Sean Rogers, MD, PhD
Co-Director
PARKINSON’S DEMENTIA AND RELATED
CONDITIONS
Diagnosis and therapy
Movement Disorders Program
Inova.org/move
Abnormal Build-up of Protein in Cells:
▪ Alpha-synuclein – Abnormally Folded Protein
▪ Garbage Disposal is overwhelmed
Classically found in “Synucleinopathies”
▪ Parkinson’s Disease
▪ Lewy Body Dementia
▪ Multisystem Atrophy
LEWY BODIES AND THEIR LOCATIONS
Ref 12 – Lewy body in the Substantia Nigra.
Location, location, location
Begins peripherally
▪ GI
▪ Skin
Travels up the Vagus Nerve3
▪ Transported by axons
Dementia - expansion to bilateral fronto/parietal lobe projections and hippocampal circuit
▪ Rapid vs slow
▪ Timing can often determine Diagnosis and Prognosis
LEWY BODIES AND THEIR LOCATIONS
Ref 14 – Lewy body locations, and amyloid plaque/neurofibrillary tangle development
Motor Symptoms:
▪ Basal ganglia – inputs of Dopamine, Acetylcholine, Norepinephrine
▪ Substantia Nigra pars compacta - ~400,000 dopamine neurons
▪ 70% loss with initial symptoms
Memory/Cognitive Symptoms
▪ Eventual extension of pathology to hippocampal circuit and bi -frontal/parietal areas
▪ Early Mild Cognitive Impairment
▪ Later can have similarities with Alzheimer's
▪ Tau = neurofibrillary tangles in AD
DEMENTIA IN PARKINSON’S DISEASE
Dementia with Lewy Bodies, Dif fuse Lewy Body Disease
30% of al l dementias 4, second to Alzheimer’s.
▪ 1.4 million people6
Classically associated with:
▪ EARLY cognitive change (within 1 yr of PD symptoms)
▪ Relatively rapid onset
▪ Fluctuating cognitive impairment
▪ Visual hallucinations
▪ Parkinsonism
▪ Sensitivity to
▪ Dopamine replacement – hallucinations, side-effects
▪ Neuroleptics – catatonia, rigidity
REM Behavioral Sleep Disorder now part of diagnostic criteria 5
LEWY BODY DEMENTIA
Pathology:
▪ Alzheimer’s pathology usually present on autopsy
(neurofibrillary tangles/tau)
▪ Significant loss of:
▪ Cholinergic neurons – cognitive change similar to AD
▪ Dopaminergic neurons – Parkinsonian symptoms
Eventually, Parkinson’s Disease Dementia and
Lewy Body Dementia are pathologically
indistinguishable
Location versus Timing
LEWY BODY DEMENTIA
Ref 16 – Silver stain identifying tangles and plaques
PET SCAN DATA COMPARING DLB, PD, PDD
18flourodopa uptake
Dopaminergic system
MP4A uptake
Cholinergic uptakeFDG uptake
Glucose metabolism
Ref 2
GREY MATTER LOSS: LBD VS ALZHEIMER’S
Cortical grey matter lossRef 15
IMPACT ON NEUROTRANSMITTER NUCLEI
Ref 15 – Location of Grey Matter loss in Lewy Body Dementia
Multisystem Atrophy (MSA)
Progressive Supranuclear Palsy (PSP)
Corticobasal degeneration (CBD)
OTHER PARKINSONIAN SYNDROMES
Cognitive impairment from a number of reasons, including:
▪ Initial reduction in Acetylcholine
▪ Later overexpression of glutamate damages cells
↑↑↑ Acetylcholine, ↓↓↓ glutamate (through NMDA)
Enhanced cognition AND reduction in hallucinations
TREATMENT
Block breakdown of Acetylcholine Stays around cell longer Improves function
▪ Donepezil (Aricept®) – inhibits acetylcholinesterase
▪ Rivastigmine (Exelon®) – inhibits butyrylcholinesterase and acetylcholinesterase
Exelon is only of the two FDA approved for Parkinson’s Dementia
▪ Patch form, reduces risk of nausea/vomiting
Because nucleus problem and not receptor problem, patients respond better than those with Alzheimer’s8
ACETYLCHOLINESTERASE INHIBITORS
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With LBD and PDD, acetylcholine is reduced
▪ Triggers an increase in glutamate to compensate for the impaired functioning.
▪ Overstimulation with glutamate causes neuronal hyper excitability and death.
Memantine (Namenda®)
▪ Blocks glutaminergic NMDA receptors
▪ Reduces glutamate activity
Corrects overexpression of glutamate
No benefit in early dementia9
Structurally similar to Amantadine reduction in dyskinesias and other PD side-effects.
NMDA BLOCKADE
Nuplazid (Pimavanserin)TM
▪ First antipsychotic medication specifically
designed for hallucinations and ‘psychosis’
associated with Parkinson’s Dementia
and Lewy Body Dementia.
▪ Serotonin Agonist with no impact on
dopamine receptors
▪ + SAPS-PD improvement with
no change in UPDRS
HALLUCINATIONS AND PSYCHOSIS
Hacksell, Uli et al. “On the Discovery and Development of Pimavanserin: A Novel Drug Candidate for Parkinson’s Psychosis.” Neurochemical Research39.10 (2014): 2008–2017. PMC. Web. 4 June 2015.
Avoid medications that block dopamine or acetylcholine
▪ Neuroleptics
▪ Cold medication
▪ Anti-emetics
▪ Older Parkinson’s medications such as Artane
AVOID
60% of Parkinson’s patients have clinical depression 10
▪ Equal numbers with Anxiety
Serotonin, Norepinephrine and Dopamine all significantly reduced in Parkinson’s
▪ Sleep, focus, mood, attention, etc.
Depression, Anxiety and Fatigue missed by Neurologists up to 50% of the time 11
Treatment with SNRI or SSRI can significantly improve cognitive function in some
patients
Depression masquerading as Dementia in the Parkinson’s community.
DEPRESSION AND ANXIETY’S ROLE
Activity!!
▪ Physical and Mental
Healthy Diet
▪ Heart health is similar to Brain health
▪ Cholesterol, blood pressure, diabetes
No strong evidence for any particular diet or supplements
WHAT ELSE CAN I DO?
Memory, cognitive functioning and mood are directly linked to Acetylcholine and
Dopamine.
▪ Treatment is complicated d/t balance of treating motor and non -motor symptoms,
incorporating different neurotransmitter circuits to give benefit without side -effects
Proper diagnosis is key, as treatment is dif ferent
▪ Parkinson’s vs
▪ Lewy Body dementia vs
▪ Parkinson’s dementia vs
▪ Parkinson’s plus syndromes
▪ +/- Depression
Integrating a Movement Disorders Specialist into your treatment team
CONCLUSIONS
Dr. Drew Falconer, Dr. Mahesh Shenai,
Dr. Sean L. Rogers
THANK YOU
Movement Disorders Program
www.inova.org/move
1500 N. Beauregard StreetSuite 300Alexandria, VA 22311
8505 Arlington BoulevardSuite 450Fairfax, VA 22031
703-845-1500
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REFERENCES