Neurodegenerative Disorders
Epidemiologic and Clinical Aspects
Pathway
Structure
Disorder A
Disorder B
Pathway
Structure
Risk
Factors
Disorder A
Disorder B
Pathway
Structure
Risk
Factors
Disorder A
Disorder B
Huntington’s Disease
•  Long Island, NY MD described disorder in 1872
•  Estimated 30,000 Americans with HD
•  10x regional variations in prevalence
•  Onset is usually between ages 30-45 although there
is a juvenile variant
•  Progressive loss of functional ability and death in all
patients within 10-30 yrs from onset
Huntington’s Disease
Movement disorder
•  Chorea -brief, semi-directed, irregular movements - not
repetitive or rhythmic
•  Athetosis – writhing, twisting
•  Eye movement abnormalities occur early
•  Motor impersistence (inability to maintain position)
•  Dystonia (muscle contractions) and bradykinesia (slowed
movement) – more prominent later in course of illness
•  Less common but can be seen – tics, tremor, myoclonus (rapid
jerks)
Choreo-athetosis
HUNTINGTON’S DISEASE
•  Autosomal dominant neurodegenerative disorder
•  Determined by genetic mutation on short arm of
chromosome 4
•  Mutation is an expanded and unstable trinucleotide repeat of
cytosine-adenosine-guanine (CAG);
•
< 35
No symptoms
•  35–39
Variable expression
•
> 39
Essentially all become symptomatic
•  Mutation codes for abnormal polyglutamine expansion within
the protein huntingtin
•  inclusion bodies of aggregated huntingtin found in HD brains
Higher number of CAG repeats associated with earlier
symptom onset
Age at
Onset
HD is on one of 9 CAG repeat diseases that
affect the nervous system
Basal Ganglia
Pathology in HD
•  Neuronal loss
throughout cortex
•  Most prominent in
striatum
•  Projections to Gpe
particularly affected
Functional
Connections
of Basal
Ganglia
How Does Caudate
Pathology Cause
Chorea?
1)  Decreased Thalamic
Inhibition via decreased
indirect pathway activity
a)  Selective loss of indirect
pathway striatal outputs
b)  Loss of inhibition of Gpe
c)  Increases GPe inhibition
of STN and GPi/SNr
d)  Reduces excitatory STN
output to Gpi & SNr
e)  SNr and GPi provide less
inhibition of thalamus
a
b
c
c
d
Glutamate
e
GABA
Neuroimaging
Huntington’s Disease
Co-morbid Symptoms
•  Cognitive impairment
•  loss of recent memory
•  poor judgment
•  impaired concentration
•  Occurs in nearly all patients
•  May precede onset of motor symptoms
•  Progresses to global dementia in later stages
Huntington’s Disease
Co-morbid Symptoms
•  Psychiatric impairment
•  Depression (10x suicide risk)
•  Personality changes
•  agitation, irritability, anxiety, apathy, social
withdrawal, impulsiveness, mania, paranoia,
delusions, hostility, hallucinations, psychosis, and
sexual disorders
•  May precede onset of motor symptoms
PARKINSONISM
(‘pill-rolling’)
(slowed movement)
(‘lead-pipe’ or ‘cog-wheel’)
Parkinsonian Syndromes
•  Idiopathic
•  Parkinson’s Disease
•  Atypical Parkinsonism
•  Symptomatic
•  Post-infectious
(‘Awakenings’)
•  Toxic (MPTP,
Manganese, CO)
•  Post-traumatic (boxers)
•  Drug-induced
(neuroleptics)
Cassius Clay/Muhammad Ali
3-time World Heavyweight Boxing Champion
NBC Today Show Interview (1991)
After Emergence of Post-traumatic Parkinsonism
Parkinson’s Disease
•  1817 - ‘Essay on the Shaking Palsy’ by James Parksinson
•  1919 –selective loss of dopamine containing SN neurons in
PD patients identified
•  1960 – dopamine deficiency discovered in striatum of PD
patients
•  1961 – akinesia improves in PD and post-encephalitic
patients with injection of levodopa, dopamine precursor
•  1967 - levodopa becomes available in pill form
Lewy body
Deposition of
a-synuclein
PD reflects Selective Dopamine Insufficiency
How Does DA Deficit
Cause PD Motor
Symptoms?
1)  Increased Thalamic Inhibition
via imbalance of Direct and
Indirect Pathways
a)  Direct - Less D1-mediated
inhibition of GPi & SNr
b)  Indirect
i)  More D2-mediated striatal
inhibition of GPe
ii)  Less GPe inhibition of
STN, GPi & SNr
iii)  More STN excitation of
GPi & SNr
b) i.
a
b) ii
b) iii
1
EPIDEMIOLOGY
Parkinson’s Disease
•  Peak age at onset = 60
•  2% lifetime risk, 4% if
affected relative
•  850K in US
•  M:F = 3:2
•  Highest rate in Hispanics,
lowest in African Americans
•  Can live 20+ yrs with
treatment
Incidence by Period
Olmstead Co., MN
GENETIC FACTORS IN PD
•  Twin Studies
•  Similar MZ – DZ concordance in 193 twin pairs
•  In 16 twin pairs with early PD (< age 50), concordance was
4/4 MZ pairs & 2/12 DZ pairs, suggesting strong genetic
contribution to early onset cases
•  Family Studies
•  Southern Italian family
•  50/592 with highly penetrant, autosomal-dominant, autopsyproven PD
•  Linkage analysis identified mutation on chromosome 4 at the
SCNA gene that codes for alpha-synuclein
•  Subsequent linkage studies in large pedigrees have identified
24 other autosomal genes associated with PD
ENVIRONMENTAL RISK FACTORS
•  Case-control studies show increased risk of
PD with exposure to:
• Herbicides, Pesticides
• Living in a rural environment
• Consumption of well water
• Proximity to industrial plants or quarries
•  Smoking/caffeine associated with lower risk
MPTP Model of PD
•  Parkinsonism seen in drug addicts exposed to
synthetic heroin (MPTP)
•  Progressed over several weeks and improved
modestly with dopamine replacement therapy
•  No other neuronal involvement (‘pure
parkinsonism’)
•  MPTP in primates induces parkinsonism and
selective degeneration of nigro-striatal DA neurons
•  Toxic to mitochondria
•  Chemical resemblance to some herbicides and
pesticides suggests possible toxic etiology of PD
via oxidative stress/other mechanisms
PARKINSON’S DISEASE
Non-Motor Features
•
•
•
•
•
Cognitive Dysfunction
Depression
Hallucinations (late)
Autonomic dysfunction
Personality change
•  restricted vs.
compulsive behavior
Parkinson-Plus Syndromes
(α-synucleinopathies)
Syndrome
Location of Deposits
Additional Symptoms
Parkinson’s Disease (PD)
Substantia Nigra (SN)
neurons
n/a
Dementia with Lewy Bodies (DLB)
SN & Neo-Cortex neurons
Non-amnestic cognitive deficits,
hallucinations, delusions
Multisystem Atrophy (MSA)
Depositions in Glia
Poor response to levodopa
Striatonigral Degeneration (MSA-P) SN mainly
Olivopontocerebellar Atrophy (MSA-C) SN, Brain stem nuclei &
Cerebellum
Shy-Drager Syndrome (MSA-A) SN & Brain Stem Nuclei
Genitourinary, orthostatic
hypotension
Ataxia, genitourinary, orthostatic
hypotension
Genitourinary, orthostatic
hypotension
Reduced
Serotonin in
PD