1 Cognitive disorders of aging: Unusual cases & new developments in diagnosis, treatment, and lifestyle factors Andrew E. Budson, M.D. Chief, Cognitive & Behavioral Neurology, Veterans Affairs Boston Healthcare System Professor of Neurology, Boston University School of Medicine Director of the Education Core, Boston University Alzheimer’s Disease Center Lecturer in Neurology, Harvard Medical School Financial Disclosure • Royalties from Publishing for – Memory Loss, Alzheimer’s Disease, and Dementia: A Practical Guide for Clinicians, AE Budson & PR Solomon, 2016 (Elsevier) – Seven Steps to Managing Your Memory: What’s Normal, What’s Not, and What to Do About It, AE Budson & MK O’Connor, 2017 (Oxford) – Chronic Traumatic Encephalopathy: Proceedings of the Boston University Alzheimer’s Disease Center Conference, AE Budson, AC McKee, RC Cantu, & RA Stern, 2017 (Elsevier) • Consultant/speaker for General Electric, Lilly, Axovant • Clinical trial investigator for Biogen, Lilly, vTv therapeutics, Axovant
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Cognitive disorders of aging: Unusual cases & new developments in diagnosis,
treatment, and lifestyle factorsAndrew E. Budson, M.D.
Chief, Cognitive & Behavioral Neurology, Veterans Affairs Boston Healthcare System
Professor of Neurology, Boston University School of Medicine
Director of the Education Core,Boston University Alzheimer’s Disease Center
Lecturer in Neurology, Harvard Medical School
Financial Disclosure• Royalties from Publishing for
– Memory Loss, Alzheimer’s Disease, and Dementia: A Practical Guide for Clinicians, AE Budson & PR Solomon, 2016 (Elsevier)
– Seven Steps to Managing Your Memory: What’s Normal, What’s Not, and What to Do About It, AE Budson & MK O’Connor, 2017 (Oxford)
– Chronic Traumatic Encephalopathy: Proceedings of the Boston University Alzheimer’s Disease Center Conference, AE Budson, AC McKee, RC Cantu, & RA Stern, 2017 (Elsevier)
• Consultant/speaker for General Electric, Lilly, Axovant• Clinical trial investigator for Biogen, Lilly, vTv therapeutics,
Axovant
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Patient 1• 59 F w/ forgetfulness
• Long history of domestic abuse with frequent blows to the head and “occasional” concussions
• Tearfulness & emotional blunting
• Language deficits including anomia, frequent paraphasic, phonemic, & neologistic errors
• Put plastic Tupperware into the oven, was cooking with incorrect ingredients.
– Always look for on scan (cannot depend on radiology)
• CSF Aβ, phospho tau (p-tau), & total tau Aβ & p-tau, total tau (www.athenadiagnostics.com)
– Pt clearly demented, unclear if AD, & knowing would change management or prognosis, e.g., young patient
• FDG-PETmetabolism in temporal and parietal cortex
– Pt clearly demented, unclear if AD, Lewy body, FTD, & knowing would change management or prognosis
From Budson & Solomon, 2016
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Dementia with Lewy Bodies
From Budson & Solomon, 2016
From Budson & Solomon, 2016
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From Budson & Solomon, 2016
behavioral variant
Frontotemporal dementia
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Aβ PET Scans FDA Approved!(but payment?)
– April 2012: Florbetapir Avid Radiopharmceuticals– October 2013: Flutemetamol GE Healthcare– March 2014: Florbetaben Piramal Imaging
• 18Florine based compounds (can be sent by Fedx) – Will detect Alzheimer’s disease (AD) pathophysiology– Use when knowing that AD pathology is present in
symptomatic patient would change management.– WARNING: will detect AD pathology in asymptomatic
patients who may not develop disease for 10-15+ years– Will have broader use when disease modifying
therapies are available.
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Amyloid Imaging with florbetapir
Alzheimer’s Disease65 year oldMoCA 21
Non-AD dementia
From Budson & Solomon, 2016
• What does she have? – Alzheimer’s? bvFTD? Dementia w/Lewy bodies? VaD?– Primary age-related tauopathy– Primary progressive aphasia & apraxia of speech– Frontotemporal Brain Sagging Syndrome– Subjective Cognitive Decline– Chronic Traumatic Encephalopathy
• How should we work her up?– Vitamin D– Brain biomarkers/amyloid imaging
• How should we treat her?– Cholinesterase inhibitors & memantine in MCI & moderate-severe
dementia– Dextromethorphan / Quinidine sulfate for psudobulbar affect– Pimavanserin for Parkinson’s Disease Dementia & psychosis– New medications being developed: symptomatic 5HT6 receptor
modulators, BACE inhibitors, monoclonal antibodies, A4 study• How should she modify her lifestyle?
– Mediterranean Diet– Cognitive/brain effects of exercise
Learning Objectives
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Patient 2• 85M, living independently, well grommed, c/o
forgetfulness • MoCA 24: misses the date, and all 5 recall words• Encodes all words twice, but 2 of the 5 word cannot be
retrieved by cues or recognized by multiple choice• Logical memory
– I: 40th percentile– II: 2nd percentile
• CERAD word list memory test (10 unrelated words):– Encodes 3, 5, 6– Recalls 3 five minutes later– Recognizes 7 words with 2 false positives. – One unrecognized word encoded 2x, another 3x
• All other neuropsychological tests were between low and high average
disturbance, ocular abnl, movement d/o• Cognitive dysfunction
• Downward displacement of cerebellar tonsils• Swelling of midbrain• Flattening of the ventral pons• Effacement of basal cisterns
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Frontotemporal Brain Sagging Syndrome
• Thought to be due to a CSF leak
• Investigations should include myelogram and/or cisternography
• Keep in your differential of patients with possible frontotemporal dementia—it’s curable!
• Our patient was found to have a duraldiverticulum at C2-C3
• Treated with blood patch; definitive treatment pending
3/13/17 first MRI
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7/6/17 post-blood patch MRI
3/13/17 vs post-blood patch 4/24/17
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3/13/17 vs post-blood patch 4/24/17
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Patient 5• 72M professional writer, c/o memory & word-finding
problems that interfered with his writing
• Blood work, MRI, unremarkable.
• MoCA 28 (missed 2 words on delayed recall but recognized on multiple choice)
• All neuropsychological tests between average and superior range
• When patient informed of these result, he angrily insisted that his cognitive function was not normal based on his difficulties writing. Asked if anything else could be done.
Patient 5 (cont)• What would you do?
• Reassure patient that he is normal
• Explain that, if any abnormalities are present, they are very mild so it isn’t a big deal
• Do additional cognitive testing
• Recommend functional brain imaging
• Recommend amyloid brain imaging
• We obtained amyloid imaging—which was positive for frequent amyloid plaques c/w Alzheimer’s disease
• Why did we do that?
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Budson & Solomon, 2016; After Sperling et al., AlzDement 2011;7:280
No cognitive complaint Subjective Cognitive Impairment
• Over time, became more aphasic, apraxic, and frontal
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Chronic Traumatic Encephalopathy
Chronic Traumatic Encephalopathy (CTE) vs. Alzheimer’s Disease
control
CTE
AD
no tau, no Aß
tau, no Aß
tau & Aß
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From Budson & Solomon, 2016
• Very preliminary, designed for research
• Can still give us some guideposts
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Criteria for Traumatic Encephalopathy Syndrome
• Include: – General Criteria
– Core Clinical Features
– Supportive Features
– Diagnostic subtypes
– Potential biomarkers
General Criteria: All 5 criteria must be met
1) Hx of multiple impacts to the head based upon– Types of injuries:
• mTBI or concussions, minimum of 4
• Moderate/severe traumatic brain injury
• “subconcussive” trauma
– Source of exposures• Involvement of “high exposure” contact sports for minimum of
6 years, including at least 2 at college level or higher
• Military Service
• History of any other significant exposure to repetitive hits to the head
• For moderate/severe traumatic brain injury, any activity resulting in the injury
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General Criteria: All 5 criteria must be met (cont.)
2) No other neurological disorder present that likely accounts for all clinical features
3) Clinical features must be present for a minimum of 12 months
4) At least 1 Core Clinical Features must be present and considered a change from baseline
5) At least 2 Supportive Features must be present
Core Clinical Features: At least 1 must be met
1) Cognitive. Difficulties in cognition as reported by either self or informant, by history, or clinician’s report of decline and substantiated by impairment on standardized tests
3) Mood. Feeling overly sad, depressed, and/or hopeless
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Supportive Features: At least 2 must be present
1) Impulsivity2) Anxiety3) Apathy4) Paranoia5) Suicidality6) Headache7) Motor Signs. Dysarthria,
dysgraphia, bradykinesia, tremor, rigidity, gait disturbance, falls, and/or other features of parkinsonism
8) Documented Decline. Progressive decline in function and/or a progression in symptoms and/or signs, for a minimum of one year
9) Delayed Onset. Delayed onset of clinical features after significant head impact exposure, usually at least 2 years and in many cases several years after the period of maximal exposure
Diagnostic Subtypes1) Behavioral/Mood Variant (younger, mean 35 yrs)2) Cognitive Variant (older, mean 59 yrs)3) Mixed Variant4) Dementia (criteria below)
a) Progressive course of Cognitive Core Features, with or without Behavioral and/or Mood Core Features
b) Cognitive impairment (or cognitive impairment exacerbated by behavioral and/or mood) severe enough to interfere with the ability to function independently at work or in usual activities, including hobbies, and instrumental activities of daily living
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Potential Biomarkers1) Cavum Septum Pellucidum. Or cavum vergae, or
fenestrations based on neuroimaging study 2) Normal Beta Amyloid CSF Levels3) Elevated CSF p-tau/tau Ratio4) Negative Amyloid Imaging5) Cortical atrophy beyond expected for age as seen
on MRI (or CT), and in particular, frontal, thalamic, hippocampal, and/or amygdalar atrophy
6) Positive Tau Imaging (experimental). PET paired helical filament tau imaging suggestive of abnormal tau deposition
7) Cortical Thinning (experimental). Based on MRI measurement
Specific clinical features by initial clinical presentation
• 85% Memory impairment
• 79% Executive dysfunc.
• 73% Attention & concentration difficulties
• 64% Sadness/depression
• 64% Hopelessness
• 58% Explosivity
• 58% Language impairment
• 55% Visuospatialdifficulties
• 52% “Out of control”
• 52% Physically violent
• 49% Verbally violent
• 46% Impulse control prob.
• 30% Suicidal ideation/attempts
• 30% Motor symptoms (parkinsonism, tremor, gait abnormalities, falls)
Neurology 2013; 81: 1122–1129
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T1 MRI scan
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FDGPET scan
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clinical exam
First 1.5 min
• What does she have? – Alzheimer’s? bvFTD? Dementia w/Lewy bodies? VaD?– Primary age-related tauopathy– Primary progressive aphasia & apraxia of speech– Frontotemporal Brain Sagging Syndrome– Subjective Cognitive Decline– Chronic Traumatic Encephalopathy
• How should we work her up?– Vitamin D– Brain biomarkers/amyloid imaging
• How should we treat her?– Cholinesterase inhibitors & memantine in MCI & moderate-severe
dementia– Dextromethorphan / Quinidine sulfate for psudobulbar affect– Pimavanserin for Parkinson’s Disease Dementia & psychosis– New medications being developed: symptomatic 5HT6 receptor
modulators, BACE inhibitors, monoclonal antibodies, A4 study• How should she modify her lifestyle?
– Mediterranean Diet– Cognitive/brain effects of exercise
Learning Objectives
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Treatment: What’s new?• New symptomatic medications being developed
which modulate neurotransmitters.
• New disease modifying therapies also being developed– Monoclonal antibodies directed against β-amyloid
– Enzyme inhibitors that stop the formation of β-amyloid
– Trials on-going in patients with mild AD, MCI due to AD, and healthy individuals with memory complaints & + amyloid PET scan.
Treatment Outcomes
Time
No effect
TreatmentSlowedprogression
Disease arrest
Symptomaticbenefit
From Budson & Solomon, 2016
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Turning back the clock
• About 25-30% show an improvement equivalent to a 1-year reversal of symptoms
• About 50-60% show an improvement equivalent to a 6-month reversal
• About 10-15% show either an improvement equivalent to less than a 6-month reversal or no improvement
• My recommendation: Give a trial, measure response– ask patient, ask caregiver, test patient
NEJM 2004 351:56-67
Change in MMSE in mild to moderate Alzheimer’s disease
Neurology 2001 57:489-95
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Time to clinically evident functional decline
• 431 patients
• mild to moderate AD
• double-blind placebo controlled trial
Neurology 2001 57:481-8
Meta analsysis: neuropsychiatric symptoms in AD
JAMA 2003 289: 210-16
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Rivastigmine in Dementia with Lewy Bodies
Lancet 2000 356:2031-6
Rivastigmine patch is FDA approved for Parkinson’s Disease Dementia
Galantamine in vascular dementia
Lancet 2002 359:1283-90
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Cholinesterase inhibitors:How long to use them?
• A double-blind placebo controlled study found continued efficacy for 4 years.
• Retrospective & prospective studies suggest beneficial effects last for at least 5 years.– CNS Drugs 2004 18:757-68.
• Should we stop treatment in moderate or severe disease?
N Engl J Med 2012;366:893-903
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• “In patients with moderate or severe Alzheimer’s disease, continued treatment with donepezil was associated with cognitive benefits that exceeded the minimum clinically important difference and with significant functional benefits over the course of 12 months.” (NEJM 2012; 366: 893-903)
• My recommendation: continue cholinesterase inhibitors as long as there is quality of life to preserve
Memantine (Namenda)• Approved for use in patients
with moderate to severe Alzheimer’s disease, with or without cholinesterase inhibitors
• Uncompetitive NMDA-receptor antagonist
• Enhances dopamine activity
• Does not alter AChE activity in the presence or absence of AChEIs
– Drowsiness and confusion, dose related, sometimes transient, worse in milder patients
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Managing agitation• Try to determine the underlying cause of agitation• Non-pharmacologic: reassure, reconsider, redirect, relax• Agitation is often due to anxiety
– Start with sertraline/Zoloft 50 to 100 mg or escitalopram/Lexapro 10-20 mg (others not as good)
• Manage sleep cycle disturbances– Limit naps, Ritalin SR 20 mg or provigil in AM if nec.