Fall Dementia: Your brain in health and agingucsfcme.com/minimedicalschool/syllabus/fall2015... ·...
Transcript of Fall Dementia: Your brain in health and agingucsfcme.com/minimedicalschool/syllabus/fall2015... ·...
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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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