1. VASCULAR DEMENTIA (VaD) A BRIEF REVIEW WITH SPECIAL EMPHASIS ON CURRENT CLINICAL IMPACT MURRAY FLASTER MD, PhD BARROW NEUROLOGICAL CLINIC

2. OVERVIEW HISTORICAL PERSPECTIVE PATHOPHYSIOLOGIC BASIS CLINICAL IMPACT

3. OTTO BINSWANGER 1894 ALOIS ALZHEIMER 1895, 1907 PIERRE MARIE 1901 EMIL KRAEPELIN 1910 C MILLER FISHER 1968 VC HACHINSKI 1974

4. HACHINSKI ISCHEMIA SCALE FEATUREVALUE –ABRUPT ONSET2 –STEPWISE DETERIORATION1 –FLUCTUATING COURSE2 –NOCTURNAL CONFUSION1 –RELATIVE PRESERVATION OF PERSONALITY1 –DEPRESSION1 –SOMATIC COMPLAINTS1 –EMOTIONAL INCONTINENCE1 –HISTORY/PRESENCE OF HYPERTENSION1 –HISTORY OF STROKES2 –EVIDENCE OF ARTHEROSCLEROSIS1 –FOCAL NEUROLOGICAL SYMPTOMS2 –FOCAL NEUROLOGICAL SIGNS2 SCORES OVER 7 SUGGEST A VASCULAR ETIOLOGY

5. In summary: Both diffuse and discrete ischemic brain pathological change and their impact on cognitive function were recognized by the turn of the last century. In the first seven decades of the 20th century, ischemia both chronic and acute was thought responsible for the vast majority of dementia cases. A cellular basis for dementia was increasingly recognized in the later half of the 20th century, while vascular dementia was recognized primarily in the restricted form of multi-infarct dementia. Today, vascular dementia is recognized as a heterogeneous group of disorders, each with its own pathophysiologic characteristics. Any of these processes can contribute to a dementing illness, and any could in theory overlap with a cellular dementia.

6. Va D AD OTHER CELLULAR AND TISSUE DEMENTIAS

7. A little epidemiology ALL DEMENTIAS –PREVALENCE OF 1% AT AGE 60; AND DOUBLES EVERY FIVE YEARS, REACHING 32% BY AGE 85. ALZHEIMER’S DISEASE –UP TO 90% OF ALL DEMENTIA CASES INCLUDE SOME SIGNIFICANT DEGREE OF ALZHEIMER’S PATHOLOGY AND CLINICAL ATTRIBUTES. “PURE” ALZHEIMER’S CASES COMPRISE UP TO 2/3rds OF THAT TOTAL. VASCULAR DEMENTIAS –PREVALENCE OF “PURE” VASCULAR DEMENTIA 10 - 19% IN US AND WESTERN COUNTRIES IN GENERAL, BUT PERHAPS DOUBLE THAT RATE IN JAPAN AND CHINA. MIXED DEMENTIAS INCLUDING A VASCULAR COMPONENT MAY RANGE FROM 10 TO 40% OF ALL DEMENTIAS. SUBCORTICAL VASCULAR DEMENTIA –NO GOOD STATISTICS AVAILABLE, PERHAPS 4% OF ALL DEMENTIAS HAVE SOME DEGREE OF SUBCORTICAL VASCULAR DEMENTIA, PERHAPS LESS THAN 1% OF VASCULAR DEMENTIA MEET CRITERIA FOR “PURE” BINSWANGER’S DISEASE. OVERALL, ALZHEIMER’S DISEASE IS IMPLICATED IN NEARLY 90% OF ALL DEMENTIA CASES, WHILE VASCULAR DEMENTIA AND LEWY BODY DISEASE REPRESENT THE SECOND AND THIRD MOST IMPORTANT CONTRIBUTORS TO THE TOTAL BURDEN OF DISEASE.

8. Va D AD OTHER CELLULAR AND TISSUE DEMENTIAS US, CANADA, WESTERN EUROPE

9. Va D AD OTHER CELLULAR AND TISSUE DEMENTIAS JAPAN AND CHINA

10. NOSOLOGY CELLULAR/MOLECULAR – ALZHMEIMER’S DISEASE (B- AMYLOID ) –DIFFUSE LEWY BODY DISEASE (SYNUCLEIN ?) –FRONTO-TEMPORAL DEMENTIAS, PSP (TAU ?) –OTHERS ( MITOCHONDRIAL DISEASES, HEREDITARY PRION DISEASE, WILSON’S DISEASE, ETC.) TISSUE/ORGAN/SYSTEMIC –NORMAL PRESSURE HYDROCEPALUS –INFECTION (SYPHILIS, HIV, HTLVIII, CJD, WHIPPLE’S ETC.) –INFLAMMATION (MS, PARANEOPLASTIC,ETC.) –HYPOXIC/METABOLIC/TOXIC (GLOBAL ISCHEMIA, B12 DEFICIENCY ETC.) –VASCULAR DEMENTIAS

11. VASCULAR DEMENTIAS LARGER ARTERY SYNDROMES (MULTI-INFARCT DEMENTIA) –CARDIAC, CAROTID, VERTEBRAL OR INTRACRANIAL ATHEROSCLEROTIC DISEASE. –CORTICAL INFARCTS, LARGER SUBCORTICAL INFARCTS ( AS MIGHT BE SEEN IN M1 OCCLUSIONS ). –RISK FACTORS/MECHANISMS ARE NUMEROUS: HYPERTENSION, HYPERLIPIDEMIA,TOBACCO SMOKE, DIABETES, CORONARY ARTERY, DISEASE ATRIAL FIBRILLATION, CARDIOMYOPATHY, VALVULAR DISEASE, PARADOXIC EMBOLISM. SMALL VESSEL SYNDROMES ( SUBCORTICAL DEMENTIA ) –BINSWANGER SYNDROME –LACUNAR STATE ( WITH OR WITHOUT SUBCORTICAL HEMORRHAGES ). –RISK FACTORS: HYPERTENSION, DIABETES, HYPERLIPIDEMIA, TOBACCO SMOKE. –VASCULITIDES (ISOLATED CNS, SYSTEMIC, ANTI-CARDIOLIPIN, MICROANGIOPATHIES SUCH AS TTP) –CADASIL, (AND NOW CARASIL) STRATEGIC INFARCT DEMENTIA ( THALAMUS, PCA INARCTION INVOLVING TEMPORAL LOBE, ANTERIOR LIMB OF INTERNAL CAPSULE ETC.) HEMORRHAGIC DEMENTIAS ( SUBARACHNOID HEMORRHAGE, SUBDURAL HEMORRAGE, RECURRENT LOBAR HEMORRHAGE ). –`CEREBRAL AMYLOID SYNDROMES (DUTCH, BRITISH, ICELANDIC) WITH HEMMORRHAGE AND ISCHEMIA. BOLD LETTERING INDICATES CLASS I AND/OR CLASS II SUPPORT

12. Va D AD OTHER CELLULAR AND TISSUE DEMENTIAS How do you differentiate these clinically? How do you separate pure from mixed forms for clinical or study purposes? Do these diseases/processes interact?

13. SEPARATING VASCULAR DEMENTIA FROM ALZHEIMER’S DISEASE IN THE ABSENCE OF CLINICALLY OBVIOUS INFARCTIONS Va D –LESS MEMORY LOSS EARLY ON –GAIT ABNORMALITIES EARLY ON –RIGIDITY EARLY ON –DYSARTHRIA –EXECUTIVE DYSFUNCTION AND OTHER “FRONTAL LOBE “ BEHAVIORAL CHANGES OUTPACE MEMORY LOSS A D –MEMORY IMPAIRMENT PREDOMINATES EARLY ON –POOR LEARNING –APHASIA WITH ANOMIA FOR DETAIL –LACK OF MOTOR ABNORMALITIES ON NEUROLOGIC EXAM UNTIL RELATIVELY LATE IN THE DISEASE PROCESS

14. THERE REMAINS AN OVERLAP BETWEEN DEMENTIA SYNDROMES CLINICALLY AND AN OVERLAP IN RISK FACTORS AND TREATMENT. HYPERTENSION AND ANTIHYPERTENSIVE THERAPY HYPERLIPIDEMIA AND STATIN THERAPY ANTI-CHOLINERGIC THERAPY ATRIAL FIBRILLATION

15. HYPERTENSION METAANALYSIS OF NINE CLASS I STUDIES ( GUEYFFIER et al 1997) SHOWED ANTI-HYPERTENSIVES REDUCED THE INCIDENCE OF RECURRENT STROKE BY 28%. THE EFFICACY OF ANTIHYPERTENSIVES INPRIMARY STROKE PREVENTION IS ALSO WELL ESTABLISHED. STROKE RISK CAN BE REDUCED BY 40%. MORE LIMITED DATA ( SMALL TRIALS AND POPULATION STUDIES ) SUPPORT THE NOTION THAT BLOOD PRESSURE CONTROL REDUCES DEMENTIA INCIDENCE ( BUT THIS RELATIONSHIP MAY BE COMPLEX ).

16. HYPERLIPIDEMIA AND STATINS STATINS (HMG CO-A INHIBITORS) REDUCE STROKE RISK BY UP TO 30% (PRAVASTATIN IN CARE TRIAL AMONG OTHERS). POPULATION STUDIES SUGGEST STATINS MAY ALSO REDUCE THE INCIDENCE OF DEMENTIA (PRESUMEABLY AD). (MORE STUDY IS NEEDED)

17. ANTI-CHOLINERGICS AND VaD BOTH DONEPEZIL (ARICEPT) AND GALANTAMINE (REMINYL) HAVE SHOWN EFFICACY IN PLACEBO CONTROLLED TRIALS OF DEMENTIA PATIENTS WITH A SIGNIFICANT VASCULAR DEMENTIA COMPONENT. RIVASTIGMINE (EXELON) MAY ALSO BENEFIT IN A SIMILAR POPULATION. THE SIGNIFICANCE OF THE OVERLAP IN EFFICACY IN BOTH VaD AND ALZHEIMER’S DISEASE PATIENTS COULD REFLECT EITHER A COMMON VASCULAR CHOLINERGIC EFFECT, A COMMON CELLULAR DEFICIENCY BUT PROBABLY NOT INADEQUATE SEPARATION OF DEMENTIA SUBTYPES.