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