatment
 Acetylcholinesterase inhibitors
o Donepezil (Aricept)
o Galantamine (Reminyl)
o Rivastigmine (Exelon)
 Glutamate antagonist PARKINSON’S DISEASE
o Memantine  Pathology
o Moderate to severe disease  (+) Inclusion bodies: lewy bodies –
 Anti-depressant fibrillar depositis of alpha synuclein
o Helps in concomitant  Etiology
depression  20% of patient with at least 1 relative
o No effect on cognitive function with Parkinsonian symptoms
 Prognosis
 Patients survive up to 8 – 10 years
(some up to 25 years)
 Mortality: infection, heart disease,
malnutrition

FRONTO-TEMPORAL DEMENTIA
PICK’S DISEASE
 Occurs both sporadically and familial form
 AD inheritance
ATAXIA CLASSIFICATION
 6th decade of life
 Based on anatomic localization of pathologic
 Atrophy of frontal and temporal lobes
changes
 Predominantly spinal
 Pure cerebellar
 Anita Harding (1993)
 Congenital
 Inherited metabolic syndromes with
known genetic or biochemical defects

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  Degenerative ataxia of unknown cause  Cognitive delay or decline
– early onset (<20 yo), late onset (>20  Movement disorders and abnormalities
yo) of muscle tone
 Inherited metabolic syndromes with known  Examples
genetic or biochemical defects  Cockayne syndrome
 Xeroderma pigmentosum
1. Acute intermittent ataxia  Ataxia telangiectasia
Disease Inheritance Chromosome o Louis-Bar disease
Maple syrup AR 2p13 o Mutation in ATM gene locus
urine disease
 Refsum disease
Episodic ataxia 1 AD 19p13
o Elevated phytanic acid in CNS
Episodic ataxia 2 AD 19p13
Hartnup disease AR 11p13  Leigh disease

2. Ataxia with spinocerebellar dysfunction 4. Ataxia with progressive myoclonic epilepsy

Type Inheritance  Group with seizure disorders with
Friedrich ataxia AR phenotypic features of myoclonic and
Ataxia with selective generalized seizure, ataxia, cognitive
Vitamin E deficiency deficits
Cerebellar ataxia AD  Unverricht-Lundborg disease
A- or hypo-  Lafora body disease
betalipoproteinemia
 Neuronal ceroid lipofuscinosis
 Myoclonic epilepsy with ragged red fibers
 Friedrich ataxia
 Mutation involving Triple repeat
expansion
 GAA repeats in 7-38 in normal alleles
 Mutation leads to abnormal protein
“Frataxin”
 Variable age of onset, younger than 20
years old
 5-10 years: Cerebellar ataxia,
dysarthria, nystagmus, impaired
proprioception, hypoactive reflexes, MULTIPLE SYSTEM ATROPHY
babinski sign  Definition
 Cardiac features: hypertrophic  Sporadic, progressive,
cardiomyopathy, CHF, subaortic neurodegenerative disorder
stenosis  Unknown etiology
 Skeletal: Pes cavus, scoliosis  Characterized by extrapyramidal,
 GI: Malabsorptive state in early years pyramidal, cerebellar, autonomic
with steatorrhea and abdominal dysfunction
distension  An A-synucleinopathy
 Metabolic: Diabetes mellitus  Pathology
 Diagnostics  Neuronal loss, extensive demyelination,
o NCV studies gliosis
 Axonal neuropathy  Oligodendroglial cytoplasmic inclusions
o MRI  Damage primarily in white matter
 Cerebellar and spinal  Found mainly in basal ganglia,
cord atrophy cerebellum, intermediolateral columns
of SC
3. Ataxia with progressive cerebellar  Clinical features
dysfunction plus systemic features  Hallmarks: parkinsonism, ataxia, autonomic
 Involve defects in DNA repair, multiple gene failure or pyramidal signs
defects invloved  Predominantly parkinsonism
 Combined with neurological and systemic  Predominantly ataxia
features

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  Combination of parkinsonism, ataxia,  Huntingtin – forms nuclear and
autonomic failure cytoplasmic aggregates
 Relatively rapid progressive and fatal (9.5 years  Imaging
from onset)  Atrophy of putamen
 MRI  Box-car shaped ventricles
 Hyperintensity in pons, peduncles,  Neuropath
cerebellum (T2)  Loss of medium spiny striatal neurons
 Slit hyperintensity in lateral margin of accompanied by gliosis
putamen – characteristic finding  Biochemical
 Decreased GABA, enkephalins and
OLIVO-PONTO-CEREBELLAR ATROPHY (OPCA) Substance P
 Form of progressive ataxia distinguished by  Genetics
pontine flattening and cerebellar atrophy  Anticipation (age of onset occurs earlier
with succeeding generations)
PROTEIN MISFOLDING DISEASES  Atrophy of caudate nucleus
 Prion encephalopaties
 Huntington’s disease
 Alpha crystallinopathy

Prion Encephalopathies
 Prion protein (PrP)
 Normal abundant protein in the brain; unknown
function
 Abnormal PrP
 Results from conformational conversion
DEMYELINATING DISEASES
of PrP
 Pathology
 Second structure dominated by B-
 Destruction of myelin sheath
pleated sheets
 Relative sparing of other elements:
 Prone to aggregation and resistant to
axon
protease digestion
 Infiltration of inflammatory cells
 Examples:
 Distribution is perivenous, primarily in
 Kuru
white matter
 Creutzfeldt-Jacob disease
 Lack of Wallerian degeneration
 Gerstmann-Straussler-Scheinker
(secondary degeneration of fiber tracts)
disease

Multiple sclerosis
Huntington’s Disease
 Disseminated sclerosis, Sclerosis en plaques
 Inheritance
 Protean clinical manifestations
 AD with 100% penetrance on Chrom 4
 Usually remitting-relapsing course
 Clinical
 Pathology
 Cognitive (subcortical dementia)
 Pink-gray lesions (due to myelin loss)
 Movement disorders (chorea, dystonia,
 Periventricular localization
motor impersistence, incoordination,
 Also involve optic nerves, chiasm and
gait instability, young patient-
spinal cord
parkinsonism)
 Distributed randomly in brain, SC and
 Psychiatric disorders (depression,
cerebellar peduncles
anxiety, impulsivity, apathy, OCD)
 Etiology and epidemiology
 Features:
 1 in 100,000 in equatorial area; 6-14 in
 Age 20-40 years
100,000 (Southern US), 30-80 in
 Progressive relentlessly to death in 10-
Canada, Northern Europe, North US
15 years
 Migration (after 15yo) – carry risk of
 Pathology
new country
 Expansion of CAG trinucleotide repeat
 Familial tendency – 15%; 1st degree
6-39 to 180 encoding polyglutamine
relatives – 10-20x greater risk
with a large protein “Huntingtin”
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 Role of Humoral system
 (+) Oligoclonal immune proteins in CSF
(produced by B lymphocytes)
 Physiologic effect of demyelination
 Uhthoff phenomenon – temporary
induction of symptoms by heat or
exercise
 Smoking, fatigue, rise of environmental
temp – worsening of symptoms
 Clinical manifestations
 Weakness and numbness in one or both
limbs
 Lhermitte sign – passive flexion of neck
induces electric-like feeling down the
shoulders and legs
 Clinical syndromes
 Optic neuritis
o 25% of MS patients
o Pain within the orbit worsened
by eye movement or palpation
o Cecocentral scotoma
o Evidence of swelling or edema
of optic nerve (papillitis)
o Uveitis and/or sheathing of
retinal veins
 Acute transverse myelitis
o Usually asymmetric and
incomplete
o Rapidly evolving paraparesis,
sensory level at the trunk,
sphincteric dysfunction,
bilateral Babinski signs
 Variants
 Acute MS
o Highly malignant form
o Combination of cerebral, BS,
spinal manifestations
o Evolves over a few weeks
o Patient may become stuporous,
comatose, decerebrate and
death in few weeks to months
o No remission
o Aka Marburg variant
 Neuromyelitis optica
o Simultaneous or successive
involvement of optic nerves and
SC
o Acute or subacute blindness of
one or both eyes preceded or
followed with transverse or
ascending myelitis
o SC lesions are necrotizing than
demyelination
o Does not present with
oligoclonal bands in CSF
 Other patterns:
 Charcot’s triad: nystagmus, scanning
speech, intention tremor
 One-and-a-half syndrome
o Intranuclear ophthalmoplegia in
one eye; horizontal gaze paresis
in another
o Involvement of Paramedian
Pontine Reticular Formation
(PPRF) and MLF
 Signs and symptoms
 Mix of generalized type
 Involvement of optic nerves, brainstem,
cerebellum and SC)
 30-40% with spinal form
 Other forms: cerebellar,
pontocerebellar, amaurotic
 Psychiatric: euphoria, depression,
global dementia; confusional psychotic
state in advanced stage
 2-3% - seizures
 Schumacher’s criteria
 2 separate CNS lesions
 2 separate attacks or 6 months
progression
 Objective findings on examination
 White matter disease
 10-50 years old
 No other disease to explain
constellation of signs
CADE_md2 6
  Treatment
 Immunomodulators
o Steroids
o Optic neuritis – IV MP followed
by oral prednisone
o Chronic progressive MS –
Prednisolone +
cyclophosphamide
o Interferon
 Plasma exchange

Acute disseminated encephalomyelitis (ADEM)

Acute necrotizing hemorrhagic encephalomyelitis

 Aka Acute hemorrhagic leucoencephalitis of
Weston Hurst
 Most fulminant of demyelinating diseases
 Affects mostly young adults and also children
 Preceded by respiratory infection
 Pathology
 White matter destroyed almost to the
point of liquefaction
 Resembles ADEM with widespread
necrosis
 Treatment
 Corticosteroids
 Plasma exchange

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