Rebecca L. Brookes

Differential relationships between apathy and depression with white matter microstructural changes and functional outcomes

Small vessel disease pathways disrupts subcortical pathways that are important for emotion regulation. Hollocks et al. use brain imaging and statistical modelling to show that white-matter damage is associated with apathy, but not depression, although the latter still has a significant impact on quality of life.

Striking the right balance: motor difficulties in children and adults with dyslexia

Balance difficulties are an enduring feature of dyslexia research, however results have been inconsistent. We propose that between-study heterogeneity may be attributable to variability in balance tasks, balance measurement, participant age, and inclusion of comorbid disorders such as ADHD. This study attempted to clarify these issues, employing quantitative, continuous measures of balance and blindfolded balance, and using both adult and child participants without comorbid ADHD. Eighty-seven individuals participated: dyslexic adults (n = 17), matched adult controls (n = 30), dyslexic children (n = 16) and matched child controls (n = 24). The study found significant balance deficits for the child dyslexic group in the eyes-open task and a result approaching significance in the blindfolded task. By contrast, the adult dyslexic group showed significant deficits in the blindfolded task only. This result is interpreted in terms of lack of sensitivity of the non-blindfolded balance task for adults, owing to ceiling effects. This highlights the need for the use of age-appropriate tests, and may explain some of the heterogeneity in the literature. It is concluded that there is a significant incidence of balance difficulties in children and adults with dyslexia, even for those without comorbid attention deficit.

Depression in small-vessel disease relates to white matter ultrastructural damage, not disability

Objective: To determine whether cerebral small-vessel disease (SVD) is a specific risk factor for depression, whether any association is mediated via white matter damage, and to study the role of depressive symptoms and disability on quality of life (QoL) in this patient group. Methods: Using path analyses in cross-sectional data, we modeled the relationships among depression, disability, and QoL in patients with SVD presenting with radiologically confirmed lacunar stroke (n = 100), and replicated results in a second SVD cohort (n = 100). We then compared the same model in a non-SVD stroke cohort (n = 50) and healthy older adults (n = 203). In a further study, to determine the role of white matter damage in mediating the association with depression, a subgroup of patients with SVD (n = 101) underwent diffusion tensor imaging (DTI). Results: Reduced QoL was associated with depression in patients with SVD, but this association was not mediated by disability or cognition; very similar results were found in the replication SVD cohort. In contrast, the non-SVD stroke group and the healthy older adult group showed a direct relationship between disability and depression. The DTI study showed that fractional anisotropy, a marker of white matter damage, was related to depressive symptoms in patients with SVD. Conclusion: These results suggest that in stroke patients without SVD, disability is an important causal factor for depression, whereas in SVD stroke, other factors specific to this stroke subtype have a causal role. White matter damage detected on DTI is one factor that mediates the association between SVD and depression.

Verbal Fluency in Cerebral Small Vessel Disease and Alzheimer's Disease

Patterns of verbal fluency deficits have been explored across different neurodegenerative disorders. This study sought to investigate the specific pattern of verbal fluency performance in cerebral small vessel disease (SVD), which is the most common cause of vascular cognitive impairment, and compare this with Alzheimers disease (AD). Participants with SVD (n = 45), AD (n = 24) and healthy controls (n = 80) completed assessments of semantic and phonemic fluency. Mixed-model analyses of covariance were used to compare performance on the different fluency tasks between the groups, and a discriminant function analysis was conducted to examine group differentiation. The SVD group was impaired in both fluency tasks when compared to the controls. In contrast, the AD group displayed impairment in semantic fluency only. Discriminant function analysis revealed that fluency scores correctly classified 80% of SVD patients and 92% of AD patients. The pattern of performance observed in the SVD group may reflect deficits in executive function and processing speed impacting equivalently on semantic and phonemic fluency. The differences between the SVD and AD groups highlighted in this study may be useful for distinguishing between these conditions.

Pattern and Rate of Cognitive Decline in Cerebral Small Vessel Disease: A Prospective Study.

Objectives Cognitive impairment, predominantly affecting processing speed and executive function, is an important consequence of cerebral small vessel disease (SVD). To date, few longitudinal studies of cognition in SVD have been conducted. We determined the pattern and rate of cognitive decline in SVD and used the results to determine sample size calculations for clinical trials of interventions reducing cognitive decline. Methods 121 patients with MRI confirmed lacunar stroke and leukoaraiosis were enrolled into the prospective St George’s Cognition And Neuroimaging in Stroke (SCANS) study. Patients attended one baseline and three annual cognitive assessments providing 36 month follow-up data. Neuropsychological assessment comprised a battery of tests assessing working memory, long-term (episodic) memory, processing speed and executive function. We calculated annualized change in cognition for the 98 patients who completed at least two time-points. Results Task performance was heterogeneous, but significant cognitive decline was found for the executive function index (p<0.007). Working memory and processing speed decreased numerically, but not significantly. The executive function composite score would require the smallest samples sizes for a treatment trial with an aim of halting decline, but this would still require over 2,000 patients per arm to detect a 30% difference with power of 0.8 over a three year follow-up. Conclusions The pattern of cognitive decline seen in SVD over three years is consistent with the pattern of impairments at baseline. Rates of decline were slow and sample sizes would need to be large for clinical trials aimed at halting decline beyond initial diagnosis using cognitive scores as an outcome measure. This emphasizes the importance of more sensitive surrogate markers in this disease.

Depressive symptoms as a predictor of quality of life in cerebral small vessel disease, acting independently of disability; a study in both sporadic small vessel disease and CADASIL

Background Cerebral small vessel disease causes lacunar stroke, and more recently has been implicated as a cause of depression. Factors causing reduced quality of life in small vessel disease, including the relative contributions of disability and depressive symptoms, remain uncertain. Methods One hundred patients with small vessel disease and 55 controls completed the Stroke-Specific Quality of Life scale. The protocol was repeated in 40 patients with the young-onset genetic form of small vessel disease, cerebral autosomal dominant arteriopathy with sub-cortical infarcts and leukoencephalopathy, and 35 controls. Disability, activities of daily living, cognition and depression were measured. Results Quality of life was significantly lower in small vessel disease versus controls: mean (standard deviation), 196·8 (35·2) vs. 226·8 (15·3), P < ·0001. Depressive symptoms were the major predictor of quality of life, explaining 52·9% of variance. The only other independent predictor was disability, explaining an additional 18·4%. A similar pattern was found in the young-onset genetic group, with reduced quality of life 202·0 (29·7) vs. controls 228·6 (13·1) P < ·0001, and depressive symptoms accounting for 42·2% of variance. Disability explained an additional 17·6%. Relationships between depression and quality of life, and disability and quality of life were independent of one another. Conclusions Depressive symptoms, often unrecognized, are a major determinant of reduced quality of life in small vessel disease. They account for greater reduction than, and are independent of, disability. This relationship may reflect the proposed causal association between white matter disease and depression. Treatment of depressive symptoms might significantly improve quality of life in small vessel disease.

Executive dysfunction, awareness deficits and quality of life in patients with cerebral small vessel disease: a structural equation model.

OBJECTIVE To investigate the relationships between executive dysfunction, awareness deficits and perceptions of quality of life (QOL) in patients with cerebral small vessel disease (SVD). METHOD We tested neuropsychological function with simultaneous measurement of awareness performance in 125 participants. Forty-five were carefully phenotyped patients with SVD, defined as a lacunar stroke with corresponding infarct on neuroimaging; and 80 were age-matched controls, providing a normal comparison for neuropsychological measures. Patients also completed the Stroke-Specific Quality of Life Scale. In patients with SVD, the impact of executive dysfunction on awareness and QOL was examined simultaneously using structural equation modeling. RESULTS A simple regression indicated a positive relationship between awareness and QOL. However, when executive function was added to the model, the results showed strong relationships between executive function and awareness, and executive function and QOL, but no direct relationship between awareness and QOL. CONCLUSION Our results show that the main neuropsychological symptom associated with SVD, namely, executive dysfunction, may predict both reductions in awareness and QOL. However, there is no direct impact of awareness deficits on QOL in patients with SVD, when executive function is included in the model.

Apathy, but not depression, is associated with executive dysfunction in cerebral small vessel disease

Objective To determine the prevalence of apathy and depression in cerebral small vessel disease (SVD), and the relationships between both apathy and depression with cognition. To examine whether apathy is specifically related to impairment in executive functioning and processing speed. Methods 196 patients with a clinical lacunar stroke and an anatomically corresponding lacunar infarct on MRI were compared to 300 stroke-free controls. Apathy and depression were measured using the Geriatric Depression Scale, and cognitive functioning was assessed using an SVD cognitive screening tool, the Brief Memory and Executive Test, which measures executive functioning/processing speed and memory/orientation. Path analysis and binary logistic regression were used to assess the relation between apathy, depression and cognitive impairment. Results 31 participants with SVD (15.8%) met criteria for apathy only, 23 (11.8%) for both apathy and depression, and 2 (1.0%) for depression only. In the SVD group the presence of apathy was related to global cognition, and specifically to impaired executive functioning/processing speed, but not memory/orientation. The presence of depression was not related to global cognition, impaired executive functioning/processing speed or memory/orientation. Conclusions Apathy is a common feature of SVD and is associated with impaired executive functioning/processing speed suggesting the two may share biological mechanisms. Screening for apathy should be considered in SVD, and further work is required to develop and evaluate effective apathy treatment or management in SVD.

Lack of awareness of neuropsychological deficit in cerebral small vessel disease: the relationship with executive and episodic memory functions.

A common cause of neuropsychological impairment in older adults is cerebral small vessel disease (SVD), but little is known as to whether lack of awareness of neuropsychological impairment is a feature of this clinical condition. In this study, we investigated awareness deficits in a well-phenotyped population of patients with SVD (n= 45; 21 with defined concomitant neuropsychological impairment) and made comparisons with 24 Alzheimers disease (AD) patients and a further 80 control participants. Awareness of performance on a range of neuropsychological measures was examined based on the Brief Memory and Executive Test Battery (BMET) (Brookes, Hannesdottir, Lawrence, Morris, & Markus, 2012), exploring the relationship between awareness and memory and executive function. The results revealed significant awareness deficits in both the SVD and AD groups. When splitting the SVD group into those with or without concomitant neuropsychological impairment, only those with neuropsychological impairment showed reduced awareness. For the SVD group, executive function was significantly correlated with awareness but memory was not. By comparison, memory was significantly correlated with awareness in the AD group, with executive function showing a trend but remaining non-significant. The results show that lack of awareness of deficit is a clinical feature of SVD and indicate that there are distinct neuropsychological associations with awareness deficit for SVD and AD.

Brief Screening of Vascular Cognitive Impairment in Patients With Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Without Dementia

Background and Purpose— Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic form of cerebral small vessel disease leading to early-onset stroke and dementia, with younger patients frequently showing subclinical deficits in cognition. At present, there are no targeted cognitive screening measures for this population. However, the Brief Memory and Executive Test (BMET) and the Montreal Cognitive Assessment (MoCA) have shown utility in detecting cognitive impairment in sporadic small vessel disease. This study assesses the BMET and the MoCA as clinical tools for detecting mild cognitive deficits in CADASIL. Methods— Sixty-six prospectively recruited patients with CADASIL, and 66 matched controls completed the BMET, with a subset of these also completing the MoCA. Receiver operating characteristic curves were calculated to examine the sensitivity and specificity of clinical cutoffs for the detection of vascular cognitive impairment and reduced activities of daily living. Results— Patients with CADASIL showed more cognitive impairment overall and were poorer on both executive/processing and memory indices of the BMET relative to controls. The BMET showed good accuracy in predicting vascular cognitive impairment (85% sensitivity and 84% specificity) and impaired instrumental activities of daily living (92% sensitivity and 77% specificity). The MoCA also showed good predictive validity for vascular cognitive impairment (80% sensitivity and 78% specificity) and instrumental activities of daily living (75% sensitivity and 76% specificity). The most important background predictor of vascular cognitive impairment was a history of stroke. Conclusions— The results indicate that the BMET and the MoCA are clinically useful and sensitive screening measures for early cognitive impairment in patients with CADASIL.