Dementia: Diagnosis and Treatment 2005

Case … Mr. Jones is a 72 y/o gentleman brought to you by his daughter for progressive memory loss. He denies any problems. She reports that he was an accountant, and is now unable to keep his own check book straight. He has also had difficulty with getting lost while driving to the store. His wife died 2 years ago, and he was diagnosed with depression at that time. 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 HTN and dementia in the elderly? 3. What are the risk factors for dementia? 4. Would apo E testing be of benefit in this case? 5. What type of dementia might Mr. Jones have? 6. What medications should be avoided with this type of dementia?

Outline 1. Risk factors and definition of dementia 2. Types of Dementias 3. MMSE and testing 4. Treatment options

Risk factors for dementia Age (risk of AD 1% age 70-74, 2% age 75-79, 8.4% over age 85) Family hx of AD or Parkinson’s (10-30% risk of AD in patients with first degree relative) Head trauma Depression (?early marker for dementia) Low educational attainment? ?hyperlipidemia ?diabetes HTN !!!

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)

Cognitive decline with aging Mild changes in memory and rate of information processing Not progressive Does not interfere with daily function

DSM Criteria 1. Memory impairment 2. At least one of the following: – Aphasia – Apraxia – Agnosia – Disturbance in executive functioning 3. Disturbance in 1 and 2 interferes with daily function 4. 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 concentration Depression: patient complains of memory loss Delirium and depression: markers of dementia? 5% people over age 65 and % over 85 have dementia, therefore pretest probability of dementia in older person with memory loss at least 60%

Alzheimer’s Disease 60-80% of cases of dementia in older patients Memory loss, personality changes, global cognitive dysfunction and functional impairments Visual spatial disturbances (early finding) Apraxia Language disturbances Personality changes Delusions/hallucinations (usually later in course)

Alzheimer’s Disease Depression occurs in 1/3 Delusions and hallucinations in 1/3 Extracellular deposition of amyloid-beta protein, intracellular neurofibrillary tangles, and loss of neurons Diagnosis at autopsy

Alzheimer’s Disease Onset usually near age 65; older age, more likely diagnosis Absence of focal neurological signs (but significant overlap in the elderly with hx of CVAs…) Aphasia, apraxia, agnosia Family hx Normal/nonspecific EEG Personality changes

Vascular dementia Onset of cognitive deficits associated with a stroke (but often no clear hx of CVA, more 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 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??

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

Dementia with Lewy Bodies Cortical Lewy Bodies on path Overlap with AD and PD Fluctuations in mental status (may appear delirious) Early delusions and hallucinations Mild extrapyramidal signs Neuroleptic hypersensitivity!!! Unexplained falls or transient changes in consciousness

Progressive Supranuclear Palsy Uncommon Vertical supranuclear palsy with downward gaze abnormalities Postural instability Falls (especially with stairs) “surprised look” Difficulty with spilling food/drink

Frontal Lobe Dementia Impairment of executive function – Initiation – Goal setting – planning Disinhibited behavior Cognitive testing may be normal/minimally abnormal; memory loss not prominent early feature 5-10% cases of dementia Onset usually 45-65

Frontal Lobe Dementia… Focal atrophy of frontal and/or anterior temporal lobes Frontal lobe degeneration of the non-AD type (lack of distinctive histopath findings seen with AD or Pick’s) May be autosomal dominant (inherited form known as frontotemporal dementia)

Pick’s Disease Subtype of frontal lobe dementia Pick bodies (silver staining intracytoplasmic inclusions in neocortex and hippocampus) Language abnormalities – Logorrhea (abundant unfocused speech) – Echolalia (spontaneous repetition of words/phrases) – Palilalia (compulsive repetition of phrases)

Primary Progressive Aphasia Patients slowly develop nonfluent, anomic aphasia with hesitant, effortful speech Repetition, reading, writing also impaired; comprehension initially preserved Slow progression, initially memory preserved but 75% eventually develop nonlanguage deficits; most patients eventually become mute Average age of onset 60

“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 Medications Alcohol Metabolic (b12, thyroid, hyponatremia, hypercalcemia, hepatic and renal dysfunction) Depression? (likely marker though…) CNS neoplasms, chronic subdural NPH

Normal Pressure Hydrocephalus Triad: – Gait disturbance – Urinary incontinence – Cognitive dysfunction

NPH Diagnosis: initially on neuroimaging Miller Fisher test: objective gait assessment before and after removal of 30 cc CSF Radioisotope diffusion studies of CSF

Creutzfeldt-Jacob Disease Rapid onset and deterioration Motor deficits Seizures Slowing and periodic complexes on EEG Myotonic activity

Other infections and dementia Syphilis HIV

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

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 Apolipoprotein E epsilon 4 allele: probably not

Prognosis Previous estimate of median survival after onset of dementia have ranged from 5-10 years Length bias: failing to consider people with rapidly progressive illness who died before they could be included in the study

Prognosis… NEJM, april 2001 Data from Canadian Study of Health and Aging, estimate adjusted for length bias, with random sample of 10,263 people over age 65 screened for cognitive impairment; for those with dementia, ascertained date of onset and conducted followup for 5 years

Prognosis… 821 subjects (396 with probably AD) Unadjusted median survival 3.3 years Median survival 3.1 years for those with probably AD

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: NO ON USE

Donepezil Aricept Cholinesterse inhibitor Easy titration (start 5/day, then 10) Side effects: GI (nausea, diarrhea) Associated with improved cognitive function; main effect seems to be lessening of rate of decline, delayed time to needing nursing home/more intensive care

Other agents… Rivastigmine Galantamine Cholinesterase inhibitors ?more side effects, more titration required Future 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-mod dementia) ?QOL improvements… Not known: severe dementia and mild CI

Memantine NEJM april 2003 Moderate to severe AD (MMSE 3-14) N-methyl D aspartate (NMDA) receptor antagonist; theory that overstimulation of NMDA receptor be glutamate leads to progressive damage in neurodegenerative diseases 28 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 AD Double blind, placebo controlled, RCT with mod AD; 341 patients Primary outcome: time to death, institutionalization, loss of ADLS, severe dementia Baseline MMSE higher in placebo group No difference in 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 sig 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… Commonly prescribed in older patients with dementia and behavioral problems (agitation, sundowning, aggression) Choices: – Haloperidol (0.5mg-1mg) – Atypical agents: Risperidone Olanzapine Quetiapine

Antipsychotics: Big Picture Concern with haloperidol for significant risk of EPS and TD with prolonged use in elderly All of risk of sedation, orthostasis and varying amounts of anticholinergic effects Studies show slight efficacy for behavioral problems in dementia BUT NOT FDA approved for this AND INCREASED RISK OF DEATH AND CVA with use of atypical agents…

Risperidone Placebo controlled trials of elderly nursing home residents with dementia Doses.5 mg to 1 mg up to bid Decrease in aggression and improved behavior scores (moderate effect) EPS: 13-23% on risperidone compared to 7- 16% with placebo

Risperidone CVA: 7.8 % - 9% vs 1.8% on placebo Mortality: 3.6% - 5.4% vs 2.4% - 3.1%

Olanzapine 5-10 mg day max (studies show NO added benefit to increasing more than 10/day) Moderate improvement in aggression and behavior scores compared to placebo NO difference with EPS rates compared to placebo CVA: % vs 0% placebo Mortality: 2.9% vs 1.6% for placebo

FDA warning Analysis of multiple placebo controlled trials of elderly patients with dementia of the atypical agents demonstrated significant increase in mortality, sudden death and CVAs in pooled data (nearly double mortality! Likely class action May also apply to older agents such as haloperidol Bottom line: caution needed, weigh benefits and risks!

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

Back to the questions… 1. What are some limitations to the MMSE? 2. Is there any association between HTN and dementia in the elderly? 3. What are the risk factors for dementia? 4. Would apo E testing be of benefit in this case? 5. What type of dementia might Mr. Jones have? 6. What medications should be avoided with this type of dementia?