Resting state connectivity and cognitive performance in adults with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Cognitive impairment is an inevitable feature of cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), affecting executive function, attention and processing speed from an early stage. Impairment is associated with structural markers such as lacunes, but associations with functional connectivity have not yet been reported. Twenty-two adults with genetically-confirmed CADASIL (11 male; aged 49.8 ± 11.2 years) underwent functional magnetic resonance imaging at rest. Intrinsic attentional/executive networks were identified using group independent components analysis. A linear regression model tested voxel-wise associations between cognitive measures and component spatial maps, and Pearson correlations were performed with mean intra-component connectivity z-scores. Two frontoparietal components were associated with cognitive performance. Voxel-wise analyses showed an association between one component cluster and processing speed (left middle temporal gyrus; peak −48, −18, −14; ZE = 5.65, pFWEcorr = 0.001). Mean connectivity in both components correlated with processing speed (r = 0.45, p = 0.043; r = 0.56, p = 0.008). Mean connectivity in one component correlated with faster Trailmaking B minus A time (r = −0.77, p < 0.001) and better executive performance (r = 0.56, p = 0.011). This preliminary study provides evidence for associations between cognitive performance and attentional network connectivity in CADASIL. Functional connectivity may be a useful biomarker of cognitive performance in this population

The Impact of Strategic White Matter Hyperintensity Lesion Location on Language

Objective: The impact of white matter hyperintensities (WMH) on language possibly depends on lesion location through disturbance of strategic white matter tracts. We examined the impact of WMH location on language in elderly Asians. Design: Cross-sectional. Setting: Population-based. Participants: Eight-hundred nineteen residents of Singapore, ages (≥65 years). Measurements: Clinical, cognitive and 3T magnetic resonance imaging assessments were performed on all participants. Language was assessed using the Modified Boston Naming Test (MBNT) and Verbal Fluency (VF). Hypothesis-free region-of-interest-based (ROI) analyses based on major white matter tracts were used to determine the association between WMH location and language. Conditional dependencies between the regional WMH volumes and language were examined using Bayesian-network analysis. Results: ROI-based analyses showed that WMH located within the anterior thalamic radiation (mean difference: −0.12, 95% confidence interval [CI]: −0.22; −0.02, p = 0.019) and uncinate fasciculus (mean difference: −0.09, 95% CI: −0.18; −0.01, p = 0.022) in the left hemisphere were significantly associated with worse VF but did not survive multiple testing. Conversely, WMH volume in the left cingulum of cingulate gyrus was significantly associated with MBNT performance (mean difference: −0.09, 95% CI: −0.17; −0.02, p = 0.016). Bayesian-network analyses confirmed the left cingulum of cingulate gyrus as a direct determinant of MBNT performance. Conclusion: Our findings identify the left cingulum of cingulate gyrus as a strategic white matter tract for MBNT, suggesting that language – is sensitive to subcortical ischemic damage. Future studies on the role of sporadic ischemic lesions and vascular cognitive impairment should not only focus on total WMH volume but should also take WMH lesion location into account when addressing language

Imaging markers of cerebral small vessel disease

Vascular cognitive impairment (VCI) is the second most common cause of cognitive impairment in the elderly population and it very often co-occurs with impairment resulting from other neurodegenerative pathologies. Cognitive impairment due to vascular pathology is potentially treatable; i.e. the progression could be slowed or even stopped by managing the underlying vascular disease. However, there is no specific treatment available for VCI up to date. One of the main reasons for this is an insufficient understanding of the disease pathophysiology. Cerebral small vessel disease is the primary pathology leading to VCI and therefore its study provides the chance to elucidate the mechanisms leading from vascular pathology to cognitive impairment. Understanding the underlying disease mechanisms is crucial for diagnosis, prevention and managing the disease. For this purpose, markers play an important role, as they indicate which disease processes are at play within the brain. This PhD-work aimed at finding optimal imaging markers for diagnosing cerebral small vessel diseases and estimating the vascular disease burden in the brain. Advances in brain imaging tools, in particular diffusion tensor imaging (DTI), have enabled the exploration of microstructural changes in the human brain, which precede the occurrence of lesions that are visible on conventional MRI. The first project focused on developing and establishing a DTI-based imaging marker for small vessel disease that is quantitative, reliable, and fully automated. This marker (peak width of skeletonized mean diffusivity, PSMD) was then systematically investigated - along with conventional imaging markers - in patients with hereditary and sporadic SVD, memory clinic patients as well as in patients with Alzheimer pathology. The results showed that PSMD outperformed the conventional markers in explaining the cognitive impairment scores. Furthermore, in longitudinal analysis, PSMD was more sensitive to disease related changes than any other imaging markers, which resulted in low sample size estimations for a hypothetical clinical trial. Additionally. PSMD showed very high interscanner reproducibility suggesting that it might be especially useful in multicenter studies. Interestingly, increases in PSMD were mostly linked to vascular but not to neurodegenerative disease. Therefore, PSMD could be a valuable tool to disentangle effects caused by these different pathologies, a common challenge in understanding cognitive impairment. This suggests that the newly established marker PSMD could be easily applied to large samples and may be of great utility for both research studies and clinical use. The second project focused on the evaluation of cortical superficial siderosis (cSS) as a potential new marker for cerebral small vessel diseases. cSS emerged recently as a marker for cerebral amyloid angiopathy (CAA). However, the presence of cSS is associated with many other signs of cSVD, such as cerebral microbleeds (CMB) and white matter hyperintensities (WMH), and therefore its specificity for CAA was questionable. The results of the second project revealed that the distribution patterns and frequency of CMB and WMH overlap between different subtypes of cSVD. This clearly demonstrated that these imaging features have limited discriminative value. More importantly, the presence of cSS was found to be strongly indicative of CAA. To summarize, the key findings reported in this PhD-work have important implications for diagnosing patients with cerebral small vessel disease, disentangling underlying pathologies, as well as for managing and treating the disease. The newly established imaging marker PSMD can be utilized to select the target population for clinical studies and may function as a surrogate marker for treatment effects. PSMD can be further used to identify patients who have a low disease burden as targets for prevention and early treatment

Cognitive impairment before and after intracerebral haemorrhage: a systematic review

Introduction: There is increasing interest in understanding cognitive dysfunction before and after Intracerebral haemorrhage (ICH), given the higher prevalence of dementia reported (ranging from 5 to 44%) for this stroke type. Much of the evidence to date examining cognitive impairment associated with cerebrovascular disease has tended to focus more on ischaemic stroke. The aim of this review was to identify and quantify studies that focused on cognitive dysfunction pre and post ICH. / Methods: We conducted a systematic search using databases PubMed, Science Direct, Scopus and PsycINFO to identify studies that exclusively assessed cognitive function pre and post ICH. Studies were included in the review if used a measure of global cognition and/or a neuropsychological battery to assess cognitive function. Nineteen studies were deemed relevant for inclusion, where n = 8 studies examined cognitive impairment pre ICH and n = 11 post ICH. / Results: Prevalence of cognitive impairment ranged between 9–29% for pre ICH and 14–88% for post ICH. Predictive factors identified for pre and post ICH were previous stroke, ICH volume and location and markers of cerebral amyloid angiopathy (CAA). Most common cognitive domains affected post ICH were information processing speed, executive function, memory, language and visuo-spatial abilities. Most common cognitive assessments tools were the Informant Questionnaire for Cognitive Decline in the Elderly (IQCODE) for pre-existing cognitive impairment and the Mini-Mental State Examination for global cognition post ICH and the Trail Making Test where neuropsychological tests were used. / Conclusion: Cognitive impairment and dementia affected almost one-third of patients, whether assessed pre or post ICH

Reaction Time Decomposition as a Tool to Study Subcortical Ischemic Vascular Cognitive Impairment

Background:The study of reaction time (RT) and its intraindividual variability (IIV) in aging, cognitive impairment, and dementia typically fails to investigate the processing stages that contribute to an overall response. Applying “mental chronometry” techniques makes it possible to separately assess the role of processing components during environmental interaction.Objective:To determine whether RT and IIV-decomposition techniques can shed light on the nature of underlying deficits in subcortical ischemic vascular cognitive impairment (VCI). Using a novel iPad task, we examined whether VCI deficits occur during both initiation and movement phases of a response, and whether they are equally reflected in both RT and IIV.Methods:Touch cancellation RT and its IIV were measured in a group of younger adults (n = 22), cognitively healthy older adults (n = 21), and patients with VCI (n = 21) using an iPad task.Results:Whereas cognitively healthy aging affected the speed (RT) of response initiation and movement but not its variability (IIV), VCI resulted in both slowed RT and increased IIV for both response phases. Furthermore, there were group differences with respect to response phase.Conclusion:These results indicate that IIV can be more sensitive than absolute RT in separating VCI from normal aging. Furthermore, compared to cognitively healthy aging, VCI was characterized by significant deficits in planning/initiating action as well as performing movements. Such deficits have important implications for real life actions such as driving safety, employment, and falls risk

On the neurobiology of apathy and depression in cerebral small vessel disease

Cerebral small vessel disease (SVD) is a cerebrovascular pathology that affects the small vessels of the brain, resulting in heterogeneous brain tissue changes. These can lead to neuropsychiatric symptoms such as apathy, a loss of motivation, and depression, which is characterised by low mood and a loss of pleasure. Apathy and depression are both prevalent symptoms in SVD, but an understanding of the relationship between underlying disease processes and the expression of these neuropsychiatric symptoms remains poor. This thesis uses magnetic resonance imaging techniques to examine the neurobiological basis of apathy and depression in SVD. We show that apathy is related to focal grey matter damage and distributed white matter microstructural change. These microstructural changes underlie large-scale white matter network disruption, which is related to apathy, but not depression. We then show that depression, as a construct, can be dissociated into distinct symptoms which are associated with overlapping and distinct areas of cortical atrophy over time. This suggests that depression as a general syndrome may be characterised by atrophy in core structures, while different symptoms are associated with atrophy in more specialised areas. Consistent with these patterns of overarching tissue damage, we find that apathy, but not depression, predicts conversion to dementia in patients with SVD. Our findings suggest that different types of SVD-related pathology lead to apathy and depression. Diffuse white matter damage may lead to widespread network disruption, resulting in apathy and cognitive impairment. In contrast, depressive symptoms are associated with focal patterns of grey matter atrophy over time. This highlights the importance of differentiating neuropsychiatric symptoms, and paves the way for targeted treatment approaches.Cambridge International Scholarship (Cambridge Trust)

The assessment of cognitive and behavioural disturbances in vascular cognitive impairment (VCI) — recommendations of an expert working group

With newer research-based classification systems, the term Vascular Cognitive Impairment (VCI) is now preferred to vascular dementia. VCI is an umbrella term that includes all forms of cognitive deficits ranging from mild cognitive impairment of vascular origin (VaMCI) to vascular dementia (VaD).The new VCI construct takes into account the fact that in addition to single strategic infarcts, multiple infarcts, and leukoaraiosis, there are other mechanisms of cerebrovascular disease such as chronic hypoperfusion that might account for the pattern of cognitive deficits associated with vascular dementia. The key to defining the spectrum of VCI is neuropsychological testing, bedside or office-based clinical examination, and neuroimaging. The lack of specific cognitive tools that are sufficiently sensitive to detect subtle deficits makes the assessment of cognitive impairment difficult. Prospective cross-sectional and longitudinal studies of VCI from different settings are therefore required.Although there have been few published reports, behavioural and psychological symptoms (BPS) are inherently present in VCI from the onset and during the course of the disease. Besides the type of population (i.e. clinical, community or nursing-home settings), the definition of VCI/VaD and the instruments used, and differences in the prevalence and pattern of BPS between various studies, could be due to other, often unconsidered, factors such as gender, age, education, use of medication and VCI/VaD severity

Do informal caregivers of people with dementia mirror the cognitive deficits of their demented patients?:A pilot study

Recent research suggests that informal caregivers of people with dementia (ICs) experience more cognitive deficits than noncaregivers. The reason for this is not yet clear. Objective: to test the hypothesis that ICs ‘mirror' the cognitive deficits of the demented people they care for. Participants and methods: 105 adult ICs were asked to complete three neuropsychological tests: letter fluency, category fluency, and the logical memory test from the WMS-III. The ICs were grouped according to the diagnosis of their demented patients. One-sample ttests were conducted to investigate if the standardized mean scores (t-scores) of the ICs were different from normative data. A Bonferroni correction was used to correct for multiple comparisons. Results: 82 ICs cared for people with Alzheimer's dementia and 23 ICs cared for people with vascular dementia. Mean letter fluency score of the ICs of people with Alzheimer's dementia was significantly lower than the normative mean letter fluency score, p = .002. The other tests yielded no significant results. Conclusion: our data shows that ICs of Alzheimer patients have cognitive deficits on the letter fluency test. This test primarily measures executive functioning and it has been found to be sensitive to mild cognitive impairment in recent research. Our data tentatively suggests that ICs who care for Alzheimer patients also show signs of cognitive impairment but that it is too early to tell if this is cause for concern or not

Investigation of dynamic functional connectivity in cerebral small vessel disease

Tese de mestrado integrado em Engenharia Biomédica e Biofísica (Biofísica Médica e Fisiologia de Sistemas), Universidade de Lisboa, Faculdade de Ciências, 2020A doença dos pequenos vasos cerebrais ou Small Vessel Disease (SVD) é a principal causa de disfunção cognitiva em idosos e refere-se a um conjunto de processos patológicos e neurológicos que afetam os pequenos vasos do cérebro. As suas manifestações clínicas variam desde deficiências cognitivas, que podem levar a uma deterioração cognitiva progressiva e até demência, e incapacidades físicas, incluindo perda funcional em fases mais avançadas da doença. A neuroimagiologia é uma ferramenta essencial no diagnóstico e caracterização da SVD, em particular, a ressonância magnética funcional em repouso (rs-fMRI) já demonstrou potencial para fornecer biomarcadores da SVD, revelando interrupções da conectividade funcional (CF) em redes neuronais. No entanto, até o momento, apenas um estudo explorou as flutuações temporais da CF comumente observadas – a chamada conectividade funcional dinâmica (dFC). Em contraste com a CF, a dFC tem em consideração a natureza dinâmica da atividade cerebral, analisando-a em escalas de tempo mais rápidas de segundos a minutos. De facto, diversos estudos de dFC reportaram que esta abordagem pode fornecer uma maior compreensão das propriedades fundamentais das redes cerebrais e servir como um biomarcador de diversas doenças, uma vez que as alterações relacionadas com as mesmas nas propriedades dinâmicas da CF parecem ter origem neuronal. Deste modo, neste trabalho, o objetivo foi investigar a dFC medida por rs-fMRI em dois grupos de pacientes com SVD – do tipo esporádico (sSVD) e arteriopatia cerebral autossómica dominante com enfartes subcorticais e leucoencefalopatia (CADASIL) - em comparação com um grupo saudável. Para tal, a dFC foi estimada entre pares de regiões do cérebro em cada tempo de repetição, TR, com o método de Phase Coherence. Neste método, os padrões de dFC para todos os pontos de tempo foram obtidos calculando o alinhamento de fase entre cada par de regiões do cérebro, estimando a fase do sinal de cada ponto de tempo, em cada uma das 90 regiões do cérebro, com a transformada de Hilbert. De seguida, os padrões de dFC ao longo do tempo e de todos os sujeitos foram analisados utilizando o método Leading Eigenvector Dynamics Analysis (LEiDA), que considera apenas o autovetor principal de cada padrão de dFC obtido, reduzindo deste modo a dimensionalidade dos dados. Este vetor captura a orientação principal das fases do sinal sobre todas as áreas, onde cada elemento do mesmo representa a projeção da fase do sinal em cada área do cérebro no autovetor principal. Em seguida, o algoritmo k-médias foi aplicado a todos os autovetores principais de dFC para obter um número finito de estados de dFC, cada um representando um padrão dFC recorrente, para um k (número de estados) variável. Como este trabalho teve como objetivo explorar se existem estados de dFC que diferenciam pacientes SVD do grupo saudável, e não determinar o número ideal de estados de dFC, o número de estados foi variado de 2 a 20. Para cada k, examinámos as diferenças em termos de probabilidade de ocorrência, duração e perfis de transição dos estados de dFC entre o grupo de doentes e o grupo de controlos saudáveis. Adicionalmente, os estados de dFC foram correlacionados com sete redes neuronais de repouso comuns, nomeadamente a rede somatomotora, a rede de atenção ventral e dorsal, a rede visual, a rede frontoparietal, a rede límbica e a rede de modo padrão. Posteriormente, a fim de determinar se as alterações nas propriedades de dFC, encontradas neste trabalho, poderiam ser potenciais biomarcadores de declínio cognitivo causadas pela SVD, foi realizado uma análise de correlação entre as pontuações dos testes neuropsicológicos em quatro domínios relevantes (função executiva, velocidade de processamento, memória de trabalho e memória de longo prazo) e as propriedades de dFC dos pacientes. Do mesmo modo, uma análise de correlação entre os mapas probabilísticos dos tratos de substância branca mais frequentemente lesionados destes pacientes e as propriedades de dFC foi, também, realizada com o objetivo de determinar se as alterações nas propriedades de dFC, encontradas nos pacientes quando comparadas com o grupo saudável, poderiam estar correlacionadas com lesões estruturais dos mesmos. Quando comparado com o grupo de controlos saudáveis, o grupo de doentes apresentou uma probabilidade de ocorrência significativamente maior num estado de dFC fracamente conectado, composto por áreas clinicamente relevantes. Este estado compreende áreas dos lobos frontais e parietais e está significativamente associado a redes neuronais envolvidas na integração de informações sensoriais e processos específicos para o controlo da atenção, nomeadamente a rede somatomotora, a rede de atenção ventral e dorsal. Estas mesmas redes foram anteriormente identificadas, em estudos de CF, como afetadas em pacientes com SVD, mas também em indivíduos com deficiências cognitivas e com doença de Alzheimer. Além disso, estudos de dFC em doenças relacionadas com a SVD, como a demência e a doença de Alzheimer, relataram que os pacientes também apresentaram maiores probabilidades de ocorrência em estados fracamente e esparsamente conectados, com ausência de fortes conexões positivas e negativas. Em particular, o único estudo de dFC em SVD também descobriu que os pacientes com SVD tiveram mais ocorrências num estado fracamente conectado nas regiões do domínio sensório-motor, quando comparado ao grupo saudável. Deste modo, podendo indicar que mudanças dinâmicas na CF nestas áreas podem ser particularmente importantes para esta doença. É também importante ressaltar que as probabilidades de transição entre este estado fronto-parietal fracamente conectado para o estado de coerência global, fortemente conectado, foram significativamente correlacionadas com melhor desempenho no domínio cognitivo da velocidade de processamento. Estas descobertas estão de acordo com resultados anteriores de estudos de dFC em indivíduos com melhores e piores desempenhos cognitivos, onde indivíduos com melhores desempenhos cognitivos tiveram maior número de transições para este estado de coerência global. Da mesma forma, as probabilidades de transição do estado fortemente conectado para o estado fronto-parietal fracamente conectado, foram significativamente correlacionadas com um pior desempenho neste mesmo domínio cognitivo. De facto, défices na velocidade de processamento estão entre as primeiras e mais proeminentes manifestações cognitivas da SVD, com diversos estudos demonstrando associações entre o declínio na velocidade de processamento e medidas quantitativas de ressonância magnética. Assim, estudos futuros devem investigar com maior detalhe transições entre estes estados, de modo a determinar se alterações nesta propriedade de dFC podem ser biomarcadores do declínio cognitivo na SVD. Em relação à análise dos mapas probabilísticos dos tratos de substância branca mais frequentemente lesionados nestes pacientes, embora nenhuma correlação significativa tenha sido encontrada com as alterações nas propriedades da dFC encontradas neste trabalho, é interessante notar que vários estudos têm relatado associações entre estas lesões e o declínio cognitivo. O facto de a substância branca ser organizada no cérebro por tratos, conectando regiões cerebrais funcionais entre si, espera-se que danos a esses tratos levem a défices funcionais. Efetivamente, dois dos tratos frequentemente lesionados nestes pacientes, conectando regiões frontais, foram anteriormente relacionados com um pior desempenho cognitivo na velocidade de processamento em pacientes com SVD e demência. É, portanto, tentador sugerir que estes mesmo tratos frequentemente lesionados nos pacientes com SVD aqui estudados, poderiam ter alguma influência no pior desempenho no teste da velocidade de processamento encontrado neste estudo, que foi correlacionado com uma maior probabilidade de transição para o estado fracamente conectado, composto por regiões do lobo frontal e parietal. A compreensão dessa relação poderia ajudar a prever em quais das regiões do cérebro a patologia da substância branca causaria maiores défices funcionais, permitindo uma prevenção e terapia precoce. No geral, os nossos resultados fornecem um novo suporte de que a conectividade funcional dinâmica pode fornecer biomarcadores mais sensíveis da SVD e deste modo, futuras investigações deverão explorar o seu potencial para prever o declínio cognitivo relacionado com a mesma.Cerebral small vessel disease (SVD) is the leading contributor to cognitive dysfunction in the elderly and it refers to a set of pathological and neurological processes that affect the smallest vessels of the brain. Its clinical manifestations vary from cognitive impairments, which can lead to progressive cognitive deterioration and even dementia, and physical disabilities, including functional loss in more advanced stages. Neuroimaging is a crucial tool in the diagnosis and characterization of SVD; in particular, resting-state functional magnetic resonance imaging (rs-fMRI) has demonstrated potential to deliver sensitive biomarkers of SVD, by revealing disruptions in functional connectivity (FC) across brain networks. However, so far only one study has explored the commonly observed FC temporal fluctuations – so-called dynamic FC (dFC). Here we aim to further investigate dFC measured by rs-fMRI in two groups of patients with SVD – sporadic SVD (sSVD) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) – compared with a healthy control group. For this purpose, dFC was estimated at each repetition time point, TR, using Phase Coherence between the BOLD signals in pairs of brain regions, and dFC patterns were then analysed over time and subjects using the Leading Eigenvector Dynamics Analysis (LEiDA) approach. Then, a finite number of dFC states, each representing a recurrent dFC pattern, was obtained by k-means clustering with varying k (number of clusters). For each k, we examined differences between SVD and healthy control groups in terms of the occurrence, duration and switching profiles of dFC states. Additionally, the correlations between each dFC state and seven common resting-state networks (RSNs) were computed. SVD patients showed a significant higher probability of a weakly connected dFC state, consisting of clinically relevant areas, when compared with healthy controls. This state comprises frontal and parietal areas and is significantly associated with the somatomotor, dorsal attention and ventral attention RSNs, which are involved in the integration of sensory information and specific processes for attention control. Further, the fact that the state is weakly connected agrees with the only previous study on dFC in SVD. Overall, our findings contribute with novel support that dFC may provide sensitive biomarkers of SVD and should be further explored in terms of its potential to predictive cognitive decline