Parkinson Disease:  Pathophysiology, Diagnosis,  DaTscan & Differential Diagnosis

Parkinson Disease: Pathophysiology, Diagnosis, DaTscan & Differential Diagnosis

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Description: Main Biochemical Abnormality: Marked striatal DA depletion, ~70% DA loss for symptom manifestations. α‐synuclein PD pathophysiology- Aggregated protein may : Form pores in cell membrane, Interfere with axonal transport, Impair proteasomal system, Interfere with chaperone role in autophagy, Selectively damage DA neurons. LRRK2: Leucine‐rich repeat kinase 2, AD, Most common cause of familial and sporadic PD- 1.5% of late‐onset PD,40% of Arab PD pts,20% of Ashkenazi Jewish PD pts, Late onset ‘idiopathic PD’ phenotype- Homozygous = heterozygous phenotype.

 
Author: Maureen A. Leehey M.D.  | Visits: 409 | Page Views: 773
Domain:  Medicine Category: Therapy 
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Contents:
Parkinson Disease: 
Pathophysiology, Diagnosis, 
DaTscan & Differential Diagnosis 
Maureen A. Leehey, M.D.
Professor of Neurology
University of Colorado Denver

Disclosures
• Grants & research support
– Neurologix, Inc., Schwartz Biosciences, Impax
Pharmaceuticals

• Consultant
– Sultan Qaboos Universtiy, MEDA Corp, Guidepoint
Global Advisors

• None related to content of this presentation

Objectives
• To understand the genetic causes of Parkinson 
disease (PD)
• To learn the current knowledge regarding the 
pathophysiology of PD
• To learn how the DaTscan can be useful in the 
diagnosis of parkinsonism
• To increase knowledge of the DDx of PD

“Primary PD”
 Resting tremor
 Bradykinesia
 Rigidity
 Postural Instability

 Asymmetric
 Levodopa response
 Levodopa ‐ induced motor 
complications

 Lewy body pathology

Parkinson Syndrome
• Incidence
– Incidence of PS/PD rising slowly with aging population

• Prevalence
– 1% over age 65
– 4% over age 80
– 57‐371/105 worldwide (USA/Canada 300/105)

• Onset
– mean PD 62.4 years
– 4‐10% cases  before age 40 
– rare before age 30 
www.wemove.org

Pathology of Parkinson Disease

Main Biochemical Abnormality
• Marked striatal DA depletion
• ~70% DA loss for symptom manifestations

www.wemove.org

Etiology of PD
• Genetics
• Environment
• Aging brain

Nongenetic PDs Risks











Aging
Male gender
Caucasian 
FH PD
Personality traits
Well water
Pulp mills
Farming 
MPTP like compounds
Pesticides












Industrial agents
CO
Metals
Rural residence
Dietary lipid & milk
↑ caloric intake
Encephalitis
Chronic inflammation
Head trauma
Stress

Chade AR, Kasten M, Tanner CM. Nongenetic causes of
Parkinson’s disease. J Neural Transm (Suppl) 2006:147-151.

Nongenetic Factors that
↓ PDs Risk





Smoking
Caffeine
NSAIDs
↑ Uric Acid

Chade AR, Kasten M, Tanner CM. Nongenetic causes of
Parkinson’s disease. J Neural Transm (Suppl) 2006:147-151.

Genetics of PDs
• Rare single gene mutations
(monogenic forms of PD)
SNCA, LRRK2, PRKN, DJ1, PINK1, and 
ATP13A2

• Susceptibility genes
MAPT, LRRK2 and SNCA

Monogenic PD

Thomas, et al. F1000 Medicine
Reports 2011, 3:7.

Monogenic PD 
Gene/protein

Pattern

Prevalence

Pathology

Common Features

Notes
Aggregation of protein in
Lewy bodies from
genetic and sporadic
forms of PD

AD

Very rare

Lewy
bodies

Early-onset dementia;
presentation variable
with mutation type

Parkin

AR (mostly)

18% EOPD
(50% with
family
history)

Rare Lewy
bodies, if
any

Early onset, slow
progression

Protein is involved in
ubiquination

DJ-1

AR

 FXS
FXS: common cause of MR
M affected > F 

FMR1 gene CGG repeat size & resultant 
clinical signs

Genotype

CGG Repeat Size

Neurological Signs

Normal

6 - 40

None

Premutation

56 - 199

POF, FXTAS

Full mutation

>200

FXS: Mental retardation,
learning disabilities, autism

FXTAS Misdiagnoses Categories (n = 98)
Misc
16%

Tremor
20%

Cerebrovascular
11%

Ataxia
17%

Dementia
12%
PDism
24%

FXTAS MCP sign

Also:   Global atrophy
↑T2 white matter 

FXTAS Neuropathology

Greco C, Hagerman RJ, Tassone F et al. Neuronal intranuclear inclusions in a new
cerebellar tremor/ataxia syndrome among fragile X carriers. Brain 2002; 125:17601771.

Maroon Bells, Aspen, Colorado
Copyright © 2004 Craig Schultz
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