16. Budson - Cognitive Aging - rsvpBOOK

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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

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.

• Exam: masked facial expression, bilateral resting tremor, glabellar tap sign, brisk reflexes

• Over time, became more aphasic, apraxic, and frontal

• 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







Learning Objectives

Check Vitamin D• In addition to

B12 & TSH• Relationship

between Vitamin D & dementia being evaluated

From Budson & Solomon, 2016, adapted from Neurology 2014;83:920-928

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Budson & Solomon, Practical Neurology 2012;12:88–96; After Sperling et al., AlzDement 2011;7:280

Biomarkers: Why? Because pathophysiology starts decades prior to symptoms

Budson & Solomon, 2016; After Sperling et al., AlzDement 2011;7:280

Budson & Solomon, Practical Neurology 2012;12:88–96

Biomarkers Biomarkers: what to look for / when to use them• Structural MRI/CT

– Qualitative atrophy of medial temporal, anterior temporal, & parietal cortex

– Always look for on scan (cannot depend on radiology)

From Budson & Solomon, 2016


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From Budson & Solomon, 2016 From Budson & Solomon, 2016

Biomarkers: what to look for / when to use them• Structural MRI/CT

– Qualitative atrophy of medial temporal, anterior temporal, & parietal cortex

– 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

Dementia with Lewy Bodies



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behavioral variant

Frontotemporal dementia

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.

Amyloid Imaging with florbetapir

Alzheimer’s Disease65 year oldMoCA 21

Non-AD dementia








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

Patient 2 (cont)• MRI shows hippocampal/MTL atrophy

• Diagnosed with amnestic MCI– Presumptive etiology: MCI due to AD

• Offered treatment with cholinesterase inhibitors

N Engl J Med 2005 352;23

• 769 patients with MCI studied for 3 years

• Vit E 2000 IU, donepezil 10 mg, or placebo

• Conclusion : no differences in the probability of progression to AD over the three years for either treatment

• Donepezil treatment associated with a lower rate of progression to AD over one year

• Vit E showed no effect

N Engl J Med 2005 352;23

Patient 2 (cont)• Patient declined treatment. RTC 6 months

• 6 mo: MoCA 26: misses 4 recall words (initial MoCA24). RTC 1 year

• 18 mo: MoCA 24: misses 5 recall words, 1 for serial 7s. RTC 1 year.

• 30 mo: MoCA 25: misses 4 recall words, date.

• What’s going on? What does this patient have?

Primary age-related tauopathy (PART)

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103-year-old woman

Tau in MTL, but not neocortex in PART, in contrast to AD—also no Aβ

PART Summary• Primary age-related tauopathy

• NFTs indistinguishable from those of AD—but are in the absence Aβ

• NFTs are only seen in MTL, basal forebrain, brainstem, olfactory bulb, & olfactory cortex (none in neocortex)

• Typical symptoms range from normal to amnestic single-domain MCI.

• “almost universally detectable at autopsy among elderly individuals”

• Important to keep in our differential of older adults with isolated memory deficits.

Patient 3• 72M w/ difficulty talking• Describes his problem 0:04-0:25

• Naming MoCA 0:09-1:45

• Category fluency 0:39-1:15

• Pyramids & Palm trees 0:30-1:51

Primary Progressive AphasiaCore criteria


Primary Progressive AphasiaNon-fluent/Agrammatic variant


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Primary Progressive AphasiaLogopenic variant

From Budson & Solomon 2016

Primary Progressive AphasiaSemantic variant


Primary Progressive Apraxia of

Speech• Video

0:17-0:57


PPA Clinical-Pathological correlation



Atrophy in Semantic variant PPA

Patient 4• 56F h/o GERD, prior obesity, 2 years of cognitive complaints. • Headache, diagnosed w/ migraine by PCP, prescribed topiramate. • Forgetfulness, apathy, poor appetite, and weight loss followed. • Stopped topiramate but cognitive & other symptoms progressed. • Cognitive symptoms included short-term memory loss & pauses

in speech. Remote memory intact. • Stopped working. Neurologist diagnosed dementia. • Symptoms then worsened: Agitation & changes in personality,

mood, & behavior. • Required assistance with household chores, shopping, &

financial tasks.• Imbalance, dizziness, nausea, vomiting, fecal incontinence, &

headaches that worsened with standing, coughing, laughing, or sneezing were present.

• Neurological exam was notable for lack of normal palate elevation, 3+ reflexes with ankle clonus, & tremor worse in left upper extremity.

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Initial testing 3/13/17

• Onset in 40s-50s• Postural headache• Apathy &/or disinhibition• Vocal tics, dysarthria, dysphagia, gait

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

7/6/17 post-blood patch MRI

3/13/17 vs post-blood patch 4/24/17

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?

Budson & Solomon, 2016; After Sperling et al., AlzDement 2011;7:280

No cognitive complaint Subjective Cognitive Impairment

Age 64.1 years 67.5 years

Education 16.1 years 15.6 years

MMSE 29.6 29.0

Brief Cog Rating Scale 5.74 8.97

Ham-D 3.13 4.43

BEHAVE-AD 0.69 1.29

Psychometric Deterior Scl 1.86 2.18

Probability of not declining

to MCI or dementia

Subjective Cognitive Decline (SCD)

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Subjective Cognitive Decline (SCD)• Self-perception

– Confirmation by external observers not required

– Validation by cognitive testing not required

• Any cognitive domain

• Decline indicates worsening over time, not just impairment (which can be static)

• If SCD is used to indicate preclinical AD, testing is required to establish normal objective performance

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.

• Exam: masked facial expression, bilateral resting tremor, glabellar tap sign, brisk reflexes

• Over time, became more aphasic, apraxic, and frontal

Chronic Traumatic Encephalopathy Chronic Traumatic Encephalopathy (CTE) vs. Alzheimer’s Disease

control

CTE

AD

no tau, no Aß

tau, no Aß

tau & Aß


• 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

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

2) Behavioral. Emotionally explosive, physically and/or verbally violent

3) Mood. Feeling overly sad, depressed, and/or hopeless

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

T1 MRI scan

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FDGPET scan

clinical exam

First 1.5 min







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


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

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

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

• “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

Amantadine Derivative1-amino-3,5-dimethyladamantane

NH+

3

CH3

H3C

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Treatment expectations

• Small but noticeable improvements:– More alert

– More talkative

– More engaged

– More outgoing

– Brighter overall

– Less agitated

– Note: Memory not improved

Memantine Side-effects

– None statistically more than placebo

– Agitation less than in placebo group

– “Dizziness”

– Drowsiness and confusion, dose related, sometimes transient, worse in milder patients

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.

• Daytime agitation– risperidone/Risperdal: start 0.25 mg QD

• Nighttime agitation– trazodone: start 50 mg QHS– quetiapine/Seroquel: start 25 mg QHS

• NEW! pimavanserin (Nuplazid) 40 mg QD for PDD• NEW! 20 mg Dextromethorphan HBr / 10

mg Quinidine sulfate (Nuedexta)

Pimavanserin for psychosis in PDDselective serotonin 5-HT2A inverse agonist

Cummings et al., Lancet. 2014 383(9916):533-40

Trials on-going in Alzheimer’s disease

NPI Aggression Domain Scores

JAMA. 2015;314:1242-54Weeks 1: 20/10 QD, 2-3: 20/10 BID, 4+: 30/10 BID

Pseudobulbar Affect (PBA)• Crying or laughing for little or no reason.

• Very common in AD, VaD, & other dementias

• New medication FDA approved to reduce PBA: – 20 mg Dextromethorphan HBr / 10 mg Quinidine

sulfate (Nuedexta)

– 1 capsule daily x 7 days, then 1 capsule Q12H

– Common adverse reactions: falls, diarrhea, UTI, dizziness, cough, vomiting, asthenia, peripheral edema, influenza, GGT, & flatulence

– Serious side-effects/contraindications from quinidine

– More DM? add 10 mg/5 ml BID to Nuedexta BID

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Learning Objectives

From: Mediterranean Diet and Age-Related Cognitive Decline: A Randomized Clinical Trial

JAMA Intern Med. 2015;175(7):1094-1103. doi:10.1001/jamainternmed.2015.1668

Mediterranean diet improves cognitive function vs. control diet

• 334 cognitively healthy adults

• Mean age 67 years

• Randomly assigned– Med diet + olive oil

– Med diet + nuts

– Control

• Fish, olive oil, avocado, fruit, vegetables, beans, nuts, whole grains, red wine

Exercise increases hippocampal volume in older adults

• 120 older adults randomized to 1 yr of exercise or stretching

⍙VO2 max correlates with ⍙ hippocampal volume

⍙ BDNF correlates with ⍙ hippocampal volume

⍙memory performance correlates with⍙ hippocampal volume

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Learning Objectives End

16. Budson - Cognitive Aging - rsvpBOOK

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