Patterns of Cognitive Performance in Subcortical Ischemic Vascular Disease (SIVD)

Vascular dementia is a heterogeneous group of diseases with a wide variety of etiological mechanisms, brain changes, and clinical manifestations.^1–3 Cortical vascular dementia, strategic infarct dementia, and subcortical vascular dementia are the major subtypes of vascular dementia.⁴

Subcortical vascular dementia is defined by the accumulation of extensive cerebral white-matter lesions and lacunar infarcts in deep gray matter, whereby dementia is the clinical end-stage of a progressive disease.⁵ Strong evidence suggests the role of white-matter lesions as determinants of cognitive decline.⁶ Since there is growing evidence that white-matter lesions cause specific changes in neurocognitive performance in patients not meeting the diagnostic criteria for dementia, the focus in research is shifting from this late stage to the early stages of the disease. Furthermore, white-matter lesions are no longer considered an innocuous finding because they are associated, in cross-sectional surveys, with various disturbances and, in follow-up studies, with poor prognosis.⁷

On the basis of MRI criteria, Erkinjuntti⁸ introduced the concept of subcortical ischemic vascular disease (SIVD). SIVD arises from small-vessel disease and is characterized by extensive cerebral white-matter lesions and lacunar infarcts in deep gray and white matter.⁴ The multicentric Leukariosis and Disability Study (LADIS) described the clinical and cognitive characteristics of MRI-defined SIVD in a sample of elderly subjects. In the latter study, SIVD was associated with motor impairment, a history of falls, and subtle impairment in activities of daily living. As compared with controls, SIVD subjects performed significantly worse in tests measuring global cognitive functioning, psychomotor speed, attention, executive functions, verbal fluency, and working memory.³ In another study, SIVD was related to progressive cognitive impairment and a considerable risk of developing dementia.⁹ However, empirical data describing the cognitive impacts of SIVD are still sparse.

Studies investigating the impact of the accumulation of subcortical lesions on cognitive performance postulate that other confounding brain measures also affect cognition;¹⁰ these include global atrophy,¹¹ central atrophy,¹² medial temporal lobe atrophy,¹³ and frontal atrophy.¹⁰ Severe white-matter lesions predict cerebral atrophy,¹⁴ especially in the frontal and medial temporal lobe.^15,16

In our retrospective analysis, we compared 58 patients meeting MRI-defined criteria for SIVD (26 women; 47.3%) with age- and gender-matched controls.

Methods

Subjects and Study Design

In our retrospective study-design, patients were identified who were admitted to the University Hospital of Salzburg, Department of Neurology, from June 1, 2007 to June 30, 2011. An electronic database selected patients who were free of unrelated psychiatric and neurological disease and had undergone a cerebral Magnetic Resonance Imaging (MRI) procedure with a minimum number of images and a neuropsychological examination (N=321). MRI and neuropsychological testing were performed within 3 months. Reasons for referral were planned carotid artery stenting because of asymptomatic carotid artery disease and subjective cognitive impairment. Patients’ records and results of brain MRI images were rechecked again manually (by M.S.) and the following exclusion criteria were applied: presence of severe psychiatric disease (e.g., depression, schizophrenia spectrum disorders), presence of severe unrelated central nervous disease (e.g., transient ischemic attack, stroke, multiple sclerosis, Parkinson’s disease, epilepsy) and leukoencephalopathy of non-vascular origin (e.g., immunological-demyelinating, metabolic, toxic, infectious).

SIVD patients were identified according to the brain-imaging criteria proposed by Erkinjuntti⁸ (N=58). The age- and gender-matched control group comprised 58 patients who did not meet the applied SIVD criteria.

Magnetic Resonance Imaging (MRI)

MRI was performed on a 3-Tesla, whole-body MRI scanner (Achieva; Philips, the Netherlands). Coronar T₁-weighted images (36 slices, TR: 451 msec, TE: 13 msec, thickness: 4 mm/1, flip: 80, Turbo Factor: 1, matrix: 512, time: 2:31 minutes); axial T₂ images (28 slices, TR: 3,048 msec, TE: 80 msec, thickness: 4 mm/1, Turbo factor: 15, EPI factor: 1, matrix: 512, time: 1:19 minutes); and fluid attention inversion recovery (FLAIR) axial sequences (28 slices, TR: 10,000 msec, TE: 125 msec, TI: 2,800 msec, thickness: 4 mm/1, Turbo factor: 32, EPI factor: 1, matrix: 560, time: 3:30 minutes) were required.

Medial temporal lobe atrophy was graded by two raters (M.S. and Y.K.), blinded to neuropsychological data, on a 5-point Likert-scale¹⁷ considering the width of the choroid fissure, the width of the temporal horn, and the height of the hippocampal formation. Frontal lobe atrophy was rated by two raters (M.S. and Y.K.) blinded to neuropsychological data on a visual 4-point Likert scale (none, mild, moderate, severe) considering sulcal and ventricular sizes. In case of rater disagreement, mean scores of the two ratings were used for calculation.

Changes in cerebral white matter were rated by an experienced neurologist (M.S.) and an experienced neuroradiologist (M.M.), blinded to neuropsychological data, according to the revised version of the Fazekas scale¹⁸ and classified as “none” (0; no white-matter lesions), “mild” (1; single lesions <10 mm and grouped lesions <20 mm in any diameter), “moderate” (2; single lesions 10 mm–20 mm, grouped lesions >20 mm with connecting bridges only between the individual lesions), or “severe” (3; confluent lesions with >20 mm in any diameter). In case of rater disagreement, consensus was reached in a second rating session.

MRI-defined SIVD was diagnosed according to the brain-imaging criteria proposed by Erkinjuntti,⁸ which include 1) cases with predominantly white-matter lesions (WML), that is, extending periventricular and deep white-matter lesions (extending caps or irregular halo and diffusely confluent hyperintensities or extensive white-matter changes) and lacunas (at least 1); and 2) cases with predominantly lacunar infarcts, that is, >5 lacunas and at least moderate WML (extending caps or irregular halo or diffusely confluent hyperintensities or extensive white-matter changes). We also required absence of cortical and/or cortico–subcortical non-lacunar territorial infarcts, watershed infarcts, hemorrhages, signs of normal-pressure hydrocephalus, and specific causes of WML of non-vascular origin (e.g., multiple sclerosis, sarcoidosis, residual lesions of vasculitis).

In case of rater disagreement, consensus was reached in a second rating session.

Neuropsychological Examination

Each patient completed the Mini-Mental State Exam,¹⁹ and the neuropsychological test battery established by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD-Plus).^20,21 The CERAD is composed of several subtests: Semantic Verbal Fluency (SVF), Phonemic Verbal Fluency (PVF), Boston Naming Test (BNT), Word-List Learning (WLL), Word-List Delayed Recall (WLDR), Word-List Recognition (WLR), Discriminability (D), Figure Copy (FC), Figure Recall (FR), and Trail-Making Tests–A and B (TMT-A, B).

The test battery assesses verbal fluency (SVF, PVF), constructional praxis (FC), figurative memory (FR), verbal short-term and long-term memory (WLL, WLDR, WLR), verbal recognition memory (D), semantic processing (BNT), speed of cognitive processing (TMT A), and divided attention (TMT B).

All given values are z-scores adjusted for level of education, age, and gender.

Statistical Analysis

SPSS Student Version 16.0 was used for computation. A p level <0.05 was considered to be statistically significant.

When comparing individuals with SIVD versus the non-SIVD reference group, the Mann-Whitney U test or chi-squared test were used as appropriate.

To delineate the association of white-matter lesion load with cognitive test scores, univariate analysis was used. Interobserver reliability is expressed by complete agreement in percent and kappa values.

Results

Demographic Characteristics

The 116 patients included had a median age of 79 (range: 44 to 89); 64 (52.7%) were men; 52 (47.3%) were women. The control group was well matched for age and gender (Table 1).

MRI Findings

When rating frontal lobe atrophy and medial temporal lobe atrophy, complete interrater agreement was reached in 72.7% and 70.9%, respectively; kappa values were 0.632 and 0.683, respectively. Rates of medial temporal lobe and frontal lobe atrophy did not differ significantly between the groups (Table 1).

Cognitive Functions

We found significant group differences between the SIVD and the non-SIVD-group on the following subtests: Semantic Verbal Fluency, Phonemic Verbal Fluency, Word-List Learning, and Trail-Making Tests A and B. No significant differences were obtained in the subtests Mini-Mental State Exam, Boston Naming Test, Word-List Delayed Recall, Word-List Recognition, Discriminability, Figure Copy, and Figure Recall (Table 2).

Using univariate analysis, white-matter lesion load (as measured by the Fazekas scale) is significantly associated with performance in Semantic Verbal Fluency (β = −0.256; p=0.010) and Trail-Making Test A (β = −0.290; p=0.006).

Discussion

In our study population, neuropsychological measures of SIVD-patients showed significant differences in test scores of verbal fluency, verbal memory, speed of cognitive processing, and divided attention, when compared with the age- and gender-matched non-SIVD-group. We did not find significant differences in constructional praxis, figurative memory, verbal recognition memory, or semantic processing.

Subcortical periventricular and deep white-matter lesions may cause cognitive impairments even in patients not suffering from dementia. Jokinen and co-authors⁴ were the first to provide a comprehensive analysis of cognitive performance in SIVD. They found impairments in executive functions and delayed recall in SIVD patients. SIVD was not associated with mental speed, short-term memory, immediate recall, or visuospatial functions. Our findings are partly in line with Jokinen et al. We also found impairments in executive functions. Although there was a non-significant trend, we did not find significantly impaired scores on delayed recall in SIVD patients. Bilino et al.²² report impaired word-list learning performance in SIVD patients. This supports our findings. Kandiah and co-authors²³ compared patients with mild Alzheimer’s disease (AD) and SIVD patients suffering from mild dementia. SIVD patients with mild dementia had greater deficits in visuospatial functioning; working memory and visuomotor speed and were also more depressed than in AD patients. Executive-function tests in general did not distinguish the two groups.

Frontal lobe atrophy and consecutive frontal lobe dysfunctions are considered to play a key role leading to the clinical consequences of SIVD. The frontal lobe seems to be most severely affected by SIVD. Furthermore, white-matter lesions are more abundant in the frontal lobe. However, regardless of where in the brain white-matter lesions are located, they are associated with frontal hypometabolism and consecutive executive dysfunction.²⁴ Among the cognitive domains impaired in patients with severe white-matter lesions, findings in frontal lobe functions (especially executive functions) seem to be the most consistent.^4,10,25,26 Frontal executive functions include volition, planning, anticipation, control of socially inadequate behavior, and control of complex activities.^{15,16,26–29} Impairments in executive functions are caused by disruptions of the dorso–lateral prefrontal–subcortical connections.²⁷ The disruptions may be caused by lesions in the thalamus, the striatum, the globus pallidus, or the subcortical white matter.^16,27 Previous studies have shown that white-matter lesions may cause brain atrophy,^{10,13,14,30,31} especially frontal atrophy.¹⁰ The findings of Mok et al.¹⁰ suggest a strong influence of the lateral fronto-orbital gyrus.

Our data suggest that SIVD is not associated with deficits in delayed memory. This contradicts the findings of Jokinen et al.,⁴ although Jokinen and co-authors hypothesize that verbal memory deficits might be mediated by executive deficits, and, therefore, they may reflect secondary impairment due to inefficient encoding and retrieval strategies.⁴ This hypothesis is supported by our finding that SIVD is related to impairment in verbal learning, but not delayed recognition. This indicates, that SIVD leads to an “executive-type” memory impairment.

This study has certain limitations. This is a retrospective analysis of a pre-selected group of patients, who were referred for planned carotid artery stenting because of asymptomatic carotid artery disease and subjective cognitive impairment. Bias due to multiple comparisons is possible. The neuropsychological test battery established by the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD-Plus)^20,21 was designed as a tool for the detection of AD. It might not be suitable for the detection of cognitive deficits caused by vascular disease. Furthermore, handedness of patients was not assessed. The imaging criteria for SIVD, white-matter lesions, and signs of atrophy in the medial-temporal and frontal lobe were based on visual rating scales. The applied visual rating scales categorizing SIVD and frontal lobe and medial-temporal lobe atrophy are easily accessible in the clinical process.