VASCULAR DEMENTIA (VaD)

A BRIEF REVIEW WITH SPECIAL EMPHASIS ON CURRENT

CLINICAL IMPACT

MURRAY FLASTER MD, PhD

BARROW NEUROLOGICAL CLINIC

OVERVIEW

• HISTORICAL PERSPECTIVE

• PATHOPHYSIOLOGIC BASIS

• CLINICAL IMPACT

• OTTO BINSWANGER 1894

• ALOIS ALZHEIMER 1895, 1907

• PIERRE MARIE 1901

• EMIL KRAEPELIN 1910

• C MILLER FISHER 1968

• VC HACHINSKI 1974

HACHINSKI ISCHEMIA SCALE

• FEATURE VALUE– ABRUPT ONSET 2

– STEPWISE DETERIORATION 1

– FLUCTUATING COURSE 2

– NOCTURNAL CONFUSION 1

– RELATIVE PRESERVATION OF PERSONALITY 1

– DEPRESSION 1

– SOMATIC COMPLAINTS 1

– EMOTIONAL INCONTINENCE 1

– HISTORY/PRESENCE OF HYPERTENSION 1

– HISTORY OF STROKES 2

– EVIDENCE OF ARTHEROSCLEROSIS 1

– FOCAL NEUROLOGICAL SYMPTOMS 2

– FOCAL NEUROLOGICAL SIGNS 2

• SCORES OVER 7 SUGGEST A VASCULAR ETIOLOGY

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.

Va D

AD

OTHER CELLULARAND TISSUE DEMENTIAS

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.

Va D

AD

OTHER CELLULARAND TISSUE DEMENTIAS

US, CANADA, WESTERN EUROPE

Va D

AD

OTHER CELLULARAND TISSUE DEMENTIAS

JAPAN AND CHINA

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

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

Va D

AD

OTHER CELLULARAND TISSUE DEMENTIAS

How do you differentiate these clinically?How do you separate pure from mixed formsfor clinical or study purposes?Do these diseases/processes interact?

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

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

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 ).

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)

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.