4: Vascular cognitive impairment

CHAPTER 4
Vascular cognitive impairment: Diagnosis and treatment

Helena C. Chui and Liliana Ramirez-Gomez

University of Southern California, Los Angeles, CA, USA

Background

History

During the past century, the estimated contribution of vascular factors to cognitive decline has swung like a pendulum from high to low to high again. In the early twentieth century, progressive loss of intellectual function in late life was ascribed to “hardening of the arteries,” so-called arteriosclerotic dementia. Alzheimer’s disease (AD) was considered a relatively rare early-onset dementia associated with neurofibrillary tangles and senile plaques, as first described by Alois Alzheimer in 1907.

When Tomlinson et al. [1] observed identical tangle and plaque lesions in late-onset dementia cases, AD, not arteriosclerosis, became the ascendant cause. Abrupt onset and stepwise decline in cognition due to cumulative strokes formed the conceptual basis of multi-infarct dementia (MID). Slowly progressive dementia due to severe arteriopathy and demyelination of subcortical white matter, so-called Binswanger’s syndrome, was regarded as relatively rare.

The landscape shifted once again with the advent of structural imaging in the 1980s. Asymptomatic white matter hyperintensities (WMH) and silent brain infarcts (SBI) were discovered on brain MRI in 20–30% of nondemented, community-dwelling elderly subjects [2]. The ability to detect early and subclinical vascular disease without overt dementia inspired a broader designation, vascular cognitive impairment (VCI). In the 1990s, epidemiologic studies noted associations between stroke risk factors and cognitive impairment (absent history of symptomatic stroke). This has led to the notion (still unproven) that vascular factors might promote AD, further broadening the saliency of potential adverse downstream effects of hypertension, diabetes, and dyslipidemia.

Concepts

VCI is a syndrome or phenotype, not a disease. At its simplest, VCI embodies the concept that cognitive impairment is due to vascular brain injury (VBI). (See Table 4.1 for terms and abbreviations used in this chapter.) Yet the sequence of underlying events can be incredibly diverse. The pathways leading from risk factors to cerebrovascular disease (CVD) to VBI are widely heterogeneous (Table 4.2). Moreover, the likelihood that VBI contributes to cognitive impairment is highly variable. Location within cognitive networks and number and size of lesions are considered to be important determinants of cognitive impairment and dementia.

Table 4.1 Terms and abbreviations.

Syndromes
MCI = mild cognitive impairment (cognitive impairment without significant compromise of instrumental or personal activities of daily living)
MCI subtypes: amnestic, amnestic plus other cognitive domain, nonamnestic single domain, nonamnestic plus other cognitive domains
Memory impairment = free recall is below expectations
Amnestic memory impairment = free recall is below expectations and is not attributed to diminished attention or retrieval (i.e., does not improved significantly with cueing)
VCI = vascular cognitive impairment (cognitive impairment ascribed to vascular disease or vascular brain injury)
VaD = vascular dementia (dementia ascribed to vascular disease or vascular brain injury)

Alzheimer disease
AD = Alzheimer’s disease (refers to progressive cognitive decline associated with widespread neurofibrillary tangles and neuritic amyloid plaques)
Clinically diagnosed AD (mild cognitive impairment or dementia ascribed to AD, without pathological data)

Cerebrovascular disease
CAA = cerebral amyloid angiopathy
CVD = cerebrovascular disease (disease of blood vessels) (e.g., atherosclerosis, arteriolosclerosis)
Atherosclerosis = disorder affecting endothelial and elastic lamina of larger arteries
Arteriolosclerosis = disorder affecting smooth muscle cell layer of arterioles
Arteriosclerosis = includes atherosclerosis and arteriolosclerosis

Vascular risk factors
VRF = vascular risk factors (refers to known risk factors for stroke (e.g., hypertension, hyperlipidemia, diabetes mellitus, atrial fibrillation))
Vascular factors = included VRF and CVD

Vascular brain injury
Stroke = sudden-onset neurological deficit ascribed to CVD
VBI = vascular brain injury (parenchymal brain injury ascribed to vascular disease)

MRI lesions
MTA = medial temporal atrophy
WMH = white matter hyperintensity on MRI (synonyms include WML (white matter lesion), WMSH (white matter signal hyperintensity), and leukoaraiosis (rarefaction of white matter on CT))
SBI = silent brain infarct on MRI
SI = silent infarct on MRI
SL = silent lacune (may include infarcts and perivascular spaces)

Table 4.2 The pathogenic spectrum of vascular cognitive impairment: RF→ CVD → VBI →VCI.

Risk factors	Vascular phenotype: “Cerebrovascular disease (CVD)”	Vascular distribution	Mechanism of brain injury	Brain pathology phenotype: vascular brain injury (VBI)	Location/neural network	Clinical phenotype or syndrome: “stroke” or vascular cognitive impairment (VCI)
Modifiable	Cerebrovascular	Single artery	Ischemia	Complete infarction	Limbic–diencephalic	Multi-infarct dementia
Hypertension	Atherosclerosis	Large artery	Acute	(Symptomatic or silent)	memory system	Strategic infarct dementia
Hyperglycemia	Arteriolosclerosis	Small arteriole	thrombosis	Incomplete infarction	Multimodal association areas	Lacunar state
Hyperlipidemia	Amyloid angiopathy	Capillary	Embolism	(demyelination;	Corticobasal ganglia-thalamocortical loops	Subcortical vascular dementia
(Apolipoproteins)	Vasculitis	Border zone	Chronic	selective neuronal loss)	Deep white matter connections	Binswanger’s syndrome
Smoking	Tortuosity	Large arteries	hypoperfusion	Hematoma	(cingulum, superior frontal occipital fasciculus, superior longitudinal fasciculus)
Obesity	Anomaly	Small arterioles	Hemorrhage	Microbleed
Nonmodifiable	Cardiac	Capillaries	Leaky BBB	Neuronal loss with gliosis
Age	Atrial fibrillation	Vein	Anoxia
Gender	Endocarditis
Race	Myopathy
Heredity	Mural thrombus
CADASIL	Blood content
CARASIL	Hypoglycemia
HCHWA-D	Hypoxemia
HCHWA-I	Hemoglobinopathy
	Coagulopathy

In order to prevent or reduce VCI, efforts must be directed to preventing CVD and VBI. VBI may result from ischemic, hemorrhage, toxic and inflammatory conditions or oxidative stress [3]. There are several forms of CVD, including atherosclerosis, arteriolosclerosis, cerebral amyloid angiopathy (CAA), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and CARASIL [4]. Risk factors for arteriosclerosis are well known, including hypertension, diabetes mellitus, and dyslipidemia, whereas risk factors for other types of CVD are less well recognized.

To complicate matters further, pathological overlap between VBI and neurodegenerative disorders is frequent, especially with increasing age. The application of “either-or” diagnostic criteria in epidemiologic studies fosters a dichotomous view of VCI and AD. Autopsy studies show a more complex reality. Macro- and microinfarcts are each found in approximately 30% of elderly persons, often combined with AD pathology [5–7]. Converging evidence indicates that ischemic infarcts and neurodegenerative lesions combine in an additive fashion to increase the risk of cognitive impairment and dementia [8–12].

Epidemiology

From a public health perspective, VCI is the second most common cause of cognitive impairment in late life after AD. One of three persons meets criteria for dementia following first stroke [13]. Persons with stroke who are not initially demented are twice as likely as normal controls to develop dementia over the next 10 years [14]. The incidence of vascular dementia (VaD) increases exponentially after 65 years of age, ranging from 3 to 19 per 1000 persons/year at age 80 years [15–17], approximately half the rate of AD. In the Canadian Study of Health and Aging of persons older than age 65 years, the prevalence of cognitive impairment no dementia (CIND) was similar to (17%) the number of combined persons with dementia or stroke (8% each) [18]. In this study, the relative contributions of VBI to CIND were believed to be considerable.

To minimize survival bias, cohorts at risk should be established in midlife and followed longitudinally. In the Honolulu Heart Program, history of high systolic blood pressure (SBP) [19] and diabetes mellitus [20] was associated with greater risk of dementia in late life (especially among persons with the apolipoprotein E ε4 allele). In the Framingham Heart Study [21], duration of diabetes was related to poorer cognitive performance. In the CAIDE study, higher midlife cholesterol levels were associated with increased risk of dementia [22, 23]. These epidemiologic studies underscore the importance of managing hypertension, diabetes mellitus, and cholesterol beginning in midlife.

MRI scans in longitudinal population-based studies reveal SBI and WMH in approximately one-third of persons over age 65 years [24–26]. These lesions increase with age, are associated with hypertension, and increase the risk of stroke and dementia [27, 28]. In the Framingham Offspring Study of middle-aged adults, SBI and severe WMH were associated with increased risk of stroke and dementia independent of vascular risk factors [29]. These studies identify subclinical VBI on MRI as relevant targets for early detection and primary prevention. Cerebral microbleeds (CMBs) are also present in one-third of persons over age 80 years based on population studies and are associated with increased risk of stroke, cognitive decline, and mortality [30].

Genetic epidemiology

Several forms of CVD are associated with genetic mutations or polymorphisms. CADASIL is caused by mutations or deletions in the Notch3 gene (chromosome 19p13) [31, 32]. A similar autosomal recessive syndrome (CARASIL) results from mutations in the HtrA serine peptidase 1 (HTRA1) [33]. Dutch, Icelandic, and Finnish forms of familial CAA are associated with hereditary cerebral hemorrhage with amyloidosis (HCHWA) [34]. At the population level, the apolipoprotein E ε4 allele increases vascular deposition of abeta in the sporadic form of CAA [35].

Case presentations

The clinical presentation for VCI is highly heterogeneous, varying in onset, progression, and profile of cognitive impairment. In the following case presentations, we illustrate two approaches to diagnosis of VCI: (i) the application of criteria for the clinical diagnosis of VaD (Table 4.3) and (ii) a neurobehavioral approach, which considers location of VBI within memory and cognitive networks (Table 4.4).

Table 4.3 Clinical Criteria for vascular dementia (VaD).

Diagnostic criteria		Dementia	VBI	Evidence of causal relationship
Hachinski Ischemic Score (HIS) (0–17 points) [38]:		No specific criteria	CVD risk factors (HTN, ASCVD)	Not specifically required
HIS ≥7 suggests MID		Memory loss	Sudden onset
HIS 5–6 suggests MIX		Sufficient to interfere	Stepwise progression
HIS ≥4 suggests AD		No clouding of consciousness	Focal neurological signs and symptoms
DSM-IV [39]			Stepwise deteriorating course and “patchy” distribution of deficits, focal neurologic signs and symptoms	Evidence from the history, physical examination, or laboratory tests of significant cerebrovascular disease that is judged to be etiologically related to the disturbance
ICD-10 [42]		Unequal distribution of deficits in higher cognitive functions with some affected and others relatively spared	There is evidence of focal brain damage, manifest as at least one of the following: unilateral spastic weakness of the limbs, unilaterally increased tendon reflexes, an extensor plantar response, or pseudobulbar palsy	From the history, examination, or test, there is evidence of significant cerebrovascular disease which may reasonably be judged to be etiologically related to the dementia (history of stroke, evidence of cerebral infarction)
ADDTC [41]	Probable	Multifaceted cognitive impairment sufficient to interfere with customary affairs of life	Infarct outside the cerebellum by imaging	Two infarcts or one infarct with temporal relationship to onset of cognitive impairment
	Possible		One infarct outside the cerebellum by imaging OR confluent white matter change	Not required
NINDS-AIREN [40]	Probable	Memory loss	Focal neurological signs	Abrupt onset
		Plus impairment in two other cognitive domains	Imaging findings	Stepwise progressionTemporal relationship to onset of cognitive impairment
	Possible		Either imaging findings, abrupt onset, stepwise, OR temporal relationship
AHA/ASA (2011) [43]	Probable	Decline in cognitive function in ≥2 domains sufficient to interfere with ADL	Imaging evidence of CVD	Clear temporal relationship between vascular event and cognitive deficit onset
		At least 4 domains tested (attention/executive, memory, language, visuospatial)		Clear relationship between severity and pattern of cognitive impairment and diffuse subcortical CVD
		Decline in ADL is independent from motor/sensory sequelae of the vascular event		No history of gradually progressive cognitive deficits before/after CVA to suggest nonvascular neurodegenerative etiology
	Possible	Above	Imaging findings, but no clear relationship (temporal, severity, or cognitive pattern) with cognitive impairment	Evidence of another potential cause for cognitive dysfunction in addition to CVD
		Severe aphasia precludes cognitive assessment	No imaging available
DSM-5 [44] Major or mild NCD	Probable	Decline in cognitive function in ≥1 cognitive domains	Imaging findings CT or MRI	Evidence from the history, physical examination, or laboratory tests of significant cerebrovascular disease that is judged to be etiologically related to the neurocognitive deficits
			Temporal relationship
			Prominent decline in attention and executive function
			Presence of clinical evidence + genetic disorder (i.e., CADASIL)
	Possible	Sufficient to interfere with ADL	Evidence of VBI without clear temporal relationship to cognitive deficits
		No clouding of consciousness

ADDTC, State of California Alzheimer’s Disease Diagnostic and Treatment Centers; ASCVD, asymptomatic cardiovascular disease; DSM, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5); HTN, hypertension; MID, multi-infarct dementia; MIX, mixed dementia (vascular and Alzheimer’s disease (AD); NCD, neurocognitive disorder; NINDS-AIREN, National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherché et l’Enseignement en Neurosciences; VBI, vascular brain injury.

Table 4.4 Neurobehavioral approach to diagnosis of VCI, AD, or mixed VCI/AD.

Feature	Favors VCI	Favors AD	Other Differential
Neuropsychological testing
Amnesic memory disorder?		+++
Semantic fluency better than phonemic fluency		++
Executive impairment worse than memory impairment	++
MRI findings
Moderate to severe hippocampal atrophy		+++	Hippocampal sclerosis
			Anoxic injury
			Herpes simplex Encephalitis
Severe WMH (CHS grade ≥7)	++	+(Can be seen in AD with CAA)	Hypertensive angiopathy
			Cerebral amyloid angiopathy
			CADASIL
Infarction within frontal-subcortical loops or other strategic locations	+++
Acute stroke with temporal relationship to onset of cognitive impairment	+++
Nonstrategic infarction	+

AD, Alzheimer’s disease; CAA, cerebral amyloid angiopathy; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CHS, Cardiovascular Health Study; VCI, vascular cognitive impairment; WMH, white matter hyperintensities.

Case 1

Four years prior, a 71-year-old Caucasian gentleman sustained a mild stroke with right-sided weakness and slurred speech. Following this, he became quiet and withdrawn, which the family thought was depression. The family noted a gradually progressive cognitive decline over the past 4 years. He now forgets conversations and, events within a few minutes, offers very little spontaneous speech, shows lack of interest, and is quite apathetic.

Past medical history is significant for a 20-year history of hypertension and a 15-year history of type 2 diabetes and hypercholesterolemia, as well as benign prostatic hypertrophy. He takes aspirin, tolazamide, metformin, troglitazone, lisinopril, and lovastatin. He is a retired salesman with 16 years of education.

On physical examination, blood pressure (BP) was 146/92 mmHg. Neurologic examination showed blunted affect, mild right spastic hemiparesis, and bilateral Babinski signs. Mini-Mental State Examination (MMSE) score was 22/30. He had word-finding difficulties, concrete thinking, and mild perseveration. Neuropsychological testing revealed severe impairment in all aspects of verbal list learning, including acquisition, immediate and delayed recall, and recognition. He was severely impaired on confrontation naming and semantic and phonemic fluency. Working memory was mildly impaired. Visuospatial skills and abstract reasoning were low average. A self-reported scale did not suggest depression.

EKG showed left ventricular hypertrophy. MRI revealed cystic infarcts in the right anterior thalamus, left genu of the internal capsule, and left posterior limb of the internal capsule (Figure 4.1). SBI were noted in the right putamen and left frontal white matter. Periventricular white matter changes were mild (grade 1 on the Cardiovascular Health Study (CHS) white matter scale [25]). Coronal T1 MRI showed moderate medial temporal atrophy (MTA) (2+ on MTA scale [36]) and moderate cerebral atrophy (Figure 4.2).

Figure 4.1 Case 1: axial MRI (T1, proton density (PD), and T2 weighted) shows cystic infarcts in the right anterior thalamus and left genu internal capsule. SBI are seen in the right putamen, left posterior limb of the internal capsule (top row), and left frontal white matter (bottom row). Periventricular white matter changes are rated grade 1 on CHS scale.

Figure 4.2 Case 1: coronal T1-weighted MRI shows moderate 2+ hippocampal atrophy on Scheltens’ rating scale [110, 111] and moderate generalized cerebral atrophy.

Comment

This patient has significant risk factors for VaD. His Framingham stroke risk profile [37] is calculated at 19 (+5 age 71; +7 treated systolic blood pressure; +2 diabetes; +5 left ventricular hypertrophy). A Framingham profile of 19 is associated with a 33% 10-year probability of first stroke. His history of prior right-sided weakness corresponds with infarct in the left posterior limb of the internal capsule, further increasing the probability of recurrent stroke.

He meets criteria for MID by Hachinski Ischemic Score [38], DSM-IV criteria for VaD [39], National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherché et l’Enseignement en Neurosciences (NINDS-AIREN) criteria for possible VaD [40], the State of California Alzheimer’s Disease Diagnostic and Treatment Centers (ADDTC) criteria for probable ischemic VaD [41], ICD-10 criteria for VaD [42], American Heart Association/American Stroke Association (AHA/ASA) criteria for possible VaD [43], and DSM-5 criteria for possible major vascular neurocognitive disorder [44] (Table 4.3). He meets NINDS-AIREN criteria for possible but not probable VaD, because there was no temporal relationship between a stroke and his gradual cognitive decline.

Apathy, withdrawal, and slowing are typical in SVD. Severe impairment in verbal memory on neuropsychological testing plus moderate atrophy of the hippocampi suggests the possibility of concomitant AD. Two cystic infarcts, however, are observed in strategic locations for memory: the right anterior thalamus and the left genu of the internal capsule. Anterior thalamic lesions are well known to disturb episodic memory [45], and lesions in the genu of the internal capsule disrupt outflow in the anterior thalamic peduncle [46]. The parsimonious clinical diagnosis is VCI.

Neuropathology

Autopsy revealed severe, complicated atheroma in the basal vessels with 55–70% stenosis and multiple lacunar infarcts in the basal ganglia. No significant AD pathology was present (Braak and Braak stage = 0; the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) criteria neuritic plaque = none). The final clinicopathologic diagnosis is pure VaD with strategic infarcts.

Case 2

An 85-year-old African American gentleman with a history of several old strokes and a combination of stepwise and progressive cognitive decline. The first stroke, 21 years ago, had no significant cognitive or physical sequelae. Eighteen years ago, a more serious stroke caused forgetfulness, mild left hemiparesis, and transient speech disturbance, leading to a right carotid endarterectomy. After this, his memory declined gradually and slowly. He has developed gradual and progressive word-finding difficulty for 5 years. He still manages his activities of daily living, drives locally, and watches television. He complains of poor memory and decreased interest in socializing but denies depression. Past medical history is significant for hypercholesterolemia. He reports no history of hypertension, diabetes, or heart disease. He takes only aspirin.

On physical examination, BP is 148/94 mmHg; pulse is 84 and regular. Spasticity and weakness are present in both upper extremities, left greater than right. Deep tendon reflexes are increased on the left, and Babinski signs are present bilaterally. Snout, glabellar, palmomental, and right grasp reflexes are present. His gait is wide based and paretic (left- greater than right-sided weakness). His MMSE score is 18 of 30. He is friendly but dysarthric and has significant word-finding difficulties. Neuropsychological testing reveals severe impairments in verbal memory, naming, and semantic fluency.

MRI shows moderate hyperintensities in bilateral periventricular white matter, SBI in the right anterior limb of the internal capsule, and prominent perivascular spaces plus encephalomalacia in the right putamen (Figure 4.3). WMH are rated 6–7 on the CHS scale [25]. Coronal sections show 3+ MTA [36] and severe cerebral atrophy (Figure 4.4).

Figure 4.3 Case 2: axial MRI (T1, PD, and T2 weighted) shows T2-weighted hyperintensities in bilateral periventricular white matter, SBI in the right anterior limb of the internal capsule, and prominent perivascular spaces plus encephalomalacia in the right putamen. White matter hyperintensities are rated 6–7 on the CHS scale.

Figure 4.4 Case 2: coronal T1-weighted MRI shows 3+ atrophy by Scheltens’ scale [110] of the hippocampus and severe cerebral atrophy.

Comment

This patient had two strokes and has a Framingham risk profile score [37] of 15 (+10 age 85; +5 untreated SBP). Left- greater than right-sided spastic hemiparesis is consistent with bilateral lesions and worse in the right hemisphere. The left hemiparesis could be related either to the ischemic events involving the right cortical spinal tract in the white matter or in the posterior limb of the internal capsule. The gradual deterioration during the past 5 years can be attributed to moderately severe WMH. He meets NINDS-AIREN criteria and AHA/ASA for probable VaD and DSM-IV and DSM-V criteria for VaD (Table 4.3).

The history of two strokes and the presence of infarcts and white matter changes on MRI offer a partial explanation of his cognitive impairment. The second stroke showed a temporal relationship with the onset of forgetfulness. Silent incomplete infarcts (note: incomplete infarct refers to MRI lesions that are hyperintense on T2 or FLAIR and minimally hypointense on T1-weighted sequences) in the right anterior limb of the internal capsule disconnect frontal-subcortical loops and contribute to dysexecutive syndrome and disinhibition. The severity of his verbal memory loss and difficulty with confrontation naming suggests the possibility of a superimposed neurodegenerative process such as AD. This is supported by significant atrophy of the hippocampus and cerebral cortex. Taking a neurobehavioral approach, the clinical diagnosis is mixed dementia due to VCI and possible AD.

Neuropathology

Postmortem revealed severe atherosclerosis in the anterior cerebral artery, infarcts in the right putamen and frontal lobe, and deep white matter, with degeneration of the corpus callosum. The white matter demonstrated spongy changes and gliosis. An infarct was noted in the medulla as well. Widespread AD pathology was present (Braak and Braak stage = VI; CERAD neuritic plaque = moderate). Final clinicopathologic diagnosis is dementia due to mixed AD and CVD.

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Tags: Non-Alzheimers Dementia

Feb 18, 2017 | Posted by admin in NEUROLOGY | Comments Off

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