Dementia and Alzheimer s Disease. David Knopman MD Mayo Clinic Rochester MN

Transcription

1 Dementia and Alzheimer s Disease David Knopman MD Mayo Clinic Rochester MN Incidence of mild dementia 140 cases per 1000 person years Age groups Metaanalysis (estimate + 95%CI) (Jorm 1998)

2 Prevalence of Alzheimer s Disease Prevalence per Men Women Age From Hy & Keller, 2000: pooled data of 20 studies Dementia and Alzheimer s Disease Dementia - cognitive decline compared to previous levels, sufficient to cause loss of independence Alzheimer s Disease - the most common disease causing dementia in the elderly typically causing memory impairment of gradual onset and inevitable progression

3 Dementia or Delirium? Dementia gradual onset near normal attention fully alert confused risk factor for delirium Delirium abrupt inattentive may be drowsy confused predictor of future dementia Memory dysfunction in AD Almost always part of the initial presentation of AD, though sometimes not the first symptom reported Typical manifestations: repeating oneself misplacing things forgetting recent events The proper description of the anterograde amnesia of AD is that of a failure of new learning

4 Symptoms of Early Dementia: Triggers for recognition Forgetfulness: for recent events, conversations, names Spatial disorientation: driving errors, getting lost, misplacing items Language deterioration: word-finding, repeats self in conversation Impaired judgment/reasoning: unable to handle money, unable to operate appliances, equipment Personality changes: social withdrawal, loss of initiative, depression, short-tempered, suspicious Distinguishing typical Aging from Dementia Typical Aging Dependence Memory Loss Impaired Function Alzheimer s Disease

5 The spectrum of function between normal and dementia normal Mild cognitive Impairment= Poor memory but other Functions preserved MCI Dementia Barriers to Early Diagnosis of dementia Denial by patient of deficits Denial or overlooking by family of problems Failure of physicians to distinguish between normal forgetfulness and incipient dementia Failure by physicians to obtain candid views of family Failure by physician to perform mental status examination Stigma associated with Alzheimer s disease

6 Pathological Bases of the Dementias AD Vascular Pick bodies Ballooned cells Fronto-temporal Dementias: Nonspecific Histologies Lewy bodies Dementia w/ Parkinsonism Arriving at the Diagnosis of Alzheimer s Disease Exclusions: other medical and psychiatric conditions especially depression, drug intoxication and metabolic derangements eliminate short-duration syndromes (delirium)

7 Arriving at the Diagnosis of Alzheimer s Disease Exclusions: other medical and psychiatric conditions especially depression, drug intoxication and metabolic derangements eliminate short-duration syndromes (delirium) Positives: Anterograde amnesia is a prominent sign/symptom At least one other cognitive deficit usually present Symptoms clearly present for >6 months Time course of Alzheimer s disease symptom onset Diagnosis ~3 yrs ~3-6 years symptomatic treatment window presymptomatic treatment severe dementia 24-hr care usually NHP ~3 yrs death

8 Neuritic plaques and b-amyloid pathology: at Alzheimer s disease center stage Pathogenesis of Alzheimer s Disease Genes Aging? Ab (42) peptide? inflammation oxidative injury? Tau phosphorylation Synapse loss Cell death

9 Genetics in Alzheimer s Disease Factors that increase familial risk: Younger age of onset of symptoms Multiple members of family with disease Susceptibility genes like APOE involved True autosomal dominant AD is very rare ~ 150 families worldwide with mutations in»alzheimer precursor protein gene (chr 21)»Presenilin 1 gene (chr 14)»Presenilin 2 gene (chr 1) Cumulative risk for AD in siblings of probands with AD (Heston Ar Gen Psych 38:1085,1981) percent Onset<70 + parents affected Onset<70 only Onset> age Probands (n=125) age of onset=66; Secondary (n=87) age of onset=71

10 Balancing secretases & A-b production gene on chr 21 Alz Precursor Protein- 700 amino acids A-beta Balancing secretases & A-b production gene on chr 21 g a b secretases Alz Precursor Protein NORMAL a > g,b A-beta g > a or b > a Ab Ab Ab A-b peptide AD

11 Hippocampal and diffuse brain atrophy in Alzheimer s disease Forebrain Cholinergic Nuclei are lesioned in AD FC PC FC = Frontal cortex PC = Parietal cortex OC = Occipital cortex H = Hippocampus B = Nucleus basalis of Meynert D = Diagonal band S = Septal nucleus D/S/B H OC

12 Cholinesterase Inhibitors in AD A rational approach to AD palliative treatment >6 different cholinesterase inhibitors with positive, similar but modest benefits. Long-term effects need to be clarified Delay of worsening may be most prominent effect Cholinergic therapies do not affect cell/synapse loss Cholinesterase Inhibitors for AD Drug Dosing GI side effects Donepezil (Aricept) once daily + Rivastigmine (Exelon) 2 per day +++ Galantamine (Reminyl) 2 per day ++

13 Potential AD-disease modifying agents Agent Vitamin E Estrogen NSAID s Statins Basis clinical trial positive end point delay 2 negative clin trials + neuropath, epidemiol negative clin trials negative prednisone + neuropath, epidemiol +epidem, +biochem Conditions that mimic Alzheimer s disease Major Depression Medication intoxications Rarely: structural brain lesions (subdural hematomas, brain tumors) CNS infections Co-morbidities that may exacerbate dementia: Major thyroid, B12 deficiency states

14 The Major Progressive Dementias Vascular Dementia Dementia with Parkinson s extra- pyramidal vascular features features + imaging Alzheimer s Disease Cerebrovascular disease in dementia Pure VAD is not often seen in dementia clinics, but it is not rare Dementia with combined cerebrovascular disease and AD is common Key features of cerebrovascular disease: Dementia temporally related to stroke Imaging findings of substantial infarction(s) Neuro signs/symptoms assoc. w/ stroke

15 Parkinson s disease and dementia Initial symptoms: dementia or bradykinesia, gait & postural disturbances tremor is rare Lewy Body pathology is most common etiology Other features - hallucinations ++ sensitivity to antipsychotics sleep disorders hypotension The Major Progressive Dementias Vascular Dementia Dementia with Parkinson s extra- pyramidal vascular features features + imaging Fronto-temporal dementia Creutzfeldt-Jakob disease Alzheimer s Disease

16 The fronto-temporal dementias A gradually appearing combination of cognitive and behavioral changes: Impaired judgment Inappropriate social conduct Impulsivity Lack of insight Lack of empathy Loss of abstract reasoning ability Different pathology from AD Creutzfeldt-Jakob Disease A dementing illness with course < 12 months from onset to death Strongly suspect CJD in rapidly progressive dementias with: pyramidal, extrapyramidal, cerebellar, extraocular signs abnormal EEG (not always abnl early) CSF and neuron-specific enolase are useful in the diagnosis

17 AAN Diagnostic Assessment for Dementia Neurologic history and examination....required history from informant mental status exam brief neurologic exam Laboratory studies:.....required CBC, electrolytes, Ca, T4, TSH, B12 CT scan w/out contrast......required Psychometrics...optional Why Early Diagnosis of Dementia? Explanation to family of changes Early use of social services Use of financial planning/services Competency for decision-making still present Appropriate treatment of comorbidity Detect reversible causes of impaired cognition Use anti-ad drugs

18 Take home points Alzheimer s disease is not synonymous with aging Alzheimer s disease is diagnosable Alzheimer s disease is treatable Caregiver support by physicians is critical