Dementia Neuropsychology and Neuroimaging Bruce R Reed Ph

Dementia, Neuropsychology and Neuroimaging Bruce R. Reed, Ph. D UC Davis 2005 Friday Harbor Medical Psychometrics Workshop

Dementia • Multiple acquired persistent impairments of cognitive function that limit important daily functions • A syndrome: a defined set of symptoms without a particular etiology • Dementia has biological causes and biological correlates, but it is not biologically defined. • Disease: a pathological process that produces a characteristic set of symptoms. Many different diseases cause dementia 2005 Friday Harbor Medical Psychometrics Workshop

Age-specific prevalence of dementia 2005 Friday Harbor Medical Psychometrics Workshop From: Liddell, 2001

Relative risk of dementia by level of education 2005 Friday Harbor Medical Psychometrics Workshop From Ott, et. al. , 1995

Higher initial capacity or cognitive reserve may delay clinical onset of dementia functional impairment 2005 Friday Harbor Medical Psychometrics Workshop

3 cognitive syndromes • Dementia: Multiple acquired impairments of cognitive function that limit important daily functions. • MCI: a single cognitive deficit or multiple mild deficits that do not cause significant limitations of daily function • No cognitive impairment 2005 Friday Harbor Medical Psychometrics Workshop

No cognitive impairment MCI Dementia 2005 Friday Harbor Medical Psychometrics Workshop

Determinants of Cognitive Test Performance 2005 Friday Harbor Medical Psychometrics Workshop

Diagnosing dementia, MCI and NCI • Can be done algorithmically or clinically • In either case the critical determinations are cognitive status and functional status • Neuropsychology is the “gold standard” for cognitive status 2005 Friday Harbor Medical Psychometrics Workshop

Neuropsychological tests • Psychometric tests of cognitive ability. Used in defining cognitive ability and status (and change), and in differential diagnosis of dementia • Performance typically characterized in percentile or other measures relative to a normative sample. 2005 Friday Harbor Medical Psychometrics Workshop

Global measures • Used to quantitate premorbid ability and present ability • Tests of native (premorbid) ability – IQ (WAIS) – NART • Tests of current ability (dementia screens, dementia severity measures – DRS – ADAS – MMSE 2005 Friday Harbor Medical Psychometrics Workshop

Domain-specific tests • Characterize the nature of impairment rather than its simple presence. • Useful – when specific impairments may be obscured on omnibus measures – in differential diagnosis – For brain behavior correlations 2005 Friday Harbor Medical Psychometrics Workshop

Cognitive Domains • • • Attention Memory Language Spatial Reasoning Executive Function Abstract Reasoning 2005 Friday Harbor Medical Psychometrics Workshop

Memory • Long term, short term, working memory, verbal memory, non verbal memory, remote memory, recent memory, semantic memory, … • Episodic memory refers to the learning, storage, and deliberate recall of context-specific information 2005 Friday Harbor Medical Psychometrics Workshop

Neuropsychological tests of memory • Are legion • Most commonly used are paragraph recall and list learning • Both require learning of novel material, and free (uncued) recall after a delay of 10 -30 minutes • Recognition testing often added • Yield multiple measures; composite or delayed recall measures used most often. 2005 Friday Harbor Medical Psychometrics Workshop

Executive function • Not a single function but a set of functions • Permit the generation, initiation, monitoring, and execution of behavior, especially under circumstances where habitual responses are unavailable or inappropriate 2005 Friday Harbor Medical Psychometrics Workshop

Neuropsychological tests of executive function • Newer, less uniformity in use than in other domains. • Trail Making Test, Wisconsin Card Sorting test • Controlled Oral Word Association Tests • Tests of working memory – Digit span – Sequence reversal, sequence alternation – Category ordering 2005 Friday Harbor Medical Psychometrics Workshop

• “domain specific” neuropsychological tests usually correlate moderately, sometimes highly • Common factors that correlate with a wide variety of tests – Age – Education – Gender 2005 Friday Harbor Medical Psychometrics Workshop

Determinants of Cognitive Test Performance 2005 Friday Harbor Medical Psychometrics Workshop

Many types of diseases cause dementia • Degenerative • Cerebrovascular • • • Endocrine/metabolic Toxic Infectious Traumatic Psychiatric neoplastic 2005 Friday Harbor Medical Psychometrics Workshop

AD is the predominant cause of dementia • 5% of persons over 65 • Accounts for – 40 -60% of all cases by itself – 20 -40% of cases have multiple pathologies including AD – A significant factor in 70 -80+% of all cases of dementia 2005 Friday Harbor Medical Psychometrics Workshop

Alzheimer’s disease • Symptoms and progression variable • Most cases (80%) fit a typical pattern – insidious onset, gradual progression of mental and functional decline over a course of years – Memory loss is the initial symptom – Personality change slight (withdrawal) – No motor signs or physical symptoms • Depression, situational anxiety/agitation, delusions, hallucinations common but not universal 2005 Friday Harbor Medical Psychometrics Workshop

Alzheimer’s Disease – Profound loss of recent memory is the hallmark symptom of Alzheimer’s disease – Forgetting is abnormally rapid – Forgetting is complete – Remote memory may be well preserved – The transition from normal to pathological can be confusing to observe. 2005 Friday Harbor Medical Psychometrics Workshop

2005 Friday Harbor Medical Psychometrics Workshop

AD: spatial impairments 2005 Friday Harbor Medical Psychometrics Workshop

Clock drawing may reveal multiple cognitive impairments 2005 Friday Harbor Medical Psychometrics Workshop

Progressive loss of knowledge and organizational ability over 4 years 2005 Friday Harbor Medical Psychometrics Workshop

AD pathology is most concentrated in brain regions critical for memory and reasoning 2005 Friday Harbor Medical Psychometrics Workshop

Atrophy of the brain caused by Alzheimer’s disease Brain affected by AD 2005 Friday Harbor Medical Psychometrics Workshop Normal elderly brain

Acetylcholine is severely depleted in AD 2005 Friday Harbor Medical Psychometrics Workshop

Markers of Alzheimer’s Disease: Hippocampal Atrophy Normal Atrophy 2005 Friday Harbor Medical Psychometrics Workshop

Alzheimer’s disease as a chronic disease latent phase clinical phase Initiation Factors • genetics • environment • life style preclinical phase symptoms diagnosi s Promoting Factors death • loss of estrogen? • head trauma? • hypoxia? • stroke? 2005 Friday Harbor Medical Psychometrics Workshop • stress? After R. Katzman,

APOE 4 increases the risk of Alzheimer’s disease and lowers the age of onset 84 20 82 18 16 80 76 74 72 age at onset 78 14 one e 4 12 10 8 two e 4's 6 4 70 2 68 0 e 3/e 3 e 2/e 2 2005 Friday Harbor Medical Psychometrics Workshop e 2/e 3 e 2/e 4 e 3/e 4 e 4/e 4 data from Tsai, et. al. , 1994 Relative risk of AD no e 4's

Ischemic Vascular dementia • Prevalence is controversial “ 2 nd or 3 rd most common” • heterogeneity • Commonly seen in conjunction with AD • Brain imaging plays a key role in this difficult diagnosis 2005 Friday Harbor Medical Psychometrics Workshop

• Cerebrovascular disease can cause – Large vessel infarcts (classic stroke) – Small vessel infarcts (may be silent) – Micro and incomplete infarcts • Stroke cases are often excluded from “dementia” series • Small vessel disease tends to affect brain structures that support function of the frontal lobes 2005 Friday Harbor Medical Psychometrics Workshop

Clinical presentation of vascular dementia • Memory less impaired than in AD; learning may be equally impaired but recall better retained • Executive dysfunction • may proceed in a stepwise fashion, may not • Can mimic AD • General medical comorbidities often greater than in AD 2005 Friday Harbor Medical Psychometrics Workshop

White Matter Hyperintensities (MR) and Lucencies (CT) Computed Tomography MRI 2005 Friday Harbor Medical Psychometrics Workshop

Markers of SIVD Lacunar Infarction White Matter Hyperintensities 2005 Friday Harbor Medical Psychometrics Workshop

Determinants of Cognitive Test Performance Ethnicity Genes Disease Environment Brain structure Ability Item 1 Item 2 2005 Friday Harbor Medical Psychometrics Workshop Item 3 Item 4

Neuroimaging • The “gold standard” for measuring brain structure during life • Structural versus functional imaging • CT versus MRI • Advantages of MRI – No radiation – Higher spatial resolution – Superior differentiation of tissues within brain 2005 Friday Harbor Medical Psychometrics Workshop

Case 2 2005 Friday Harbor Medical Psychometrics Workshop

Quantitating MR images • Qualitative ratings • Segmentation 2005 Friday Harbor Medical Psychometrics Workshop

Methods: MRI • Research scan using a single magnet • T 2, PD 3 mm axial slices; T 1 -weighted 3 D sequence • Lacunes marked manually • Segmentation is accomplished in an automated fashion using all three MR data sets • Automated output is then operator edited 2005 Friday Harbor Medical Psychometrics Workshop

2005 Friday Harbor Medical Psychometrics Workshop

Imaging targets • • Macroscopic structure (1 -3 mm resolution) Total brain volume Regional brain volume Cortical thickness Volume of hippocampus Infarcts White matter integrity 2005 Friday Harbor Medical Psychometrics Workshop

Imaging markers of disease • AD: cortical atrophy; hippocampal atrophy; ERC atrophy • Vas. D: infarcts, WML, – (cortical atrophy) – (hippocampal atrophy) • There are no structural imaging markers of normal cognitive function 2005 Friday Harbor Medical Psychometrics Workshop

Dementia, neuroimaging, and neuropsycholgy • AD • Dementia or MCI • Neuropsychology – Severe episodic memory loss – Other cognitive impairments • MRI – Cortical atrophy – Hippocampal atrophy – Absence of cerebrovascular disease 2005 Friday Harbor Medical Psychometrics Workshop • Vas. D • Dementia or MCI • Neuropsychology – Severe executive dysfunction – Other cognitive impairments • MRI – cerebrovascular disease (WML and infarcts) – Cortical atrophy – Hippocampal atrophy absent or mild

Individual paths of change over 6 years 2005 Friday Harbor Medical Psychometrics Workshop Wilson et. al. Psychol & Aging 2002