Dementia: Diagnosis and Treatment

Dementia: Diagnosis and Treatment

Debra L. Bynum, MD

Division of Geriatric Medicine

University of North Carolina at Chapel Hill

Case

Mr. Jones is a 72-year-old gentleman brought to you by his daughter for progressive memory loss. He denies any problems. Previously an accountant, he is now unable to balance his check book. He has had difficulty with getting lost while driving to the store. He was diagnosed with depression two years ago after his wife died. In addition, he has HTN and DM. His father was diagnosed with Alzheimer’s disease at the age of 85. On exam, his BP is 170/90; he is oriented, scores 26/30 on the MMSE (0/3 recall and difficulty with the intersecting pentagon); he is unable to do the clockface.

A few months later, his MMSE is 24/30; on exam he has some mild cogwheel rigidity and a slight shuffling gate, but no tremor. His daughter reports that he has been having vivid visual hallucinations and paranoid thought.

Questions:

1. What are some limitations to the MMSE?

2. Is there any association between HTNand dementia in the elderly?

3. What are the risk factors for dementia?

4. What type of dementia might Mr. Jones have?

Outline

Risk factors and definition of dementia

Types of dementias

MMSE and testing

Treatment options

Question:

What are some risk factors for the development of dementia?

Risk Factors for DementiaAge Family hx of AD or Parkinson’s (10-30% risk of AD in patients with first degree relative)Head traumaDepression (?early marker for dementia)Low educational attainment??hyperlipidemia?diabetesHTN !!!

Risk Factors for AD

Gender (confounding in literature – women more likely to live longer, be older….)

Down’s syndrome

?estrogen (probably not)

?NSAIDS (probably not)

Question:

What is the definition of a dementia? What is the “line” between “normal” memory loss with age and dementia…

Cognitive Decline with Aging

Mild changes in memory and rate of information processing

Not progressive

Does not interfere with daily function or independence

Mild Cognitive Impairment

12% of people over age 70

Usually memory affected

Does not significantly interfere with daily function

3 times increased risk of developing AD

10–15% /year will develop dementia

DSM Criteria

1. Memory impairment2. At least one of the following: Aphasia Apraxia Agnosia Disturbance in executive functioning

3. Disturbance in 1 and 2 interferes with daily function or independence4. Does not occur exclusively during delirium

Activities of Daily Living

ADLs: bathing, toileting, transfer, dressing, eating

IADLs (executive functioning): Maintaining household Shopping Transportation Finances

Diagnosis of Dementia

Delirium: acute, clouding of sensorium, fluctuations in level of consciousness, difficulty with attention and concentrationDepression: patient complains of memory lossDelirium and depression: markers of dementia?5% people over age 65 and 35–50 % over 85 have dementia, therefore pretest probability of dementia in older person with memory loss at least 60%

Question:

What are some classic features of an Alzheimer’s type dementia?

Alzheimer’s Disease

Role of the Hippocampus

Patient HM with surgery for seizures to remove bilateral medial temporal lobes resulting in severe anterograde amnesia

Formation of new memories

Spatial navigation

Early evidence for damage in this area


60–80% of cases of dementia in older patientsEarly personality changesLoss of short term memoryFunctional impairmentVisual spatial disturbances (early finding)ApraxiaLanguage disturbancesDelusions/hallucinations (usually later in course)


Depression occurs in 1/3Delusions and hallucinations in 1/3Extracellular deposition of amyloid-beta protein, intracellular neurofibrillary tangles, and loss of neurons at autopsyClinical diagnosis: 87% of diagnosed AD confirmed pathologically (but high pretest probability increases predictive value of clinical diagnosis!!!)


Onset usually near age 65; older age, more likely diagnosisAbsence of focal neurological signs (but significant overlap in the elderly with hx of CVAs…)Aphasia, apraxia, agnosiaFamily hx (especially for early types)Normal/nonspecific EEG MRI: bilateral hippocampal atrophy (suggestive)

Question:

What features would make you think more about a vascular etiology to a dementia?

Vascular Dementia

Onset of cognitive deficits associated with a stroke (but often no clear hx of CVA but multiple small, undiagnosed CVAs)

Abrupt onset of sxs with stepwise deterioration

Findings on neurological examination

Infarcts on cerebral imaging (but ct/mri findings often have no clear relationship)

Overlap

Most patients previously categorized as either Alzheimer’s type or vascular type dementias probably have BOTH

Likelihood of AD and vascular disease significantly increases with age, therefore likelihood of both does as well

Vascular risk factors predispose to AD -- ?does it allow the symptoms of AD to be unmasked earlier??

Question:

What is the risk of dementia with Parkinson’s disease?

Dementia with Parkinson’s

30% with PD may develop dementia; Risk Factors: Age over 70 Depression Confusion/psychosis on levodopa Facial masking upon presentation

Hallucinations and delusions May be exacerbated by treatment

Some Other Dementias

Dementia with Lewy Bodies

Cortical Lewy Bodies on path

10–20% of dementias

Compare to PD: Lewy Bodies in substantia nigra

Overlap with AD and PD

40% patients with AD have LBs on path


Visual hallucinations (early)

Parkinsonism

Cognitive fluctuations

Dysautonomia

Sleep disorders

Neuroleptic sensitivity

Memory changes later in course


Visual hallucinations 2/3 of patients with DLB Rare in AD May precede other symptoms of DLB Psychosis, paranoia and other psychiatric

manifestations early in course


Cognitive Fluctuations 60–80% Episodic Loss of consciousness, staring spells, more

confused or delirious like behavior Days of long naps Significant impact on functional status


Parkinsonism 70–90% More bilateral and symmetric than with PD Tremor less common Bradykinesia, rigidity, gait changes


Sleep disorders REM sleep behavior disorder/parasomnia Acting out of dreams: REM dreams without

usual muscle atonia 85% of patients with DLB May precede other symptoms by years

DLB: Neuroleptic Hypersensitivity

30–50% of patients

May induce Parkinsonian symptoms or cognitive changes that are not reversible, leading to rapid decline in overall status

NOT dose related

Slightly less likely with newer atypical antipsychotics, but can STILL happen

DLB: Treatment

More progressive course than AD or Vascular dementia

Possibly better response to cholinergic drugs than AD or vascular dementias

?response of psychiatric type symptoms to cholinergic agents/cholinesterase inhibitors

Progressive Supranuclear Palsy

Uncommon

Vertical supranuclear palsy with downward gaze abnormalities

Postural instability

Falls (especially with stairs)

“Surprised look”

Difficulty with spilling food/drink

Frontotemporal Dementia

Impairment of executive function Initiation Goal setting Planning

Disinhibited/inappropriate behavior (90%)Cognitive testing may be normal; memory loss NOT prominent early feature5–10% cases of dementiaOnset usually 45–65 (rare after age 75)Familial: 20–40%

Pick’s Disease

Subtype of frontal lobe dementiaPick bodies (silver staining intracytoplasmic inclusions in neocortex and hippocampus)?Serotonergic deficit?Language abnormalities and behavioral disturbances Logorrhea (abundant unfocused speech) Echolalia (spontaneous repetition of words/phrases) Palilalia (compulsive repetition of phrases) Fluent or non-fluent forms

Primary Progressive Aphasia

Patients slowly develop non-fluent, anomic aphasia with hesitant, effortful speechRepetition, reading, writing also impaired; comprehension initially preservedSlow progression, initially memory preserved but 75% eventually develop non-language deficits; most patients eventually become muteAverage age of onset = 60Subset of FTD

“Reversible” Causes of Dementia

?10% of all patients with dementia; in reality, only 2–3% at most will truly have a reversible cause of dementia

“Modifiable” Causes of Dementia

MedicationsAlcoholMetabolic (b12, thyroid, hyponatremia, hypercalcemia, hepatic and renal dysfunction)Depression? (likely marker though…)CNS neoplasms, chronic subduralNPH

Question:

An elderly patient with ataxia, incontinence, memory loss and “large ventricles” scan should raise suspicion for …?

Normal Pressure Hydrocephalus

Triad: Gait disturbance Urinary incontinence Cognitive dysfunction

NPH: Clinical Features

Gait Early Feature Most responsive to shunting Magnetic/gait apraxia/frontal “ataxia”

Cognitive Psychomotor slowing, apathy, decreased attention

Urinary Urgency or incontinence

NPH

Hydrocephalus in absence of papilledema, with normal CSF pressureBegins as transient/intermittent increased CSF pressure, leading to ventricular enlargement; ventricular enlargement leads to normalization of CSF pressureThought to be due to decreased CSF absorption at arachnoid villiCauses: SAH, tumors, CVA

NPH

Diagnosis: initially on neuroimaging Ventricular enlargement our of proportion to

sulcal atrophyMiller Fisher test: objective gait assessment before and after removal of 30 cc CSFRadioisotope diffusion studies of CSFMRI: turbulent flow in posterior third ventricle and within aqueduct of sylviusMRI flow imaging SPECT (Single Photon emission CT): decreased blood flow in frontal and periventricular areas

NPH: ?Shunting?

Limited data

Gait may be most responsive

Predictors of better outcome: Lack of significant dementia Known etiology (prior SAH) New (< 6 months) symptoms Prominence of gait abnormality

Creutzfeldt-Jacob Disease

Rapid onset and deterioration

Motor deficits

Seizures

Slowing and periodic complexes on EEG

Myotonic activity

Other Infections and Dementia

Syphilis

HIV

Question:

What are some tools available to assess for the presence and severity of cognitive impairment?

MMSE

24/30 suggestive of dementia (sens 87%, spec 82%)Not sensitive for MCISpuriously low in people with low educational level, low SES, poor language skills, illiteracy, impaired visionNot sensitive in people with higher educational background

MMSE Tips

No on serial sevens (months backwards, name backwards… assessment of attention)Assess literacy priorAssess for dominant hand prior to handing paper overDo not over lead3-item repetition, repeat all 3 then have patients repeat; 3-stage command, repeat all 3 parts of command and then have patient do…

Other Evaluation Tools

Trails B test Numbers 1–25 and letters scattered across page;

patient must connect, 1-A, 2-B, 3-C, etc; normally able to do in <10 minutes

Good for patients with high function/educationVerbal Fluency Test Name all within category in 30 seconds – 1 minute Letters FAS, animals, vegetables Tests executive function and language, semantic

memory Normally should name 20–30 in 60 seconds Highly associated with educational level Insight with grouping, rhyming, categories

Additional Evaluation

Clockface

Short assessments with good validity: 3-item recall and clockface

Neurological exam (focality, frontal release signs such as grasp, jawjerk; apraxia, cogwheeling, eye movements)

Lab testing and neuroimaging

Treatment of AD

Tacrine

Cholinesterase inhibitor

1 systematic review with 5 RCTs, 1434 people, 1–39 weeks

No difference in overall clinical improvement

Some clinically insignificant improvement in cognition

Significant risk of LFT abnormalities: NOT USED

Donepezil

AriceptCholinesterse inhibitorEasy titration (start 5/day, then 10)Side effects: GI (nausea, diarrhea)Can be associated with bradycardiaMain effect seems to be lessening of rate of decline, delayed time to needing nursing home/more intensive care

Other Agents

RivastigmineGalantamineCholinesterase inhibitors?more side effects, more titration requiredFuture directions: Prevention of delirium in at-risk patients

(cholinergic theory of delirium) Behavioral effects in those with severe dementia? Treatment of Lewy Body dementia Treatment of mixed Vascular/AD dementia

Comments about Cholinesterase Inhibitor Studies

Highly selected patients (mild – moderate dementia)

?QOL improvements

Not known: severe dementia and mild CI

Memantine

NEJM April 2003Moderate to severe AD (MMSE 3–14)N-methyl D aspartate (NMDA) receptor antagonist; theory that overstimulation of NMDA receptor by glutamate leads to progressive neurodegenerative damage28-week, double blinded, placebo controlled study; 126 in each group; 67% female, mean age 76, mean MMSE 7.9

Memantine

Found less decline in ADL scores, less decline in MMSE (-.5 instead of –1.2)

Problem: significant drop outs (overall 28% dropout rate) in both groups; data analyzed did not account for drop outs, followed those “at risk”

Selegiline

Unclear benefit

Less than 10mg day, selective MAO B inhibitor

Small studies, not very conclusive

Vitamin E (Alpha Tocopherol)NEJM 1997: selegiline, Vit E, both , placebo for tx of ADDouble blind, placebo controlled, RCT with mod AD; 341 patientsPrimary outcome: time to death, institutionalization, loss of ADLS, severe dementiaBaseline MMSE higher in placebo groupNo difference in Primary outcomes; adjusted for MMSE differences at baseline and found delay in time to NH from 670 days with Vit E to 440 days with placebo

Ginkgo Biloba

1 systematic review of 9 double blind RCTs with AD, vascular, or mixed dementia

Heterogeneity, short durations

High withdrawal rates; best studies have shown no significant change in clinician’s global impression scores

Other Treatments

NO good evidence to support estrogens or NSAIDS

Other Treatments

Behavioral/agitation: Nonpharmacologic strategies Reasons for NH placement:

Agitation Incontinence Falls Caregiver stress

?Antipsychotics

NO data to support any significant benefit for treating behavioral symptoms of dementia with antipsychotic agents

Small group of patients with active psychoses, disturbing hallucinations, or aggressive behaviors who may have some benefit

Antipsychotics

Side Effects: Sedation Anticholinergic effects Prolonged QT Edema Orthostasis Weight gain Confusion

Warnings: FDA black box warning for increased mortality (OR

1.5–1.7), and increased ?increased stroke risk

Antipsychotics

NO if you suspect DLB

Antipsychotics

Risperidone (0.5 BID)

Olanzepine (zyprexa): 2.5–5 mg/day

Quetiapine (seroquel) Rapid titration, use in PD 12.5–200 mg/day

Clozapine Use in PD (least risk of tremor) Agranulocytosis and limited use

Ziprasidone (geodon) QT prolongation

Prevention?

HTN and DM linked to ALL types dementiaStudies of treating systolic hypertension in the elderly (SHEPS and others): decreased risk of development of cognitive impairment in patients in treatment groupDecreased risk included vascular AND Alzheimer type dementiasCholinesterase inhibitors seem to work as well (or as poorly) for both vascular and Alzheimer type of dementiasWhat is the link? Both common, ?unmasking?

?Link with Hyperlipidemia

Conflicting data

Retrospective studies suggest decreased risk in those patients who are treated with statins

PROSPER study 6000 patients age 70–80 with vascular risk

factors given pravastatin or placebo 3 year: no effect on cognitive function ?Long enough follow up?

Future

Treating vascular risk factors to decrease development/unmasking of dementia?Actively seeking to differentiate different types of dementia, while alsoRecognizing significant OVERLAP of dementia etiologies in older patientsMove toward agents other than cholinesterase inhibitors?Move away from broad use of antipsychotic agents

Dementia: Diagnosis and Treatment

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