Leukoaraiosis Predicts Short-term Cognitive But not Motor Recovery in Ischemic Stroke Patients During Rehabilitation.

BACKGROUND: Leukoaraiosis has been shown to impact functional outcomes after acute ischemic stroke. However, its association with domain specific recovery after ischemic stroke is uncertain. We sought to determine whether pre-existing leukoaraiosis is associated with short-term motor and cognitive recovery after stroke. METHODS: We retrospectively studied ischemic stroke patients admitted to acute inpatient rehabilitation (AIR) between January 2013 and September 2015. Patient baseline characteristics, infarct volume, prestroke modified Rankin Scale, stroke cause, rehabilitation length of stay, and Functional Independence Measure (FIM) scores were recorded. Leukoaraiosis severity was graded on brain magnetic resonance imaging using the Fazekas scale. Multiple linear regression was used to determine factors independently associated with the total, cognitive, and motor FIM scores at AIR discharge, respectively. RESULTS: Of 1600 ischemic stroke patients screened, 109 patients were included in the final analysis. After adjustment, the initial National Institute of Health Stroke Scale (ß -0.541, confidence interval [CI] -0.993 to -0.888; P = 0.020) and pre-existing leukoaraiosis severity (ß -1.448, CI -2.861 to -0.034; P = 0.045) independently predicted the total FIM score. Domain specific analysis showed that infarct volume (ß -0.012, CI -0.019 to -0.005; P = 0.002) and leukoaraiosis severity (ß -0.822, CI -1.223 to -0.410; P = 0.0001) independently predicted FIM cognitive scores at discharge from AIR. Leukoaraiosis did not predict FIM motor score (P = 0.17). CONCLUSIONS: Leukoaraiosis severity is an independent predictor of total and cognitive, but not motor FIM scores after AIR for acute ischemic stroke. This highlights that leukoaraiosis affects poststroke recovery in a domain specific fashion, information that may aid counseling of patients and families as well as tailor rehabilitative efforts.

Use of Multimodal Magnetic Resonance Imaging Techniques to Explore Cognitive Impairment in Leukoaraiosis.

Leukoaraiosis, also referred to as white-matter hyperintensities (WMHs) or age-related white matter changes, is the most frequently seen lesion on brain magnetic resonance images (MRI) in the elderly. LA is a subject of intense research interest, and is correlated with stroke, cognitive impairment or dementia, disturbances, affective disorders, and poor prognoses. Rapid advances in neuroimaging have enabled greater understanding of LA associated with aging-related cognitive decline or dementia. Recently, the techniques of multimodal MRI, such as structural MRI (sMRI), resting-state functional MRI (rs-MRI), cerebrovascular reactivity (CVR), diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS), and dynamic contrast-enhanced MRI (DCE-MRI), have been used to explore the underlying mechanism of cognitive impairment in patients with LA. These multimodal MRI techniques may provide further insights into the structural and functional changes of LA with cognitive dysfunction.

White Matter Changes and Cognitive Decline in a Ten-Year Follow-Up Period: A Pilot Study on a Single-Center Cohort from the Leukoaraiosis and Disability Study.

AIMS: To describe the contribution of white matter lesions to the long-term neuropsychological profiles of different groups of clinical diagnoses, and to identify neuropsychological predictors of cognitive impairment in a 10-year follow-up. METHODS: The Lisbon subcohort of the Leukoaraiosis and Disability (LADIS) study was re-evaluated performing a clinical, functional and cognitive evaluation [including Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale - Cognition (ADAS-Cog) and ADAS-Cog with the extension for vascular impairment (VADAS-Cog), the 9-word version of the California Verbal Learning Test (CVLT-9), the Trail-Making test and the Stroop test] as well as an MRI scan. Using clinical diagnostic criteria, participants were identified as having no cognitive impairment (NI), cognitive impairment but no dementia (CIND) or dementia (DEM), and the effect of time on clinical diagnosis and neuropsychological profiles was analyzed. RESULTS: From the initial group of 66 participants, 37 out of 41 survivors (90%) were re-evaluated (mean age 81.40 years, 57% women). Fifteen patients (41%) had DEM, 12 (32%) CIND and 10 (27%) NI. Over time, the three groups presented distinct profiles in the MMSE [F2, 62 = 15.85, p = 0.000], ADAS [F2, 62 = 15.85, p = 0.000] and VADAS [F2, 48 = 5.87, p = 0.008]. Logistic regression analysis identified higher scores on MMSE (ß = 1.14, p = 0.03, OR = 3.13, 95% CI 1.09-8.97) as predictors of NI after 10 years of follow-up. CONCLUSION: Higher scores on baseline MMSE were the only neuropsychological predictors of NI after 10 years.

Neglect performance in acute stroke is related to severity of white matter hyperintensities.

BACKGROUND: Leukoaraiosis and its progression have longitudinally been associated with cognitive decline and dementia. Its role in acute cognitive function and response to acute cerebral ischemia is less well understood. We evaluated whether the presence and extent of leukoaraiosis, or white matter hyperintensities (WMH), had an impact on performance on tests of hemispatial neglect in acute ischemic stroke patients. METHODS: A series of 206 acute ischemic right-hemispheric stroke patients at Johns Hopkins Hospital underwent brain MRI and cognitive assessment for hemispatial neglect within 5 days of symptom onset. Error rates on neglect tests were evaluated, as were dichotomized measures of neglect, including 'any', 'severe' or 'worst' neglect, based on Z scores of at least 2 on 1, 2 or 3 tests (respectively) within a neglect battery. Acute infarct volumes were measured on diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery images were reviewed for WMH, using the Cardiovascular Health Study (CHS) rating scale (ranging from 0 to 9, with 9 being 'most extensive'). Linear regression was used to evaluate 'error rate on neglect test' as the dependent variable, as a measure of neglect severity, with 'WMH category' as the primary independent variable, including adjustment for age, sex, race and infarct volume (on DWI). Logistic regression was used to evaluate a binary definition of neglect (defined as above) relative to the same independent variable and covariates. RESULTS: Each 1-point increase in CHS leukoaraiosis category was associated with 1.20-fold increased odds (95% CI: 1.00-1.43) of having any neglect, 1.23-fold increased odds (95% CI: 1.02-1.49) of having severe neglect and 1.33-fold increased odds of having worst neglect (95% CI: 1.01-1.76) after adjusting for infarct volume, age, sex and race. Increasing age and infarct size were also important predictors of neglect severity, with a 2.36% higher error rate (95% CI: 0.75-3.97%) on the line cancellation test associated with each category increase in CHS score; similar results were found for each of the neglect tests. Line cancellation neglect scores were worse in individuals with both severe WMH and large infarcts (p interaction, unadjusted=0.03). CONCLUSIONS: More severe leukoaraiosis is associated with more hemispatial neglect after acute ischemic stroke, independent of infarct volume, age and sex. We found not only more frequent neglect but also more severe neglect, based on error rates on neglect tests, in individuals with increasing leukoaraiosis. This emphasizes the importance of preexisting brain microvascular disease in outcomes of stroke patients. Further studies of the possible mechanism behind this association are needed.

[Risk factors and predictive factors of cognitive deterioration in patients of vascular cognitive impairment no dementia with subcortical ischemic vascular disease].

OBJECTIVE: To explore the independent risk factors and predictive factors of cognitive deterioration in patients of vascular cognitive impairment no dementia with subcortical ischemic vascular disease (VCIND-SIVD). METHODS: The clinical and neuropsychological characteristics of 96 VCIND-SIVD patients were collected and their cognitive states re-assessed after one year. The distribution of continuous and categorical variables was examined with univariate analysis. And Logistic regression in multivariate modeling was employed to identify the risk and predictive factors of cognitive deterioration. RESULTS: After 1-year follow-up, 8 patients dropped out, 2 died and the remainder remained. There were 48 males and 38 females with an average age of 64.3 ± 5.4 years. Among them, 17 (19.8%) deteriorated into dementia, 24 (27.9%) upgraded to normal cognition and 45 (52.3%) maintained their cognitive status. They were divided into dementia group (cognition deteriorating into dementia) and control group (elevated/sustained cognition). After univariate analysis of general information and vascular risk factors, Logistic regression demonstrated that education level (P < 0.05, OR = 0.7) was a preventive factor of dementia while age (P < 0.05, OR = 1.2), hypertension (P < 0.05, OR = 5.6) and high homocysteine (P < 0.05, OR = 4.2) were independent risk factors of dementia. After univariate analysis of neuropsychological scores, Logistic regression demonstrated that visual reproduction-immediate recall (P < 0.05, OR = 3.4), digit span forward (P < 0.05, OR = 1.2), clock drawing test (P < 0.05, OR = 6.8) and completion time of London tower (P < 0.05, OR = 5.4) were predictive factors of dementia. CONCLUSION: VCIND-SIVD patients with low score of visual reproduction-immediate recall, digit span forward, clock drawing test and completion time of London tower should receive vigorous controls of hypertension and high homocysteine.

Suitability of the Montreal cognitive assessment versus the mini-mental state examination in detecting vascular cognitive impairment.

The Mini-Mental State Examination (MMSE) has been criticized as being an insufficient screening test for patients with vascular cognitive impairment because of its insensitivity to visuospatial and executive functional deficits. The Montreal Cognitive Assessment (MoCA) was designed to be more sensitive to such deficits, and thus may be a superior screening instrument for vascular cognitive impairment. Twelve patients with extensive leukoaraiosis detected on magnetic resonance imaging (average age, 76.0 ± 8.7 years) underwent neurologic and cognitive testing, including MMSE and the Japanese version of the MoCA (MoCA-J). Accepted cutoff scores of <27 for the MMSE and <26 for the MoCA-J were taken to indicate cognitive impairment. Z-scores were calculated to evaluate the discriminating ability of individual MMSE and MoCA-J subtest scores. Although there was a strong correlation between the total MMSE and total MoCA-J scores (r = 0.90; P < .0001), MMSE scores were skewed toward the higher end of the range (range, 18-30; median, 28), whereas MoCA-J scores were normally distributed (range, 9-28; median, 21). Of the 7 patients with an unimpaired MMSE score, 6 (86%) had an impaired MoCA-J score. Z-scores were >5 for 4 MMSE subtests (orientation, registration, naming, and language) but for only 1 MoCA-J subtest (naming). The MoCA-J better discriminated cognitive status in subjects with extensive leukoaraiosis. Our findings suggest that the MoCA-J is more sensitive than the MMSE in screening for cognitive impairment in patients with subcortical vascular cognitive impairment.

Association of physical activity with the visuospatial/executive functions of the montreal cognitive assessment in patients with vascular cognitive impairment.

BACKGROUND: The Montreal Cognitive Assessment (MoCA) is more suitable than the Mini-Mental State Examination (MMSE) for the detection of vascular cognitive impairment. In this study, we performed a correlation analysis of MoCA/MMSE scores with daily physical activity in patients with subcortical ischemic white matter changes. METHODS: Ten patients (average 75.9 ± 9.1 years old) with extensive leukoaraiosis detected on magnetic resonance imaging underwent cognitive testing, including the MMSE and the Japanese version of the MoCA (MoCA-J). Physical activity was monitored with the Kenz Lifecorder EX device (Suzuken, Nagoya, Japan) to assess daily physical activity in terms of caloric expenditure, motor activity, number of steps, and walking distance for 6 months. Correlations of individual physical activity with total and subscale scores of MMSE/MoCA-J or 6-month interval change of MoCA-J scores were assessed. RESULTS: The total or subscale scores of the MMSE did not correlate with any parameters of physical activity. However, the mean number of steps and walking distance significantly correlated with the total MoCA-J scores (r = .67 and .64, respectively) and its visuospatial/executive subscores (r = .66 and .66, respectively). The mean interval change of MoCA-J was + .6; those who improved number of steps (n = 4; 80.5 ± 3.0 years of age) had significantly preserved MoCA-J scores compared to those who did not (n = 6; 73.0 ± 11.6 years of age; +2.0 versus - .3; P = .016). CONCLUSIONS: These results suggest that MoCA is useful to detect a biologically determined specific relationship between physical activity and executive function. In addition, physical exercise, such as walking, may help enhance cognitive function in patients with vascular cognitive impairment of subcortical origin.

[Influence of leukoaraiosis on the cognition of patients with Parkinson disease].

OBJECTIVE: To explore the role of leukoaraiosis (LA) on the cognitive function in patients with Parkinson disease (PD). METHODS: The cohort for this study included 63 patients with PD, whom were divided into 3 groups according to cognitive status:with intact cognition (PD-IC, n = 23), with mild cognitive impairment (PD-MCI, n = 23) and with dementia (PDD, n = 17). All the patients were recruited from the Department of Neurology, First Affiliated Hospital, Anhui Medical University between September 2011 and July 2012. The cognitive functions were evaluated by mini-metal state examination (MMSE), the Cambridge cognitive examination-Chinese version (CAMCOG-C), clinical dementia rating (CDR), clock drawing task (CDT) and verbal fluency test, etc. Depression symptoms were assessed by the geriatric depression scale (GDS) while motor symptoms by the Unified Parkinson's Disease Rating Scale-motor (UPDRS-motor) and the Hoehn and Yahr scale (HY). All the patients underwent magnetic resonance imaging (MRI) with a 3.0-T system. LA was rated using the semiquantitative visual rating system proposed by scheltens et al. RESULTS: Both the PD-IC (2.43 ± 2.79) and PD-MCI (4.48 ± 4.33) groups showed significantly lower deep hyperintensities (DHs) scores than the PDD group (7.88 ± 6.69, P = 0.004 and 0.040, respectively), especially in frontal (1.09 ± 1.31; 1.83 ± 1.90; 3.24 ± 2.64, P < 0.05) and parietal areas (0.09 ± 0.29; 0.65 ± 1.03; 1.53 ± 2.32, P < 0.05). There were no significant differences in periventricular (1.57 ± 1.75; 2.52 ± 2.37; 3.24 ± 2.64, P > 0.05), basal ganglia (0.09 ± 0.42; 0.30 ± 0.77; 0.53 ± 1.33, P > 0.05) and infratentorial white matter hyperintensities scores (--; 0.13 ± 0.63; 0.18 ± 0.73, P > 0.05) among three groups. The DHs showed a significant correlation with age (P = 0.003), MMSE (P = 0.009), verbal fluency test (P = 0.009), orientation (P = 0.047) and executive function (P = 0.027) in CAMCOG-C. The multiple regression analysis showed that the MMSE scores were associated significantly with education (P < 0.001, ß = 0.600), DHs (P = 0.001, ß = -0.678) and HY (P = 0.035, ß = -0.480). DHs were the most significantly associated with MMSE scores. CONCLUSION: There was a significant correlation between DHs and multiple domain cognitive impairment in PD, especially in executive function. DHs, which were the most significantly variable associated with MMSE scores, may contribute to cognitive impairment in PD.

Low cerebrospinal fluid sulfatide predicts progression of white matter lesions: The LADIS study.

BACKGROUND/AIMS: Demyelination and axonal degeneration are the hallmarks of established white matter lesions (WML). The neurochemistry of ongoing WML is only partially known. We explored cerebrospinal fluid (CSF) substances as markers of brain tissue damage in relation to progression of WML rated on magnetic resonance imaging. METHODS: CSF from elderly individuals with WML was analyzed for amyloid markers, total τ, hyperphosphorylated τ, neurofilament protein light subunit, sulfatide and CSF/serum-albumin ratio. After 3 years, a follow-up magnetic resonance imaging was performed. Progression of WML was rated using the Rotterdam Progression Scale (RPS). RESULTS: 37 subjects (age 73.6 ± 4.6 years) were included. Subjects with more pronounced progression (RPS > 2; n = 15) had lower mean sulfatide concentration at baseline as compared to subjects with no or minimal progression (RPS 0-2; n = 22) according to univariate analyses (p = 0.009). Sulfatide was the only biomarker that predicted the RPS score according to regression analysis, explaining 18.9% of the total variance (r = 0.38, p = 0.015). CONCLUSION: The correlation of CSF sulfatide levels and RPS scores may reflect a remyelination response to the demyelination process associated with WML. Furthermore, the results strengthen the notion that WML pathology is different from that of Alzheimer's disease.

[Characteristics of cognitive impairment in patients with leukoaraiosis].

OBJECTIVE: To explore the characteristics of cognitive impairment in patients with leukoaraiosis (LA). METHODS: Forty-six LA patients and 38 age and gender-matched healthy subjects were recruited from the Department of Neurology, Beijing Chaoyang Hospital, Capital Medical University between September 2010 and March 2011. All participants underwent the neuropsychological tests recommended by the National Institute of Neurological Disorders and Stroke-Canadian Stroke Network Vascular Cognitive Impairment Harmonization Standards (NINDS/CSN). The were divided into 3 different groups (mild, moderate and severe) according to the Fazekas scale. The differences of neuropsychological performances were compared among 3 groups. RESULTS: The LA patients were associated with comprehensive cognitive function deficits, including MMSE (24.4 ± 3.2 vs 28.3 ± 1.2), MoCA (20.4 ± 3.0 vs 26.2 ± 0.8), digital span forward (5.7 ± 0.9 vs 6.8 ± 1.0), digital span backward (3.5 ± 0.7 vs 4.1 ± 0.7), Stroop-B (69 ± 13 vs 43 ± 5), Stroop-C (141 ± 42 vs 65 ± 10), trail making test-A (73 ± 15 vs 31 ± 7), trail making test-B (126 ± 18 vs 82 ± 6) and digit symbol test (25 ± 6 vs 37 ± 5, P < 0.05). However, there was no difference in the performance of verbal fluency (12.7 ± 2.5 vs 13.4 ± 2.5, P > 0.05). Correlation analysis showed that the severity of LA had a negative correlation with the performance of MoCA (r = -0.601, P = 0.002). CONCLUSIONS: The LA patients are closely correlated with cognitive impairments of attention, memory, executive function and information processing speed. It may be attributed to the frontal-subcortical circuitry dysfunction.

[Correlates of cognitive impairment in patients with leukoaraiosis by magnetic resonance spectroscopy].

OBJECTIVE: To explore the pathological changes in patients with leukoaraiosis (LA) by magnetic resonance spectroscopy (MRS) and examine its relationship with cognitive function. METHODS: Twenty-three LA patients and 23 age and gender-matched healthy subjects were recruited from the Department of Neurology, Beijing Chaoyang Hospital, Capital Medical University between August 2010 and November 2010. All participants underwent the neuropsychological tests. Multi-voxel chemical shift imaging was performed and the regions of interest were positioned in bilateral frontal white matter. The relative metabolite ratios, involving N-acetyl aspartate/choline ratio (NAA/Cho), N-acetyl aspartate/creatine (NAA/Cr) and choline/creatine (Cho/Cr), were estimated. The correlation of the MRS data and the performance of cognitive function was analyzed. RESULTS: The LA patients were associated with a worse performance of mini mental state examination (MMSE) versus the healthy controls (24 ± 3 vs 28 ± 1, P < 0.05). Univariate analysis of the MRS data revealed the ratios of NAA/Cho and NAA/Cr significantly decreased in bilateral frontal white matter lesions in the LA group versus the control group (1.72 ± 0.20 vs 1.96 ± 0.36, 1.67 ± 0.17 vs 1.85 ± 0.21, P < 0.05). The values of NAA/Cr and NAA/Cho in normal appearing white matter increased versus the LA group (1.83 ± 0.24 vs 1.72 ± 0.20, 1.78 ± 0.28 vs 1.67 ± 0.17) and decreased versus the control group (1.83 ± 0.24 vs 1.96 ± 0.36, 1.78 ± 0.28 vs 1.85 ± 0.21). But no significant differences were found (P > 0.05). The ratio of Cho/Cr did not differ among 3 groups (P > 0.05). The pathological change of NAA/Cr in white matter lesion in LA patients was markedly correlated with the performance of MMSE (r = 0.47, P < 0.05). CONCLUSION: NAA may be a marker of axonal loss/dysfunction in LA patients. And the changes of NAA/Cr have a positive correlation with cognitive impairment.

[Study on syndrome factors of leukoaraiosis patients with mild cognitive impairment].

OBJECTIVE: To explore the syndrome factors of leukoaraiosis patients with mild cognitive impairment (LACI), thus providing evidence for syndrome typing. METHODS: The prospective schedule was adopted including 103 LACI patients (as the LACI group) and 100 leukoaraiosis patients without mild cognitive impairment (as the control group). Syndrome factors were extracted from the patients' symptoms with frequency statistics and factor analysis. RESULTS: Fifteen common factors were extracted from the LACI group, and 12 common factors from the control group. After analyzed the distribution of syndrome factors in the LACI group, the most common factors were ranked as follows: yang deficiency (33.98%), phlegm (22.33%), yin deficiency (19.42%), qi deficiency (10.68%), fire (9.71%), blood deficiency and blood stasis (3.88%). As for the control group, the most common factors were ranked as follows: yang deficiency (31.00%), qi deficiency (27.00%), yin deficiency and fire (24.00%), blood deficiency and blood stasis (12.00%), phlegm and yang deficiency and blood deficiency (6.00%). CONCLUSIONS: The main syndrome factors of LACI were yang deficiency, phlegm, yin deficiency, and fire. The secondary syndrome factors were qi deficiency, blood deficiency, and blood stasis. It was mainly involved with Shen and Pi, with secondary organs as Gan and Xin. Deficiency syndrome is its pathogenesis. Phlegm and fire, and other pathological factors are essential for its development and aggravation, with more syndrome factors accompanied in complex condition.

2001­2011: a decade of the LADIS (Leukoaraiosis And DISability) Study: what have we learned about white matter changes and small-vessel disease?

Over the last 20 years, evidence about the clinical correlates of cerebral white matter changes (WMC; also called leukoaraiosis)has been accumulating. WMC are now listed among the neuroimaging expressions of cerebral small-vessel disease and 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. The Leukoaraiosis And DISability (LADIS) study has contributed substantially to this body of knowledge.LADIS is a European multicenter collaboration that was started in 2001 with the aim of assessing the independent role of WMC in predicting disability in subjects aged 65­84. The main results of the LADIS study have been released in 2009 with the demonstration that severe WMC more than double the risk of transition from an autonomous to a dependent status after 3 years of follow-up. The LADIS study has also contributed more focused sub-studies assessing the possible role of WMC in the decline of cognitive and motor performances,depressive symptoms associated with aging and cerebrovascular diseases, urinary disturbances, and also the role of other brain lesions (lacunar infarcts, cerebral atrophy,and corpus callosum morphology). The LADIS study provides a good example of harmonization of instruments (MRI protocol, clinical, neuropsychological, and functional scales)within an international collaboration. Currently, the LADIS study is providing data about the natural history of WMC. In this paper, we review the background and the main results of the LADIS study. This review puts forward some considerations for future studies in the field.

Memory complaints with and without memory impairment: the impact of leukoaraiosis on cognition.

White matter alterations, leukoaraiosis (LA) on structural MRI, are associated with cognitive deficits and increased risk of dementia. LA may also impact on subjective memory complaints in otherwise healthy older adults. Little is known about the interplay between LA memory complaints and cognition. We investigated cognitive phenotypes associated with LA in 42 non-demented older adults categorized as having subjective cognitive complaints with no objective cognitive impairment-the subjective cognitive impairment group (SCI; n = 12), amnesic mild cognitive impairment (aMCI; n = 20), or healthy controls (HC; n = 11). We measured LA severity on MRI with a 40-point visual rating scale. Controlling for age and Mini-Mental State Examination (MMSE) score, analyses revealed multiple between-group differences. Follow-up linear regression models investigating the underlying contributors to each clinic group's cognitive profile indicated that LA contributed to learning slope variance (after accounting for age and MMSE) but only for the SCI group. Although the SCI group showed a significantly steeper learning slope when compared to HC and aMCI, increasing LA severity negatively impacted this group's rate of learning. This, in conjunction with the significant contribution of age on SCI learning slope performance variance suggests that greater LA burden at a younger age may contribute to subtle changes in learning for individuals with subjective cognitive complaints.

White matter hyperintensities and cognition across different Alzheimer's biomarker profiles.

BACKGROUND/OBJECTIVES: To examine the association between white matter hyperintensities (WMH) and cognitive domains such as memory and executive function (EF) across different clinical and biomarker categories of Alzheimer's disease (AD). DESIGN: Cross-sectional study. SETTING: Alzheimer's Disease Neuroimaging Initiative. PARTICIPANTS: A total of 216 cognitively normal (CN) participants and 407 participants with mild cognitive impairment (MCI) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) at baseline. MEASUREMENTS: Based on the 2018 research framework, participants were classified using AT(N) (amyloid-ß deposition [A], pathologic tau [T], and neurodegeneration [(N)]) biomarkers into one of three categories: biomarker negative [A - T- (N)-], amyloid negative but other biomarker positive [A - T ± (N)+ or A - T + (N)±] or amyloid positive [A + T ± (N)±]. Linear regression models were then used to examine the association between WMH and memory composite scores and EF composite scores. RESULTS: Higher WMH burden was associated with worse EF in both CN and MCI subgroups while a significant association between WMH and memory was only found in the MCI subgroup. Furthermore, WMH was associated with EF in the group with A - T ± (N)+ or A - T + (N)± biomarker category, but not for A - T - (N)- (normal biomarker) and A + T ± (N) ± (AD pathology). The association between higher WMH and worse memory was independent of amyloid levels in individuals with MCI with evidence of AD pathology. CONCLUSION: Vascular disease, as indexed by WMH, independent of AD pathology affects cognitive function in both CN and MCI subgroups. Future studies using the AT(N) research framework should consider white matter lesions as a key biomarker contributing to the clinical presentation of AD.

Diffusion-weighted imaging and cognition in the leukoariosis and disability in the elderly study.

BACKGROUND AND PURPOSE: The mechanisms by which leukoariosis impacts on clinical and cognitive functions are not yet fully understood. We hypothesized that ultrastructural abnormalities of the normal-appearing brain tissue (NABT) assessed by diffusion-weighted imaging played a major and independent role. METHODS: In addition to a comprehensive clinical, neuropsychologic, and imaging work-up, diffusion-weighted imaging was performed in 340 participants of the multicenter leukoariosis and disability study examining the impact of white matter hyperintensities (WMH) on 65- to 85-year old individuals without previous disability. WMH severity was rated according to the Fazekas score. Multivariate regression analysis served to assess correlations of histogram metrics of the apparent diffusion coefficient (ADC) of whole-brain tissue, NABT, and of the mean ADC of WMH with cognitive functions. RESULTS: Increasing WMH scores were associated with a higher frequency of hypertension, a greater WMH volume, more brain atrophy, worse overall cognitive performance, and changes in ADC. We found strong associations between the peak height of the ADC histogram of whole-brain tissue and NABT with memory performance, executive dysfunction, and speed, which remained after adjustment for WMH lesion volume and brain atrophy and were consistent among centers. No such association was seen with the mean ADC of WMH. CONCLUSIONS: Ultrastructural abnormalities of NABT increase with WMH severity and have a strong and independent effect on cognitive functions, whereas diffusion-weighted imaging metrics within WMH have no direct impact. This should be considered when defining outcome measures for trials that attempt to ameliorate the consequences of WMH progression.

[Diffusion tensor imaging of elderly leukoaraiosis and its correlation with cognitive function].

OBJECTIVE: To apply diffusion tensor imaging (DTI) for investigating the correlation between leukoaraiosis (LA) lesion's fraction anisotropy (FA) as well as average diffusion coefficient (DCavg) and LA severity, so as to explore DTI changes in microstructure of white marrow with normal ordinary MRI and its correlation with cognitive function. METHODS: Sixty LA patients and 30 healthy elderly people accepted DTI examination to detect the value of DCavg and FA of LA lesion and normal white marrow. The Mini-Mental State Examination (MMSE) was used for assessing cognitive function. RESULTS: LA severity (0 grade to 3 grade) was positively associated with DCavg, i.e. the more severe was LA, the higher DCavg was (0.66 +/- 0.05 to 1.09 +/- 0.06, P < 0.05); and it was negatively associated with FA, i.e. the more severe was LA, the lower FA was (0.42 +/- 0.04 to 0.26 +/- 0.03, P < 0.05). Neuropsychology tests (Mini-Mental State Examination, MMSE) had a significant relationship with DCavg and FA of normal appearing white matter (NAWM) in LA patients (P < 0.05), especially in anterior horn (Pearson Correlation Coefficient 0.422, P < 0.05) and in centrum semiovale (Pearson Correlation Coefficient -0.495, P < 0.01). CONCLUSIONS: In DTI examination, DCavg and FA of LA displays characteristic changes. Therefore, DTI can detect the macrostructaral changes of white marrow with normal MRI and these changes are related to cognitive function.

Location of lacunar infarcts correlates with cognition in a sample of non-disabled subjects with age-related white-matter changes: the LADIS study.

OBJECTIVES: In cerebral small vessel disease, white-matter hyperintensities (WMH) and lacunes are both related to cognition. Still, their respective contribution in older people remains unclear. The purpose of this study is to assess the topographic distribution of lacunes and determine whether it has an impact on cognitive functions in a sample of non-disabled patients with age-related white-matter changes. METHODS: Data were drawn from the baseline evaluation of the LADIS (Leucoaraioisis and Disability study) cohort of non-disabled subjects beyond 65 years of age. The neuropsychological evaluation was based on the Mini Mental Status Examination (MMSE), a modified Alzheimer Diseases Assessment Scale for global cognitive functions, and compound Z scores for memory, executive functions, speed and motor control. WMH were rated according to the Fazekas scale; the number of lacunes was assessed in the following areas: lobar white matter, putamen/pallidum, thalamus, caudate nucleus, internal/external capsule, infratentorial areas. An analysis of covariance was performed after adjustment for possible confounders. RESULTS: Among 633 subjects, 47% had at least one lacune (31% at least one within basal ganglia). The presence of lacunes in the thalamus was associated with lower scores of MMSE (beta = -0.61; p = 0.043), and worse compound scores for speed and motor control (beta = -0.25; p = 0.006), executive functions (beta = -0.19; p = 0.022) independently of the cognitive impact of WMH. There was also a significant negative association between the presence of lacunes in putamen/pallidum and the memory compound Z score (beta = -0.13; p = 0.038). By contrast, no significant negative association was found between cognitive parameters and the presence of lacunes in internal capsule, lobar white matter and caudate nucleus. CONCLUSION: In non-disabled elderly subjects with leucoaraisosis, the location of lacunes within subcortical grey matter is a determinant of cognitive impairment, independently of the extent of WMH.

Cognitive consequences of multiple lacunes and leukoaraiosis as vascular cognitive impairment in community-dwelling elderly individuals.

The aim of our study was to investigate the effects of silent brain lesions on cognitive function of community-dwelling elderly individuals. Brain magnetic resonance imaging and other medical examinations were performed on 350 nondemented elderly individuals (121 male and 229 female, average age 72.4 years) who resided in the rural community of Sefuri Village, Saga, Japan. The mini mental state examination and modified Stroop test (MST) were used to identify cognitive impairment. White matter lesions (WMLs) and cerebral atrophy on magnetic resonance imaging were measured quantitatively. Multivariate analyses were done using a logistic regression model with a software package. Cognitive impairment defined by mini mental state examination score less than 24 was present in 55 individuals (15.7%). They had a lower educational level, significantly larger quantity of WMLs, and more remarkable cerebral atrophy. Frontal lobe dysfunction was detected in 52 individuals (14.9%) through prolonged MST score (>36 seconds). Impaired frontal lobe function was related to number of silent lacunar infarcts, larger WMLs, and more prominent cerebral atrophy. MST score in individuals with two or more infarcts was significantly more prolonged compared with MST score in those without infarction. These results suggest that WMLs may cause rather diffuse cognitive decline, whereas multiple lacunar infarcts are specifically involved in frontal lobe dysfunction. Silent ischemic lesions in apparently healthy elderly individuals seem to form a distinctive group of people with vascular cognitive impairment without dementia. This group should be the primary target of prevention of vascular dementia.

Leukoaraiosis Is Associated With a Decline in Language Abilities in Chronic Aphasia.

Background. A fraction of stroke survivors with chronic aphasia experience declines in language abilities over time, but the reason for this remains unclear. Objective. To evaluate the effect of leukoaraiosis on baseline aphasia severity and long-term changes in aphasia severity. This study directly compares the predictive capacity of leukoaraiosis severity to that of lesion damage, a factor known to account for a substantial proportion of variance in the degree of language impairment and recovery. Methods. Using a longitudinal database of behavioral and neuroimaging data from 35 individuals in the chronic stage of recovery after a single-event left-hemisphere stroke (9 females, mean stroke age = 55.8 ± 9.1 years, mean months poststroke at initial evaluation = 36.3 ± 40.8), we examined 2 lines of inquiry: (1) to what extent does leukoaraiosis severity at initial evaluation predict aphasia severity and (2) to what extent does leukoaraiosis severity at initial evaluation predict longitudinal change in aphasia severity. Participants underwent high-resolution magnetic resonance imaging for the purpose of lesion volume analysis and leukoaraiosis severity rating. Biographical information was also considered. Results. Lesion volume and time poststroke at initial assessment best predicted initial aphasia severity (adjusted R2 = 0.37). Leukoaraiosis severity and initial aphasia severity significantly predicted decline in language abilities at follow-up, accounting for approximately one-third of the variance (adjusted R2 = 0.33). More severe leukoaraiosis was associated with a 4.3 odds increase of decline. Conclusions. Leukoaraiosis is a significant risk factor for declining language abilities in aphasia and should be considered for better identification of individuals at risk for long-term decline, which can guide clinical decision making.