The VCI Continuum

• Vascular cognitive impairment (VCI) = umbrella term for all cognitive disorders attributable to cerebrovascular disease
• Replaces the older, narrower term “vascular dementia”
• Spectrum:
  • Vascular MCI: Objective cognitive deficits (typically executive/processing speed) with preserved functional independence
  • Vascular dementia: Cognitive deficits severe enough to impair daily functioning
• Can be caused by large vessel disease, small vessel disease, strategic infarcts, hemorrhage, or hypoperfusion

Major Subtypes

Strategic Infarct Locations & Cognitive Syndromes

• A single, often small stroke in a cognitively critical location can produce dementia disproportionate to the infarct size
• Abrupt onset of cognitive deficits temporally related to the stroke event

Genetics & Pathology

• CADASIL = Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy
• Gene: NOTCH3 mutation on chromosome 19
• Inheritance: Autosomal dominant with high penetrance
• Pathology: Non-amyloid, non-atherosclerotic small vessel disease → progressive vascular smooth muscle cell degeneration
• Hallmark pathological finding: Granular osmiophilic material (GOM) deposited in the media of small arterioles — visible on electron microscopy of skin biopsy
• GOM = aggregated extracellular domains of mutant NOTCH3 protein

Clinical Stages

Neuroimaging

• MRI white matter hyperintensities (WMH): Symmetric, confluent, progressive
• Anterior temporal pole WMH — highly characteristic (present in >90% of CADASIL); unusual in other small vessel diseases
• External capsule involvement — another distinctive early finding
• Subcortical lacunar infarcts (basal ganglia, thalamus, pons, centrum semiovale)
• Microbleeds in ~30–40% (mostly subcortical)
• WMH typically precede symptoms by years — abnormalities detectable on MRI by age 20–35 even in asymptomatic carriers

Diagnosis & Management

• Gold standard: Genetic testing for NOTCH3 mutations (cysteine-altering missense mutations in EGF-like repeats)
• Skin biopsy: Ultrastructural detection of GOM by electron microscopy — ~95% specificity when positive; less sensitive than genetic testing
• No specific treatment — vascular risk factor modification (especially hypertension control)
• Thrombolysis (tPA) is contraindicated — increased hemorrhagic risk due to small vessel fragility and microbleed burden
• Genetic counseling for family members (50% transmission risk per offspring)
• Avoid smoking; migraine-specific treatments for headache (triptans generally used cautiously)

CAA Overview

• Deposition of amyloid-beta (Aβ) protein in cortical and leptomeningeal vessel walls → vessel fragility
• Prevalence increases dramatically with age: found at autopsy in ~50% of patients >80 years
• ~80% of Alzheimer disease patients have concurrent CAA — shared amyloid pathology
• Sporadic (most cases) or hereditary (Dutch, Iowa, Flemish types with APP mutations)

CAA Manifestations Relevant to Cognition

• Lobar microbleeds: Strictly cortical/subcortical on GRE/SWI; spare deep nuclei and brainstem (deep microbleeds = hypertensive SVD, not CAA)
• Lobar intracerebral hemorrhage: Recurrent lobar ICH in the elderly without hypertension
• Cortical superficial siderosis (cSS): Hemosiderin lining the cortical surface; transient focal neurological episodes (“amyloid spells”)
• White matter hyperintensities: Posterior-predominant (vs. periventricular in hypertensive SVD)
• Cognitive decline: Executive dysfunction, processing speed reduction; each additional lobar microbleed and cSS progression correlate with cognitive decline
• CAA-related inflammation (CAA-ri): Subacute cognitive decline + asymmetric WMH + microbleeds; responds to corticosteroids

Modified Boston Criteria 2.0 (2022) — Key Points

• Probable CAA: Age ≥50 + ≥2 hemorrhagic markers (lobar ICH, lobar microbleeds, cSS) in strictly lobar distribution; OR 1 hemorrhagic + 1 non-hemorrhagic marker (multispot WMH, enlarged perivascular spaces in centrum semiovale >20)
• Possible CAA: Age ≥50 + 1 hemorrhagic marker in strictly lobar location
• Definite CAA: Postmortem only — Congo red staining with apple-green birefringence under polarized light

VASCOG Diagnostic Criteria for VCI

• VASCOG (Vascular Behavioral and Cognitive Disorders) — international consensus criteria for VCI
• Requires both cognitive impairment AND cerebrovascular disease with a plausible temporal/causal relationship

Cognitive Domain Profile

• Executive function and processing speed are disproportionately affected early (vs. memory-predominant in AD)
• Impaired attention, set-shifting, planning, multitasking
• Psychomotor slowing — often the earliest measurable deficit
• Memory may be relatively preserved initially (retrieval deficit pattern — improves with cueing, unlike AD storage deficit)

Temporal Relationship

• Cognitive decline onset within 3 months of a recognized stroke event (for post-stroke VCI)
• Stepwise or fluctuating course (vs. gradual progressive in AD)
• For subcortical SVD: insidious onset acceptable if supported by imaging

Neuroimaging Evidence (Required)

• Must demonstrate cerebrovascular disease sufficient to account for cognitive deficits:
  • ≥2 large vessel infarcts
  • Single strategically placed infarct (thalamus, caudate, angular gyrus)
  • Multiple lacunar infarcts (basal ganglia, white matter) + extensive WMH
  • Extensive/confluent white matter hyperintensities (Fazekas grade 3)

Neuroimaging in VCI

Fazekas Scale for White Matter Hyperintensities

VCI vs. AD: Key Distinguishing Features

AD + Vascular Pathology Co-existence

• Most common dementia pathology in the elderly at autopsy — pure AD or pure VCI alone is less common than their co-occurrence
• Autopsy studies: ~50–60% of clinically diagnosed AD patients have significant concurrent cerebrovascular pathology
• Additive / synergistic effect: Less AD pathology is needed to produce clinical dementia when vascular disease is also present — vascular lesions lower the threshold for symptomatic expression of AD
• Conversely, subclinical AD pathology may become clinically manifest only after a stroke event

Clinical Implications

• Consider mixed dementia when:
  • Clinical features of both AD (progressive amnesia) AND VCI (stepwise component, executive dysfunction, gait) coexist
  • MRI shows both medial temporal atrophy (AD) AND significant vascular burden (WMH, lacunes, infarcts)
  • Amyloid PET is positive AND extensive vascular disease is present
• Treatment: Address BOTH pathologies — vascular risk factor control + cholinesterase inhibitors (for the AD component)
• Prognosis may be worse than either condition alone due to synergistic neurodegeneration

Vascular Risk Factor Management

• Hypertension control is the #1 intervention — strongest evidence for preventing and slowing VCI progression
• SPRINT MIND (2019): Intensive BP control (target SBP <120 mmHg) reduced the risk of MCI (but not dementia) compared to standard control (<140 mmHg); however, trial was stopped early
• PROGRESS (2003): Perindopril ± indapamide reduced recurrent stroke and cognitive decline in patients with prior stroke
• Diabetes management: Avoid both hyperglycemia and hypoglycemia; optimal glycemic control reduces microvascular complications
• Statin therapy: Per stroke prevention guidelines; no strong evidence for cognitive benefit alone, but cardiovascular risk reduction is beneficial
• Antiplatelet / anticoagulant therapy: As indicated for stroke prevention (aspirin, clopidogrel, or anticoagulation for AF); does NOT directly treat cognitive symptoms
• Lifestyle modifications: Regular aerobic exercise (most evidence), Mediterranean-style diet, smoking cessation, moderate alcohol intake, cognitive engagement, social interaction

Cognitive Enhancers & Pharmacotherapy

• No FDA-approved medication specifically for VCI/vascular dementia
• Cholinesterase inhibitors (donepezil, galantamine, rivastigmine):
  • Modest evidence for benefit in vascular dementia (smaller effect size than in AD)
  • Donepezil showed small improvements in cognition in two RCTs but no consistent functional benefit
  • May be reasonable in mixed dementia (targeting the AD component)
• Memantine: NMDA receptor antagonist; limited and inconsistent evidence in pure VCI; may benefit mixed dementia
• Antidepressants: SSRIs for post-stroke/vascular depression (common comorbidity affecting cognition)
• No role for: Nootropics, ginkgo biloba, vitamin E — no proven benefit in VCI

Non-Pharmacologic Interventions

• Aerobic exercise: Strongest evidence for cognitive benefit in VCI; improves cerebrovascular reserve and executive function
• Cognitive rehabilitation: Strategy-based approaches for executive dysfunction (external aids, structured routines)
• Occupational therapy: Functional adaptation, safety assessment
• Speech therapy: For post-stroke aphasia and cognitive-communication deficits

CADASIL vs. CARASIL vs. Other Genetic SVD