Dementia: Diagnosis and Treatment Dr Malekzadeh

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.

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

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 or independence 4. Does not occur exclusively during delirium

Risk Factors for Dementia Age 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 !!!

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

Alzheimer’s Disease 60–80% of cases of dementia in older patients Early personality changes Loss of short term memory Functional impairment Visual spatial disturbances (early finding) Apraxia Language disturbances Delusions/hallucinations (usually later in course)

دمانسسالمگروه 82ارجاع درون متنی 91ارجاع برون متنی 42حذف 30جایگزینی 245جمع مقایسه خطاهای دستوری در گفتار افراد سالم و مبتلا به دمانس

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 (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)

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

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

Dementia with Lewy Bodies Visual hallucinations (early) Parkinsonism Cognitive fluctuations Dysautonomia Sleep disorders Neuroleptic sensitivity Memory changes later in course

Dementia with Lewy Bodies 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

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

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

Pick’s Disease Subtype of frontal lobe dementia Pick 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

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

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 Aricept Cholinesterse inhibitor Easy titration (start 5/day, then 10) Side effects: GI (nausea, diarrhea) Can be associated with bradycardia 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

Comments about Cholinesterase Inhibitor Studies Highly selected patients (mild – moderate 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 by glutamate leads to progressive neurodegenerative damage 28-week, double blinded, placebo controlled study; 126 in each group; 67% female, mean age 76, mean MMSE 7.9

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 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