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Michael D. Geschwind, MD, PhD

UCSF Department of Neurology

Memory and Aging Center

Michael D. Geschwind, MD, PhDProfessor of Neurology

UCSF Memory and Aging Center

UCSF Mini‐Medical School Fall 2015Dementia:

Your brain in health and aging

Dr. Geschwind’sDisclosures

• Consulting for MedaCorp, Gerson Lehrman Group, Clinical Advisors, Guidepoint Global, Quest Diagnostics, Best Doctors, Med-Legal

• May discuss off-label use of approved drugs

Memory and Aging Center

~170 employees: >30 faculty (neurologists, geriatrician, psychiatrist, pathologists, neuropsychologists, nurses, genetics counselors), social workers, technology team (IT), research assistants

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UCSF Neurology and the Memory and Aging Center:

What We Do

Patient Care

Research

Education

Mini-Medical School Fall Outline• 0/14/15 Rapidly Progressive Dementia: From Prions to Antibodies

Dr. Michael GeschwindDr. Jeff Gelfand

• 10/21/15 Normal and Abnormal Aging and the BrainDr. Joel KramerDr. Kristine Yaffe

• 10/28/15 Sleep DisordersDr. Tom NeylanDr. Elissaios Karageorgiou

• 11/4/15 Language and Brain: From Dyslexia to Progressive AphasiaDr. Marilu Gorno-TempiniDr. Isabel HubbardDr. Kevin Shapiro

• 11/18/15 Chronic Traumatic EncephalopathyDr. Gil RabinoviciDr. Raquel Gardner

• 12/2/15 Alzheimer’s disease, FTD and Parkinson’s diseaseDr. Howie RosenDr. Bruce MillerDr. Caroline Tanner

Outline of Talk• Introduction to the brain

• Dementia Basics

• Causes of dementia

• Rapidly progressive dementia

– Prion diseases (models for other neurodegenerative diseases)

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Neuron is a key cell in the nervous system

Major brain regions

http://www.timvandevall.com/human-brain-diagram/

Front Back

Main functions of various brain regions and networks

http://www.brainwaves.com/

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Brain function often relies on networks of connectivity

In brain disorders, these networks are disrupted

Photo of brain cut showing gray and white matter

Different brain MRI sequences can show anatomy and/or abnormalities

Front

Back

Anatomical (T1) sequence showing gray and white

matter & small old strokes

FLAIR sequences show white matter

abnormalities well

21 yo with MSHealthy 23 yo

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What is dementia?

• Dementia: An acquired, persistent intellectual impairment involving multiple cognitive domains (memory, language, navigation, etc.), sufficient to cause a significant decline from a previous level of functioning.

• Mild Cognitive Impairment (MCI): Cognitive decline greater than expected for age and education, but not sufficient to cause a decline from a previous level of functioning.

Dementia is not normal aging!

Causes of dementia

Kester & Scheltens P Pract Neurol 2009;9:241-251; Lobo et al. Neurology 2008;54(Suppl 5):S4–9. Harvey et al. JNNP 2003;74:1206–9.

©2009 by BMJ Publishing Group Ltd

Age >= 65

Age < 65

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Neurodegenerative diseases are associated with specific protein

signaturesDisease Protein

Alzheimer’s amyloid (Aβ-42) & tau

Frontotemporal dementia tau, Ubiquitin, TDP-43, …

Dementia Lewy Bodies α-synuclein, Aβ-42

Parkinson’s alpha-synuclein

Huntington’s huntingtin

Jakob-Creutzfeldt disease (CJD)/prion

prion

Alzheimer’s disease under the microscope: plaques and tangles

Univ Utah

Amyloid plaques (Aβ-42)

Neurofibrillary tangles (tau)

Courtesy of John Trojanowski

In Alzheimer’s plaques and tangles spread through the brain as the disease progresses

Early Middle Late

Atrophy (shrinkage) due to nerve cell loss occurs over time

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Key Concepts in Dementia• Dementia is an “umbrella” term

• Often disorders of misshapen proteins

– act as templates for protein misfolding

– cause other proteins to misshape

– spread in brain (Domino-like effect)

• Certain brain regions preferentially affected → circuits disrupted

• Neurodegenerative diseases are not only causes of dementia

Current & past symptoms

Fam. Medical/Social/Medication history

Review relevant diagnostic tests (blood, urine, imaging, spinal fluid, EEG)

Physical/neurological exam & cognitive testing

Additional tests Diagnosis

- Usually responsive to immunosuppression

How doctors evaluate dementiaFirst get the data

Localize the problem(s)

Create list of likely/urgent causes (“differential”)

Treatment

Physician’s thought process • Time course – slow, fast, vs sudden-onset

– 75 yo man with 3 years of memory problems

• Key symptoms and exam findings

• Localization in body or nervous system

• Pattern recognition based on most likely causes

– Group by likelihood & urgency of diagnosis

• Occam's Razor

• Rule out mimics or other reversible causes

• “When you hear hoof beats, first think horses, not zebras”

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VITAMINS approach to dementia diagnosis

• Vascular (Strokes, clotting of brain veins, vasculitis, intravascular lymphoma)

• Infectious (HIV, Lyme, encephalitides, Whipple’s, fungal, parasites)

• Toxic-Metabolic (medications, vitamin excess/deficiency, toxins, genetic metabolic disorder)

• Autoimmune (Antibody-mediated, rheumatological, cancer-related)

• Metastases/Neoplastic (cancer)

• Iatrogenic – review med list!!

• Neurodegenerative (Alzheimer’s, Parkinson’s, Frontotemporal, Dementia with Lewy Bodies, …)

• Systemic/Seizures/Structural

What are rapidly progressive dementias (RPDs)?

• Most dementias progress over years (survival ~ decade or more)

• RPDs – onset to dementia in <1-2 yrs

• Prototypical RPD - Prion diseases (e.g. Jakob-Creutzfeldt disease)

– proteinaceous infectious particles

• Prion disease – rare, but now model for most other neurodegenerative diseases

Sporadic (85-90%)Creutzfeldt-Jakob disease (CJD)

Genetic (10-15%) ~60% no CJD FMH!!

Familial CJD (fCJD)

Gerstmann-Sträussler-Scheinker (GSS)

Fatal familial insomnia (FFI)

Acquired(Iatrogenic/environmental; <1%)

Kuru –Papua New Guinea -endocanabalism

Variant CJD (vCJD) – mostly in UK; due to BSE

Iatrogenic – due to medical procedures (e.g., hGH, duramatergrafts)

Animal & Human Prion DiseasesScrapie – sheep and goats

Bovine spongiform encephalopathy (BSE or “mad cow”) – UK epidemic, but isolated cases in N. America and other countries

Chronic Wasting Disease (CWD) – mule deer, elk, moose in N. America. Might spread via saliva, urine, feces

Transmissible mink encephalopathy (TME) – mostly captive populations

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?

Prions are misfolded forms of normal proteins, that become transmissible

PrPSc

PrPScPrPSc

PrPC

Protein X

Sporadic Jakob-Creutzfeldt Disease (sJCD)

• Peak age onset 55-75 years

– median 68, mean 61, range 12-98 years

• Uniformly fatal; survival ~7 months; ~90%< 1 yr

• Incidence of ~1.5/million cases per year

• Lifetime risk of dying from CJD: 1/9,000

• Annually about

– ~6000 cases worldwide

– ~300 cases in USA

– ~30 cases in CA

WHO Revised 1998^

Dementia w/

2 of 4 following:1. Myoclonus

2. Pyramidal/EP

3. Visual/Cerebellar

4. Akinetic Mutism

ANDTypical EEG orElevated spinal fluid

protein 14-3-3 (if

< 2 year duration)*AND no other condition

to explain^1998

How do we diagnose sporadic prion disease?UCSF 2007

Rapid cognitive decline w/

2 of 6 following:1. Myoclonus

2. Pyramidal/EP

3. Visual

4. Cerebellar

5. Akinetic Mutism

6. Other focal cortical sign (neglect, aphasia,

apraxia,…)

AND

Typical EEG or BrainMRI

European 2009 ^Dementia w/

2 of 4 following:1. Myoclonus

2. Pyramidal/EP

3. Visual/Cerebellar

4. Akinetic Mutism

ANDTypical EEG orElevated spinal fluid

protein 14-3-3 (if

< 2 year duration)* orBrain MRI

^Geschwind et al 2007

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– Month 1: Lost in the house, trouble with reading, using computer, word finding, visual distortion - his hands appeared too big, stopped driving

– Month 2: repeated what others said, difficulty speaking, stopped biking, can’t use utensils, unable to help with chores

– Month 3: cannot be left alone, easily angered/frustrated

– Exam @ month 3

61 y/o gentleman with 3 months of confusion, forgetfulness, vision and word finding problems

His diffusion weighted brain MRIDWI sequence – bright white areas are abnormal

ADC sequence – dark “ribbon” on brain surface abnormal

Diagnoses of RPD, prion and suspected CJD Subjects Referred to vs. Evaluated at UCSF

Memory & Aging Center (8/01-6/9/2015)N=2535

Referred to UCSF

N=622

Evaluated at UCSF

Not CJD44%

Potential sCJD3%

sCJD29%

gPrD14%

gPrD @ risk1%

gPrDmutation negative

7%

Acquired CJD<1%

Not CJD25%

Potential sCJD27%

sCJD31%

gPrD10%

gPrD @ risk3%

gPrD mutation negative

3%

Acquired CJD1%

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Diagnoses of patients referred to UCSF as “CJD” but found to have non-prion RPDs (8/2001-9/2007)

Diagnostic Category %

Neurodegenerative (CBD > DLB > FTD > AD > PSP) 39

Autoimmune 22

Unknown dementia 12

Infectious 6

Psychiatric 6

Malignancy 6

Toxic/metabolic 4

Vascular 4

Other 1

Total % 100

N =178

Geschwind et al. 2007 Annals

Other RPD

Series

• 22 “RPD” (onset to death < 4 years)• CJD (36%)> FTLD-MND (23%) > PSP/CBD (18%) > DLB (14%) > AD

(9%)

• 68 RPD (< 1 year to dementia from cognitive onset)– Secondary dementias (26.5%) – infections, rheumatologic, toxic-

metabolic…

– AD = FTD (16-17% each)

– Vascular = CJD = Misc (9%) each

• 49 “RPD” (selected from CSF 14-3-3 test group)

• NDD (37%; DLB, AD±CVD, FTD-MND, FTD)> CJD (31%)> VD (8%) > Tox-Metabolic (8%) > Neoplastic, Infxn, Autoimmune, NCSE, .. (2%)

VITAMINS approach to RPD• Vascular (Venous thrombosis, strokes, vasculitis,

intravascular lymphoma)

• Infectious (HIV, Lyme, encephalitides, Whipple’s, fungal, parasites)

• Toxic-Metabolic (heavy metals, medications, B12, Bismuth, Wernicke’s, porphyria)

• Autoimmune (Anti-body mediated, Hashimoto’s Enceph)

• Metastases/Neoplastic (PCNSL, gliomatosis cerebri, paraneoplastic)

• Iatrogenic – review med list!!

• Neurodegenerative (CJD, DLB, AD, FTD, CBD, PSP)

• Systemic/Seizures/Structural (Sarcoid, Bechet’s, NCSE, Masses,..)

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T1 T1 w/ contrastT1 w/ contrast

62 yo M w/ RPD x 2 months with confusion → ataxia→encephalopathy→hospice

T1 T1 w/ contrastT1 w/ contrast

Diagnosis: B-cell lymphoma by brain biopsy

62 yo M w/ RPD x 2 months with confusion → ataxia→encephalopathy→hospice

Mechanism of prion diseases recently linked to other neurodegenerative

diseases• Marc Diamond, former UCSF professor, found

that the tau protein can spread in a prion-like manner from cell to cell

• Animal models have since shown that AB-42, tau, alpha-synuclein (protein involved in Parkinsonian diseases) shown to behave in a prion-like manner

• Increasing evidence in humans that these proteins behave in a prion-like manner, albeit slower and less virulent

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Final thoughts• Dementia is not normal aging

• Might be preventable and possibly treatable, depending on the cause

• Neurodegenerative diseases are based on specific protein abnormalities, which spread through networks

• Diagnosis - part science (data) and part art (acquisition & interpretation of data)

• Brain imaging is critical

• Much of what we’ve learned about brain disease is through research – both clinical and laboratory

• Hope that through the course, you will develop better understanding of brain function in health and disease

UCSF Memory and Aging Center 2014

Bruce Miller, Howie Rosen, Joel Kramer, Carolyn Fredericks, Sven Forner, Kelly O’Leary, Stacy Metcalf, Katherine Wong, Eduardo Caverzasi, Matteo Paoletti, Our Fellows & Students, ….

Institute for Neurodegenerative Diseases Stan Prusiner, Steve DeArmond, Abby Oehler, Kurt Giles, Joel Watts, Ana Serban, Shiganari Hayashi, and past members - Sina Ghaemmaghami, Giuseppe Legname, Pierre Lessard, Jiri Safar, David Colby, Fred Cohen, Barney May, Kristen Pomeroy

Funding (current and past)NIH/NIA R01 AG031189NIH PPG – Novel Prion TherapeuticsFight for Mike –Homer Family FoundationNIA K23 AG021989-01NIH Contract - CDI McBean Family FoundationJohn Douglas French Foundation

UCSF Memory & Aging Center (MAC)

OtherPatients and FamiliesNPDPSC/CDCCJD FoundationCJD Aware!

Jeffrey Gelfand (UCSF)

Josep Dalmau (UPENN/Barcelona)Sarosh Irani (Oxford)

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