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

VICCCS Subtypes of Vascular Cognitive Impairment

• VICCCS (Vascular Impairment of Cognition Classification Consensus Study) — 2014/2017 international consensus harmonizing VCI nomenclature
• Defines four major subtypes of vascular dementia:
  • Post-Stroke Dementia (PSD): Dementia developing within 6 months of a clinically symptomatic stroke event
  • Subcortical Ischemic Vascular Dementia (SIVD): Dementia from chronic small vessel disease (lacunes + WMH); includes Binswanger disease
  • Multi-Infarct Dementia (MID): Dementia caused by multiple cortical/subcortical infarcts with cumulative cognitive burden
  • Mixed Dementia: Vascular pathology coexisting with AD or other neurodegenerative disease (DLB, FTD, etc.)
• VICCCS also defines “Mild VCI” (formerly vascular MCI) and “Major VCI” (vascular dementia) along the severity axis

DSM-5 Major and Minor Vascular Neurocognitive Disorder

• DSM-5 criteria for Vascular Neurocognitive Disorder require:
  • Cognitive decline objectively documented (1–2 SD below normative reference for Minor; >2 SD for Major)
  • Evidence consistent with vascular etiology, demonstrated by EITHER:
    • Temporal relationship of cognitive decline with one or more cerebrovascular events, OR
    • Prominent decline in complex attention and frontal-executive function (the characteristic vascular cognitive profile)
  • Neuroimaging evidence of significant cerebrovascular disease sufficient to account for the deficits
  • Symptoms not better explained by another brain disease or systemic disorder
• Major = interferes with independence in everyday activities (equivalent to dementia)
• Minor = modest decline that does NOT interfere with independence (equivalent to MCI)

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 (sensitivity ~89% and specificity ~86%; O'Sullivan 2001); 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. Immunostaining for NOTCH3 ectodomain on skin biopsy has higher sensitivity than EM-based GOM detection and is now commonly used
• No specific treatment — vascular risk factor modification (especially hypertension control)
• IV thrombolysis is not absolutely contraindicated in CADASIL — case series show feasibility but increased theoretical ICH risk due to microbleed burden; decision is individualized. CADASIL is not listed as a contraindication in AHA/ASA guidelines
• 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 ~55–75% of patients >80 years (autopsy series)
• CAA of some degree is found in the majority (estimates 70–90%) of AD brains at autopsy; moderate-to-severe CAA in roughly 25–45% — 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

Anti-Amyloid Monoclonal Antibody Safety in CAA

• Anti-amyloid mAbs (lecanemab, donanemab) increase ARIA-E/ARIA-H risk — mechanism involves perivascular inflammation and bleeding from amyloid-laden vessels
• CAA is a relative contraindication to anti-amyloid mAb therapy, especially with cortical superficial siderosis or multiple (≥4) microbleeds
• APOE ε4 homozygotes have the highest ARIA risk and require pre-treatment MRI screening + counseling regarding risk/benefit
• Pre-treatment MRI to assess microbleed burden, cSS, and prior macrohemorrhage is mandatory before initiating therapy

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, severe CSO-EPVS defined as >20 enlarged perivascular spaces in the hemisphere with the greatest number); criteria require absence of other cause of hemorrhage
• Possible CAA: Age ≥50 + 1 hemorrhagic marker in strictly lobar location; criteria require absence of other cause of hemorrhage
• Probable CAA with supporting pathology: Clinical/imaging criteria for probable CAA PLUS pathological tissue from biopsy or evacuated hematoma showing some degree of CAA (but not meeting full post-mortem criteria for Definite CAA)
• Definite CAA: Full post-mortem examination required — demonstrates severe CAA on Congo red staining (apple-green birefringence under polarized light) + compatible hemorrhagic lesion + no other diagnostic lesion

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:
  • Multiple large vessel infarcts, OR
  • A single strategic infarct (thalamus, caudate, angular gyrus), OR
  • ≥2 lacunes outside the brainstem (or 1–2 lacunes + extensive WMH), OR
  • 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) significantly reduced incident MCI and the composite of MCI + probable dementia; probable dementia alone did not reach statistical significance, likely due to early trial termination
• 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

Clinical Triad & Imaging

• Susac syndrome = autoimmune endotheliopathy of brain, retina, and inner ear microvasculature
• Classic triad:
  • Branch retinal artery occlusion (BRAO) — often multiple, sometimes asymptomatic; detected on fluorescein angiography
  • Sensorineural hearing loss (SNHL) — typically low-frequency, may be sudden
  • Encephalopathy — subacute cognitive decline, confusion, headache, psychiatric features
• MRI hallmark: Corpus callosum “snowball” lesions (central callosal microinfarcts, highly characteristic); supratentorial WMH, leptomeningeal enhancement
• Demographics: Young women predominate (F:M ~3:1; typical age 20–40)
• Treatment: Immunosuppression — corticosteroids, IVIG, rituximab, mycophenolate; aggressive early therapy improves outcomes

Mitochondrial Encephalomyopathy with Lactic Acidosis & Stroke-Like Episodes

• MELAS = Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like episodes
• Genetics: m.3243A>G mutation in MT-TL1 (mitochondrial tRNA-Leu) is the most common (~80%); maternally inherited
• Stroke-like episodes do NOT respect vascular territories — often posterior (parieto-occipital), cortical/gyriform, with overlapping perfusion abnormalities
• Lab markers: Elevated lactate (serum and CSF); elevated lactate-to-pyruvate ratio
• Muscle biopsy: Ragged-red fibers on modified Gomori trichrome stain (subsarcolemmal mitochondrial accumulation); COX-negative fibers
• Other features: Short stature, sensorineural hearing loss, diabetes mellitus, cardiomyopathy, migraine, seizures, progressive cognitive decline
• Acute treatment: L-arginine (IV during acute stroke-like episodes; oral for prophylaxis) — thought to improve endothelial NO bioavailability and reduce episode severity/frequency
• Supportive: coenzyme Q10, riboflavin, antiepileptics for seizures; avoid valproate (mitochondrial toxicity)