Small Vessel Disease and Dementia:

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1 KDA Programme lecture October 2005 Small Vessel Disease and Dementia: Prof Raj N Kalaria FRCP University of Newcastle upon Tyne Wolfson Research Centre Newcastle General Hospital United Kingdom r.n.kalaria@ncl.ac.uk

2 Ischaemic Strokes (80%) TIA - impaired CBF abrupt onset but rapidly diminishing neurological deficit lasting <24 hr; Differential diagnosis (focal seizures), ease of diagnosis Atherosclerosis (thromboembolic) of arteries (50%) majority extracranial; few intracranial Emboli from circulation (heart) (20%) Lacunar infarcts- large or small CNS arteries (~25%) Rare causes- vasculitides, bacterial, arterial dissection, etc (5%)

3 Vascular Dementia Overview Historical aspects Current definition of terms, risk factors Clinical criteria, differential diagnosis, neuroimaging /WMLs Subtypes of VaD Pathological aspects of VaD» Large vessel dementia» Small vessel disease and subcortical involvement» Familial forms of VaD» Risk factors and Alzheimer overlap

4 Historical Perspectives- VaD A Alzheimer Senile Dementia ( hardening of arteries ) E Kraeplin Arteriosclerotic dementia O Binswanger (SVD Binswanger s disease) W Scholz Drusige Entrartung (CAA) 1960/70- Tomlinson et al AD reinvented / Infarct volume & dementia V Hachinski Multi-infarct dementia V Hachinski Leukoariaosis 1990s- V Hachinksi et al VaD, VCI

5 Diagnosis of VaD: NINDS-AIREN Criteria Dementia Impaired memory 2 other cognitive domains impaired Cerebrovascular disease Neurological exam Neuroimaging Probable/Possible diagnosis Temporal relationship between CVD and dementia Abrupt onset / stepwise progression Absence of disorders that could account for deficits (eg, AD) Diagnosis of VaD Román GC, et al. Neurology. 1993;43:

6 What Are the Most Common Forms of Dementia? Vascular dementia 15-20% Other dementias, eg, DLB, PDD 10-25% 60-70% Alzheimer's disease Frataglioni L, et al. Neurology. 2000;54:S10-15.

7 Prevalence of AD and VaD AD» most common form of dementia in the elderly 1» affects 10% of people > 65 years and ~50% of people > 85 years 2» ~4.5 million patients in the US 3» ~3 million patients in the EU VaD» second most common form of dementia in the elderly 1» ~9-39% of people aged > 65 years with dementia have VaD 4» > 1 million patients in the US 5» > 0.6 million patients in Europe 6 1 Lobo A, et al. Neurology. 2000;54:S Evans DA, et al. JAMA. 1989;262: Hebert LE, et al. Archives of Neurology. 2003;60: Kase et al. (1989) Dementia and Stroke: The Framingham study. 5 Román GC. J Neurol Sci. 2002; : Launer LJ, Hofman A. Neurology. 2000;54:S1-8.

8 AD Versus VaD: Classical Clinical Features AD VaD Presence of vascular conditions and risk factors Onset and progression Insidious and Abrupt and gradual stepwise Neuroimaging positive X for CVD Psychiatric comorbidity May be present Frequent Executive dysfunction None or mild Focal neurological signs X and symptoms Memory impairment May not be prominent Gait disturbances X Emotional lability X Increased urinary frequency X Diagnostic criteria DSM-IV, NINCDS-ADRDA DSM-IV, NINDS-AIREN

9 Ageing, Stroke and AD Cognitive measures Clinical findings Imaging Neuropsych testing Genetics/ blood analysis Autopsy Age (Yrs) Ageing ctrl AD Stroke-MID AD+stroke

10 VaD Differential Diagnosis Alzheimer s disease and AD with CVD Normal pressure hydrocephalus (NPH) Dementia with Lewy bodies Frontotemporal dementia (FTLD) Parkinson s disease and dementia Progressive supranuclear palsy Multisystem atrophy Frontal lobe tumours Intracranial mass WMLs and Dementia (?)

11 Risk factors for VaD Vascular Dementia (10-50% of all dementia) Age (>65 yrs 1-10%) Arterial Hypertension Arterial Fibrillation Cardiac abnormalities-mi, CHD Atherosclerosis- high lipids Diabetes mellitus Smoking Genetic factors Male gender Alzheimer s disease (common dementia) Age Family history Down s syndrome Head injury Apolipoprotein E-ε4 Vascular factors Smoking Female gender

12 Subtypes of VaD Multi-infarct dementia (MID) Small vessel disease /dementia (SVD) Strategic infract dementia Hypoperfusive dementia Haemorrhagic dementia Other causes of VaD (vasculitis) Hereditary VaD (CADASIL, CARASIL) AD with CVD

13 How accurate was the diagnosis? (VaD and AD) VCI/ VaD Mixed dementia? AD VaD/MID Plq/NFT AD clinically diagnosed VaD 87% AD either alone (58%) or with cerebrovascular disease (42%) (mixed - neurodegeneration) (Nolan et al, 1998)

14 VCI or VaD Increasing age VaD Mixed pathologies AD Pure VaD? Pure AD Even Auguste D exhibited CBV pathology

15 Common lesions in AD and VaD Pathological feature* AD VaD Cerebral amyloid angiopathy 98% 30% Small vessel disease/ MVD 90% 50% Total infarctions 36% 100% Microinfarcts 31% 70% Intracerebral haemorrhage 7% 15% White matter pathology 40% 80% Loss of cholinergic markers 75% 40% CVD/ Atherosclerosis 77% 60% *Data from several (RNK) series AD n=300; VaD n=45 cases

16 AD and VaD CEREBROVASCULAR INJURY Progression Other factors- Genetic Environmental AD Hypoperfusion (Oligaemia) (microinfarction) White matter lesions Cell death APP/Aβ CAA-NFT-Cholinergic neuronal loss VaD

17 Vascular risk factors, genetic factors, age, lifestyle Large Vessel Small Vessel Partial Vessel Hypotensive Occlusion Occlusion Occlusion Disorders Large Cortical Small Infarcts White Matter Infarcts (Lacunes) Lesions MID Brain Atrophy SIVD VCI: Cognitive impairment, Dementia, Non-cognitive features (e.g. depression).

18 VaD: what do we know? Autopsy frequencies of VaD vary widely (0.03% to 58%; mean ~17%). Use of current clinical diagnostic criteria suggests worldwide prevalence to be 10-15% (as high as~35%). Atherothromboembolism and intracranial small vessel disease (arteriosclerosis): main causes of infarction. Lacunar infarcts or multiple microinfarcts in the basal ganglia, thalamus, brainstem and white matter - associated >50% of the cases

19 VaD subtypes defined by blood vessel size and pathological process Large vessel dementia (multiple infarcts) Small vessel dementia (SVD and microinfarction) Strategic infarct dementia (infarcts in strategic locations) Hypoperfusive dementia Dementia related to angiopathies (hypertension, amyloid) Haemorrhagic dementia Other causes of VaD (vasculitis) Hereditary VaD (CADASIL, CARASIL, HERNS)

20 VaD has a variety of Pathological Mechanisms and Clinical Features Cortical VaD Subcortical VaD Pathology large-vessel disease small-vessel disease Infarcts large cortico-subcortical strategic subcortical Clinical Onset abrupt majority gradual Progression stepwise majority slow Neurological signs/symptoms focal none or mild Cognition memory, cortical function memory Executive dysfunction common classic

21 Survival after lacunar strokes (SVD) Study Period Months follow-up % survival Rochester Oxfordshire Brainin et al Clavier et al Salgado et al Ballard, Kalaria et al* Data from Sacco et al, 1991; Bamford et al, 1987; Brainin etal1992; Clavier et al 1994, Salgado et al, 1996; unpublished data

22 Type of pathology in VaD Pathological feature* All studies (n=56) Infarctions (cortical and subcortical) 75% Cystic infarcts 25% Lacunar infarcts (WM) 50% Micro-/ small infarcts ~50% Cerebral amyloid angiopathy 10% Hippocampal atrophy/ sclerosis 55% IVD appears to correlate with widespread small ishaemic lesions distributed throughout the CNS. (Vinters et al, 2000)

23 How pure was the pathology? 10% 2% 40% AD (+DLB) Mix- Lge VLs Mix- Small VLs 40% pure VaD other 8% large numbers of VaD cases without co-existing neuropathologic evidence of AD suggests that pure VaD is very uncommon. (Hulette et al, 1997)

24 Lacunes and Lacunar infarcts Lacunes complete or cavitating infarcts; up to 15 mm; common in subcortical structures

25 SVD and Microinfarcts Small vessel disease (SVD) loss of SMC hyalinised wall perivascular space Microinfarcts <5 mm diameter multiple +/- involve vessels

26 Small vessel disease and infarcts Branches of MCA and anterior choroidal artery

27 Cerebral Microinfarction a b c Microvascular pathology (SVD) in the absence of macroinfarction and neurodegenerative changes (AD, WMLs) a = cortical microinfarct b = peri-infarct gliosis c = adjacent normal cortex microinfaction was the best correlate with CVD cases (Esiri et al, 1997)

28 Infarct volume and Dementia Pathological feature* <15 ml >15 ml Alzheimer lesions (OR 5.3) 43% 13% Cortical Lewy bodies 14% 6% Bilateral infarcts 93% 75% FC, PC or OC infarcts 32% 72% Basal ganglia infarcts 43% 38% Thalamic infarcts 36% 75% White matter disease (OR 7.8) 93% 62% Microinfarcts (OR 17.5) 71% 13% *Data from Newcastle series,

29 Familial stroke disorders causing CI Type Gene Product CADASIL NOTCH3 Notch3 CARASIL (Maeda syndrome)*?? HERNS* 1 Chr 3? Cerebroretinal vasculopathy (CRV)* Chr 7?? Hereditary vascular retinopathy (HVR)* Chr 3? Familial Moya Moya* Chr 7? Swedish MID?? * Described in Japanese, Chinese-American and Mutations also reported in American, French, and Dutch families 1. Hereditary endotheliopathy retinopathy nephropathy with stroke

30 Principal features of CADASIL Worldwide occurrence of CADASIL. Variable clinical phenotypic features contributed by epigenetic and/or genetic factors. Commonly misdiagnosis as MS, cerebral vasculitis, Binswanger s disease, leukoencephalopathy of undetermined cause or AD. Mis-sense mutations in Notch3 General absence of hypertension or hypercholesterolemia. Exceptionsdata on homocysteine and DM

31 VaD and AD Alzheimer pathology or markers in VaD Aβ concentrations (brain) (Lewis et al, 2000) τau forms (CSF) (Skoog et al, 1996) Cholinergic neuronal markers (ChAT) (Perry et al, 1976; Kalaria et al, 2000) Other neurotransmitters (5HT, DA) (Wallin et al, 1992)? APOE genotype and ε4 alleles (several studies)

32 Cholinergic projections from nbm Axial MRI of patient IV.1 of Axial MRI of CADASIL patient Swedish family. of English family. Abbreviations: Cc, corpus collosum. From J Stroke CVD Sept 2002.

33 CADASIL and Cholinergic neuronal pathology nbm cells- CADASIL Cholinergic tracts- CADASIL ChAT activity (nmol/h/mg protein) Frontal cortex ** 0.5 nbm cell abnormalities and cholinergic fibre damage in white matter lesions 0.0 Elderly Ctrls CADASIL

34 Vascular Factors in dementia Current evidence for vascular disease Strokes or TIAs as 3 fold risk for AD Hypertension- Anti-hypertensives may be protective Atherosclerosis of carotid arteries and aortic pathology. APOE ε4 increases risk AD pathology in CHD Homocysteine and APOE ε4 high risk cholesterol as risk for AD. Statins appear to be protective

35 Risk factors- Silent Infarcts CVD risk factors similar to stroke High prevalence in the healthy elderly (~5% at 60 yrs) Strongly predicts new one- mean interval 3.4 yrs More frequent asymptomatic (silent) infarcts in AD than controls without dementia 1 89% were subcortical (lacune in basal ganglia); only 9% cortical 2 Double the risk of dementia and steeper cognitive decline (memory performance) than those without 3 1 Skoog et al. NEJM 1993;328: ; Barber et al. JNNP 1999; 67: Vermeer et al. Stroke 2003;34: Vermeer et al. NEJM 2003;348:13.

36 Symptomatic treatment of VaD Various agents used -moderate to low improvement Include vasodilators, nootropics, antioxidants, propentofylline, glutamate antagonist Calcium antagonist nimodipine in subgroup of VaD- less deterioration by MMSE 1,2 Cholinesterase inhibitors: Donepezil, Rivastigmine and Galantamine 3-6 Memantine: well tolerated, some improvement in cognition 7 1 Pantoni et al. J Neurol Sci. 2002;175:116 & Pantoni J Neurol Sci. 226: Pantoni et al. Stroke. 2005;36: Wilkinson et al, 2003 Neurology 2003;61:479; 4 lack et al, Stroke 2003;34:2323; 6 Erkinjuntti et al, Lancet 2002;359: Areosa et al. Cochrane Database Sys Rev : CD

37 Pathophysiology of VaD VaD: epidemiology, pathology and prevention Stroke causes, death and disability Risk factors for stroke (VaD) and impairment (non-modifiable and modifiable) Lacunar infarction and small vessel disease (SMC degeneration/ hyalinosis, fibrosis) Inheritance of CVD; CADASIL Modifiable risks and prevention: homocysteine, physical activity and life style Current prevention options: BP, statins, antithrombotics