DIFFERENTIAL DIAGNOSIS OF NEUROCOGNITIVE DISORDERS Maria D. Llorente MD Associate Chief of Staff, Mental Health Washington DC VA Medical Center Professor of Psychiatry, Georgetown University School of Medicine
DISCLOSURES Member, Executive Committee for VA sponsored clinical trial evaluating effectiveness of memantine v. vitamin E v. placebo for Alzheimer s disease. Forrest supplied memantine for the study.
DEMOGRAPHIC TRANSITION By 2045, average life expectancy will be 80 years By 2030, almost 20% of Americans will be 65+ By 2030, proportion of older Hispanics will nearly double from 5.6% to 10.9%
EPIDEMIOLOGIC TRANSITION Chronic disease and degenerative illness now surpass infectious agents as the leading causes of death and disability in developed countries 80% of adults 65+ have at least one chronic illness, and half have at least 2 Prevalence of depression and dementia increase with age Women are more likely to be affected due to longer life expectancies
US Aging Population by County
DIAGNOSIS OF NEUROCOGNITIVE DISORDERS: 2 STEP PROCESS 1. Establish the diagnosis: new DSM 5 Nomenclature 2. Determine the etiology
ESTABLISH THE DIAGNOSIS Category of Delirium, Dementia and Amnestic and Other Cognitive Disorders in DSM-IV is now: (1)Delirium NEUROCOGNITIVE DISORDERS (2)Mild Cognitive Disorder (3)Major Cognitive Disorder
DETERMINE ETIOLOGY Obtain history regarding mode of onset and progression Examine patient for neurological findings R/O potentially treatable causes
POTENTIALLY TREATABLE ETIOLOGIES B12 deficiency Thyroid disease Syphilis Depression Delirium Medications Substances of abuse
DEPRESSION Pseudodementia or depression with cognitive findings Frequent I don t know responses Mood disturbance Psychomotor slowing Responsive to antidepressants Relationship with Dementia: -prodrome of vascular dementia - early reaction to perceived cognitive decline - source of hippocampal damage through a glucocorticoid cascade
Benzodiazepines Narcotics MEDICATIONS Anticholinergics (diphenhydramine, cimetidine, famotidine, ranitidine, anticholinergic load ) Lithium (Ace Inhibitor)
ALCOHOL USE, AT-RISK DRINKING, ABUSE What is a standard drink? 1 Standard Drink = A GLASS OF WINE 6 oz. A SINGLE SHOT OF HARD LIQUOR (Whiskey, gin, rum, vodka, etc) 1.5 oz. 1 CAN OF BEER OR ALE 12 oz. A SMALL GLASS OF LIQUEUR, OR APERITIF 4 oz.
No more than one drink per day for adults older than 65 Never more than 4 drinks on any single occasion
DIFFERENTIAL DIAGNOSIS OF DEMENTIA Alzheimers Disease Vascular Dementia Diffuse Lewy-Body Frontotemporal dementia HIV-associated dementia
ALZHEIMER S DISEASE Most common cause of dementia Currently affects 4 million people in US, will affect 14 million by 2050 (NIA) Average duration is 8-10 years (Brookmeyer et al., 1998). Annual national direct and indirect costs of caring for AD patients are estimated to be as much as $100 billion (Ernst and Hay, 1994; Ernst et al., 1997; Huang et al., 1988)
RISK FACTORS Age (inflammatory, free radicals) Ethnicity: AA & Latino >Caucasian Gender F>M Head injury Lower educational level High Cholesterol in APOE 1-3 Genetics (Familial Forms: Chromosomes 1, 14, 21) APOE-4 (Chromosome 19)
CHOLINERGIC CHANGES IN AD The most prominent neurotransmitter abnormalities are cholinergic Reduced activity of choline acetyltransferase (synthesis of acetylcholine) 1 Reduced number of cholinergic neurons in late AD (particularly in basal forebrain) 2 Selective loss of nicotinic receptor subtypes in hippocampus and cortex 1,3 1. Bartus RT et al. Science. 1982;217:408-414. 2. Whitehouse PJ et al. Science. 1982;215:1237-1239. 3. Guan ZZ et al. J Neurochem. 2000;74:237-243.
PRESENTING SYPTOMS COGNITIVE - Memory - Visuospatial - Executive Function BEHAVIORAL - Aggressive - Non-aggressive - Apathy
PATHOLOGICAL CHANGES
PROGRESSION OF ALZHEIMER S DISEASE 30 25 Early diagnosis Mild-moderate Severe Cognitive symptoms MMSE score 20 15 10 Loss of IADL s Behavioral problems 5 0 Nursing home placement Death 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 8 8.5 9 Years Feldman H, Gracon S. In: Clinical Diagnosis and Management of Alzheimer s Disease. 1996:239-253.
GENETICS OF AD-EARLY ONSET Age 30-60 (less than 5% of cases) Some idiopathic, but most Familial AD Single gene mutations Chromosome 21: Abnormal APP Chromosome 14: abnormal Presenilin 1 Chromosome 1: Abnormal Presinilin 2 Autosomal Dominant
GENETICS OF AD-LATEONSET Most cases of AD Chromosome 19: APOE-4 APOE-2: rare may protect APOE-3: most common; neither protects nor increases risk APOE-4: present in 25-30% of pop n; but seen in 40% of AD Partly explains variation in age at presentation
GENETICS OF AD-LATEONSET Risk is tripled if APOE-4 heterozygous Risk increases 15 fold if APOE-4 homozygous
VASCULAR DEMENTIA May occur immediately or within first three months of cerebrovascular event (post-stroke dementia) May occur insidiously, in step-wise fashion (multi-infarct dementia) and associated with chronically reduced blood flow to brain Associated risk factors: CAD with MI, high cholesterol/triglycerides, hypertension, diabetes, male gender, African-American race More likely to exhibit problems with balance or gait than persons with AD
MRI FINDINGS White Matter Hyperintensities Lacunar infarcts
DIFFUSE LEWY-BODY DISEASE Features of both AD and Parkinson s Cognitive symptoms occur at same time or within one year of motor sx Often has rapid onset, and rapid decline Hypersensitivity to antipsychotics
DIFFUSE LEWY-BODY DISEASE Fluctuating cognition with variations in attention and alertness from day to day or even hour to hour Recurrent visual hallucinations (up to 75% of patients with DLB) Motor features of Parkinsonism (shuffling gait, blank expression, sialorrhea, difficulty swallowing, cogwheel rigidity, low speech volume, reduced arm swing Tremor less prominent + Orthostatis, syncope
PATHOPHYSIOLOGY Abnormal cytoplasmic inclusions (alpha-synuclein) throughout brain (Lewy Bodies) Loss of dopaminergic neurons in substantia nigra Loss of acetyl-cholinergic neurons in basal nucleus of Meynert with cerebral cortical atrophy Plaques like in AD, less common NFT
FRONTOTEMPORAL DEMENTIA Described by Arnold Pick in 1892 as focal syndromes associated with degeneration of the frontal and temporal lobes Second most common form of degenerative dementia in middle age i.e. presenile dementia Onset typically between 45 and 65 Equal incidence in males and females Mean duration from time of diagnosis 8 years Strong family history of dementia
CORE FEATURES Insidious onset and gradual progression Early decline in social interpersonal conduct (disinhibition, tactlessness, breaches of social etiquette) Early impairment in regulation of conduct (inertia, passivity plus overactivity, pacing) Early emotional blunting and lack of empathy Early loss of insight along with lack of concern/distress with conflict
BEHAVIORAL DISORDER Decline in personal hygiene and grooming Mental rigidity and inflexibility Distractibility and impersistence Hyperorality and dietary changes Perseverative and stereotyped behavior both simple and complex Utilization behavior (drinking from an empty cup) Speech: echolalia, aspontaneity, mutism
NEUROPATHOLOGY Commonly, but not inclusively abnormal accumulation of tau Microvacuolar type: loss of large cortical nerves Picks type: swellings and inclusion bodies, represent only 25% of cases. 15% of cases also have significant motor neuron disease
Post-mortem neuropathology demonstrates bilateral atrophy of the frontal and anterior temporal lobes. NEUROPATHOLOGY
GENETICS Family history of dementia in up to 50% of cases Genetic linkage studies established mutation of microtubule associated protein tau (MAPT) on Chromosome 17 with autosomal dominant inheritance Chromosome 9 linkage associated with motor neuron disease
HIV ASSOCIATED DEMENTIA (HAD) HAART has improved survival and decreased incidence of HAD to 7-10% Linear increase with increasing age:15-34 years (6%), 35-54 (8%), 55-74 years (12%) and 75 and older (19%). Diabetes and higher viral loads at time of diagnosis are risk factors(cd4 counts less than 200 cells/µl Coinfection with hepatitis C, history of ETOH abuse/dependence
HAD SYMPTOMS Motor: slowing, poor coordination, LE weakness, imbalance, dropping of things, loss of bladder/bowel control Cognitive: poor concentration and attention, memory loss, slowed processing, loss of sense of humor, increased latency of response Behavioral: personality change, mood swings, impulsivity, disinhibition, psychosis
HAD COURSE Pre-HAART: mean time to death after dx of HAD was 6 months Post-HAART: average now is 44 months Hx of IV drug use and psychomotor slowing associated with more rapid progression Currently, two subtypes : inactive form with fixed deficits, chronic gradually progressive form Improved neuropsych performance correlated with declines in CSF HIV RNA levels
LABORATORY WORK-UP CBC with diff Electrolyte and metabolic panel. Thyroid function tests. Vitamin B-12 and folate levels. VDRL, RPR and, depending on history, for human immunodeficiency antibodies. Urinalysis.
ADDITIONAL TESTING Brain CT or MRI scan Depending on history: LP and/or EEG Depression screen Neuropsychological testing
CONCLUSIONS Today s elderly are healthier and better prepared financially to cope with aging Healthcare needs of this group however present a challenge because of rapid increase in numbers Dementia has multiple etiologies Early identification facilitates longterm planning
QUESTIONS OR COMMENTS