PD – Circuitry changes

PD HDNormal

Causes of PD

Genetics Several identified mutations associated with PD LRRK2 mutations – some are autosomal dominant, but not all cause PD

More common among PD cases among Ashekenazi Jews and N. Afrikan Berber Arabs

Environmental? Earliest identified risk factor was use of well-water At least two pesticides (rotenone and paraquat) associated with increased risk Intravenous drug use in some cases…

Parkinsonism – Symptoms and Signs like PD, but another cause

Great NOVA show

Encephalitis lethargica (“Von Economo’s Disease)

PD - Prognosis

Many treatments available or under investigation (more about that in Week 8) Drugs, but side-effects can be limiting Surgery - not without risks Electrical simulation of the brain - not without risks Cell implants (e.g., stem cells) – still under investigation

No cures available yet Caffeine may be protective Smoking reduces PD risk (NOT suggesting it is healthful overall!)

Creutzfeld-Jacob Disease (CJD)

CJD is a rare, rapidly progressing, invariably fatal neurodegenerative disorder.

The disease is found most frequently in patients 55–65 years of age, but cases can occur in people older than 90 years and younger than 55 years of age.

In more than 85% of cases, the duration of CJD is less than 1 year after onset of symptoms.

Very curious disease, that has revolutionized our understanding of disease…

George Ballanchine

CJD is a “Spongiform encephalopathy”CJD is characterized by rapidly progressive dementia.

Initially, individuals experiencemuscular incoordinationpersonality changes,impaired memory, judgment, and thinkingimpaired vision

People with the disease also may experience insomnia, depression, or unusual sensations.

CJD Subtypes

There are 4 recognized subtypes:

Sporadic CJD: the person has no known risk factors for the disease; 85 % of cases.

Hereditary CJD: family history of the disease and/or tests positive for a genetic mutation associated with CJD. About 5 to 10 % of CJD cases in the US are hereditary. Hereditary CJD is autosomal dominant (i.e., 50% chance of getting from an affected parent)

Iatrogenic CJD: transmitted by a medical procedure that caused exposure tissue from a patient with CJD. About 1% of CJD cases

Variant CJD – caused by exposure to tissue from cows with “Mad Cow Disease”

Iatrogenic CJD – unusual transmissibility

A case of CJD associated with a corneal transplant was reported. Animal experiments showed that corneas of infected animals could transmit CJD, and the causative agent spreads along visual pathways.

CJD transmission caused by silver electrodes previously used in the brain of a person with CJD. Transmission occurred despite decontamination of the electrodes with ethanol and formaldehyde.

In some cases the exposure occurred weeks after the instruments were used on a person with CJD.

CJD has unusual transmissibility

Can be acquired by eating contaminated tissue Reminiscent of “kuru”

Transmitted by cannibalism and/or handling of human brain tissue Can be transmitted only to primates Does not appear to involve any inflammation, fever Found that heritable CJD could be transmitted to primates!?

Reminiscent of the sheep disease scrapie infectious agent was not bacteria, nor viruses, nor involved DNA or RNA!?...

For both, transmission more effective the more closely-related the species, and symptoms can take a year to develop!?...

Carlton Gajdusek1976 Nobel Prize

The answer?

The protein in CJD, Mad Cow etc. is “PrP” (Prion Protein); PrPSC => scrapie; PrPCJD => CJD

Stanley PruisnerNobel Prize 1997

Nobel Prize "for his discovery of Prions - a new biological principle of infection"

Prions (Proteinaceous infectious bodies)

CJD - Prognosis

No treatments available, yet

Most die within 1 year of diagnosis

Alzheimer’s Disease

• Named after Dr. Aloysius “Alois” Alzheimer• In 1906, he noticed changes in the brain tissue of a woman who had

died of an unusual mental illness. • Her symptoms included memory loss, language problems, and

unpredictable behavior. • Her brain and contained many abnormal clumps (now called

amyloid plaques) and tangled bundles of fibers (now called neurofibrillary tangles).

Dr. Alzheimer Auguste Deter

Normal neurons

AD Pathology

Alzheimer’s Disease Irreversible (so far) destruction of brain and loss of mental function

Progressive over 5-10 years >50% of cases of dementia are AD (2nd most common: vascular disease) As many as 5 million Americans age 65 and older may have Alzheimer’s disease.

Three main AD groups: Familial: mutations of gene for amyloid precursor protein (APP), or presenilin-1 or -2

Presenilin-1 and presenilin-2 are proteins that process APP Down syndrome: trisomy 21 (APP gene is on Chr.21)

Most have plaques and tangles by 40, AD by 60 Sporadic (most common, ~90% of AD cases)

Risk factors: age (>65), head trauma, ApoE4 gene, hypertension, obesity, high Aluminum exposure Potential protective factors:

high educational level, mental and physical exercise,

Alzheimer’s Disease – Early Symptoms Short term memory problems

Rapid forgetting, inability to “keep up with what is happening”, acquire new information

Long-term memory problems Difficulty remembering vary familiar things, events, people, faces, words

AD does not affect all memory capacities equally. Older memories of the person's life, facts learned, and how to do things are less affected

Early signs include Mild Cognitive Impairment Amnestic MCI is more associated with AD, NOT ALL MCI PROGRESSES TO AD!

AD is NOT normal aging, and not inevitable

Potential Cause of AD #1: A

Potenitial Cause of AD #2 – Tangles (made of “Tau protein”

P

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Potential Cause of AD #3: N-APP

Brain Disorders - Summary Neurodegenerative disease is not an inevitable part of normal aging

Any given brain disease can have many causes All diseases seem to have cases with clear genetic causes

Brain disorders must often be diagnosed by symptoms rather than underlying cause Depression, sleep problems, memory loss, etc. can look the same, but have different causes Cases can have unique presentations and not fit clear, exclusive disease categories This makes diagnosis and choosing how to treat difficult

“Proteinopathy” is a common feature, but of unknown causality

Neurodegenerative diseases have a a huge unmet medical need Donate time or money, or at least volunteer for studies for which you are eligible

Neurological & Psychiatric Disorders Have Had a “Bad Rap”

The brain is a part of your body, like eye lens, bones, prostate, etc. Mental Disorders are physical problems, like cataracts, diabetes etc.

Lack of “will power” or “character” are not the cause of brain disorders Nor of cataracts, or osteoporosis, prostate cancer, etc.

The stigmatization of mental disorders is illogical, ignorant, and callous Any one of us could develop a brain disorder…tomorrow…

Thank you for your attention

Questions? Comments?