Temporal course of cognitive and behavioural changes in motor neuron diseases.

BACKGROUND: Cognitive and behavioural dysfunction may occur in people with motor neuron disease (MND), with some studies suggesting an association with the C9ORF72 repeat expansion. Their onset and progression, however, is poorly understood. We explored how cognition and behaviour change over time, and whether demographic, clinical and genetic factors impact these changes. METHODS: Participants with MND were recruited through the Phenotype-Genotype-Biomarker study. Every 3-6 months, the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was used to assess amyotrophic lateral sclerosis (ALS) specific (executive functioning, verbal fluency, language) and ALS non-specific (memory, visuospatial) functions. Informants reported on behaviour symptoms via semi-structured interview. RESULTS: Participants with neuropsychological data at ≥3 visits were included (n=237, mean age=59, 60% male), of which 18 (8%) were C9ORF72 positive. Baseline cognitive impairment was apparent in 18 (8%), typically in ALS specific domains, and associated with lower education, but not C9ORF72 status. Cognition, on average, remained stable over time, with two exceptions: (1) C9ORF72 carriers declined in all ECAS domains, (2) 8%-9% of participants with baseline cognitive impairment further declined, primarily in the ALS non-specific domain, which was associated with less education. Behavioural symptoms were uncommon. CONCLUSIONS: In this study, cognitive dysfunction was less common than previously reported and remained stable over time for most. However, cognition declines longitudinally in a small subset, which is not entirely related to C9ORF72 status. Our findings raise questions about the timing of cognitive impairment in MND, and whether it arises during early clinically manifest disease or even prior to motor manifestations.

Mild motor impairment as prodromal state in amyotrophic lateral sclerosis: a new diagnostic entity.

Amyotrophic lateral sclerosis, when viewed as a biological entity rather than a clinical syndrome, probably evolves along a continuum, with the initial clinically silent phase eventually evolving into clinically manifest amyotrophic lateral sclerosis. Since motor neuron degeneration is incremental and cumulative over time, it stands to reason that the clinical syndrome of amyotrophic lateral sclerosis is probably preceded by a prodromal state characterized by minor motor abnormalities that are initially insufficient to permit a diagnosis of amyotrophic lateral sclerosis. This prodromal period, however, is usually missed, given the invariably long delays between symptom onset and diagnostic evaluation. The Pre-Symptomatic Familial ALS Study, a cohort study of pre-symptomatic gene mutation carriers, offers a unique opportunity to observe what is typically unseen. Here we describe the clinical characterization of 20 pre-symptomatic mutation carriers (in SOD1, FUS and C9orf72) whose phenoconversion to clinically manifest disease has been prospectively studied. In so doing, we observed a prodromal phase of mild motor impairment in 11 of 20 phenoconverters. Among the n = 12 SOD1 A4V mutation carriers, phenoconversion was characterized by abrupt onset of weakness, with a short (1-3.5 months) prodromal period observable in a small minority (n = 3); the observable prodrome invariably involved the lower motor neuron axis. By contrast, in all n = 3 SOD1 I113T mutation carriers, diffuse lower motor neuron and upper motor neuron signs evolved insidiously during a prodromal period that extended over a period of many years; prodromal manifestations eventually coalesced into a clinical syndrome that is recognizable as amyotrophic lateral sclerosis. Similarly, in all n = 3 C9orf72 hexanucleotide repeat expansion mutation carriers, focal or multifocal manifestations of disease evolved gradually over a prodromal period of 1-2 years. Clinically manifest ALS also emerged following a prodromal period of mild motor impairment, lasting >4 years and ∼9 months, respectively, in n = 2 with other gene mutations (SOD1 L106V and FUS c.521del6). On the basis of this empirical evidence, we conclude that mild motor impairment is an observable state that precedes clinically manifest disease in three of the most common genetic forms of amyotrophic lateral sclerosis (SOD1, FUS, C9orf72), and perhaps in all genetic amyotrophic lateral sclerosis; we also propose that this might be true of non-genetic amyotrophic lateral sclerosis. As a diagnostic label, mild motor impairment provides the language to describe the indeterminate (and sometimes intermediate) transition between the unaffected state and clinically manifest amyotrophic lateral sclerosis. Recognizing mild motor impairment as a distinct clinical entity should generate fresh urgency for developing biomarkers reflecting the earliest events in the degenerative cascade, with potential to reduce the diagnostic delay and to permit earlier therapeutic intervention.

Preventing amyotrophic lateral sclerosis: insights from pre-symptomatic neurodegenerative diseases.

Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic lateral sclerosis. While much is still unknown, advances in other neurodegenerative diseases offer valuable insights. Indeed, it is increasingly clear that the well-recognized clinical syndromes of Alzheimer's disease, Parkinson's disease, Huntington's disease, spinal muscular atrophy and frontotemporal dementia are also each preceded by a pre-symptomatic or prodromal period of varying duration, during which the underlying disease process unfolds, with associated compensatory changes and loss of inherent system redundancy. Key insights from these diseases highlight opportunities for discovery in amyotrophic lateral sclerosis. The development of biomarkers reflecting amyloid and tau has led to a shift in defining Alzheimer's disease based on inferred underlying histopathology. Parkinson's disease is unique among neurodegenerative diseases in the number and diversity of non-genetic biomarkers of pre-symptomatic disease, most notably REM sleep behaviour disorder. Huntington's disease benefits from an ability to predict the likely timing of clinically manifest disease based on age and CAG-repeat length alongside reliable neuroimaging markers of atrophy. Spinal muscular atrophy clinical trials have highlighted the transformational value of early therapeutic intervention, and studies in frontotemporal dementia illustrate the differential role of biomarkers based on genotype. Similar advances in amyotrophic lateral sclerosis would transform our understanding of key events in pathogenesis, thereby dramatically accelerating progress towards disease prevention. Deciphering the biology of pre-symptomatic amyotrophic lateral sclerosis relies on a clear conceptual framework for defining the earliest stages of disease. Clinically manifest amyotrophic lateral sclerosis may emerge abruptly, especially among those who harbour genetic mutations associated with rapidly progressive amyotrophic lateral sclerosis. However, the disease may also evolve more gradually, revealing a prodromal period of mild motor impairment preceding phenoconversion to clinically manifest disease. Similarly, cognitive and behavioural impairment, when present, may emerge gradually, evolving through a prodromal period of mild cognitive impairment or mild behavioural impairment before progression to amyotrophic lateral sclerosis. Biomarkers are critically important to studying pre-symptomatic amyotrophic lateral sclerosis and essential to efforts to intervene therapeutically before clinically manifest disease emerges. The use of non-genetic biomarkers, however, presents challenges related to counselling, informed consent, communication of results and limited protections afforded by existing legislation. Experiences from pre-symptomatic genetic testing and counselling, and the legal protections against discrimination based on genetic data, may serve as a guide. Building on what we have learned-more broadly from other pre-symptomatic neurodegenerative diseases and specifically from amyotrophic lateral sclerosis gene mutation carriers-we present a road map to early intervention, and perhaps even disease prevention, for all forms of amyotrophic lateral sclerosis.

Cilostazol for Secondary Prevention of Stroke and Cognitive Decline: Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: Cilostazol, a phosphodiesterase 3' inhibitor, is used in Asia-Pacific countries for stroke prevention, but rarely used elsewhere. In addition to weak antiplatelet effects, it stabilizes endothelium, aids myelin repair and astrocyte-neuron energy transfer in laboratory models, effects that may be beneficial in preventing small vessel disease progression. METHODS: A systematic review and meta-analysis of unconfounded randomized controlled trials of cilostazol to prevent stroke, cognitive decline, or radiological small vessel disease lesion progression. Two reviewers searched for papers (January 1, 2019 to July 16, 2019) and extracted data. We calculated Peto odds ratios (ORs) and 95% CIs for recurrent ischemic, hemorrhagic stroke, death, adverse symptoms, with sensitivity analyses. The review is registered (CRD42018084742). RESULTS: We included 20 randomized controlled trials (n=10 505), 18 in ischemic stroke (total n=10 449) and 2 in cognitive impairment (n=56); most were performed in Asia-Pacific countries. Cilostazol decreased recurrent ischemic stroke (17 trials, n=10 225, OR=0.68 [95% CI, 0.57-0.81]; P<0.0001), hemorrhagic stroke (16 trials, n=9736, OR=0.43 [95% CI, 0.29-0.64]; P=0.0001), deaths (OR=0.64 [95% CI, 0.49-0.83], P<0.0009), systemic bleeding (n=8387, OR=0.73 [95% CI, 0.54-0.99]; P=0.04), but increased headache and palpitations, compared with placebo, aspirin, or clopidogrel. Cilostazol reduced recurrent ischemic stroke more when given long (>6 months) versus short term without increasing hemorrhage, and in trials with larger proportions (>40%) of lacunar stroke. Data were insufficient to assess effects on cognition, imaging, functional outcomes, or tolerance. CONCLUSIONS: Cilostazol appears effective for long-term secondary stroke prevention without increasing hemorrhage risk. However, most trials related to Asia-Pacific patients and more trials in Western countries should assess its effects on cognitive decline, functional outcome, and tolerance, particularly in lacunar stroke and other presentations of small vessel disease.

Relationship between neuropsychiatric disorders and cognitive and behavioural change in MND.

OBJECTIVE: In this population-based study, we aimed to determine whether neuropsychiatric history, medication or family history of neuropsychiatric disorders predicted cognitive and/or behavioural impairment in motor neuron disease (MND). METHODS: People with MND (pwMND) on the Scottish Clinical, Audit, Research and Evaluation of MND (CARE-MND) register, diagnosed from January 2015 to January 2018, with cognitive and/or behavioural data measured using the Edinburgh Cognitive and Behavioural ALS Screen were included. Data were extracted on patient neuropsychiatric, medication and family history of neuropsychiatric disorders. We identified patients with cognitive impairment (motor neuron disease with cognitive impairment (MNDci)), behavioural impairment (motor neuron disease with behavioural impairment (MNDbi), both (motor neuron disease with cognitive and behavioural impairment (MNDcbi)) or motor neuron disease-frontotemporal dementia (MND-FTD). RESULTS: Data were available for 305 pwMND (mean age at diagnosis=62.26 years, SD=11.40), of which 60 (19.7%) had a neuropsychiatric disorder. A family history of neuropsychiatric disorders was present in 36/231 (15.58%) of patients. Patient premorbid mood disorders were associated with increased apathy (OR=2.78, 95% CI 1.083 to 7.169). A family history of any neuropsychiatric disorder was associated with poorer visuospatial scores, MNDbi (OR=3.14, 95% CI 1.09 to 8.99) and MND-FTD (OR=5.08, 95% CI 1.26 to 20.40). A family history of mood disorders was associated with poorer overall cognition (exp(b)=0.725, p=0.026), language, verbal fluency and visuospatial scores, and MND-FTD (OR=7.57, 95% CI 1.55 to 46.87). A family history of neurotic disorders was associated with poorer language (exp(b)=0.362, p<0.001), visuospatial scores (exp(b)=0.625, p<0.009) and MND-FTD (OR=13.75, 95% CI 1.71 to 110.86). CONCLUSION: Neuropsychiatric disorders in patients and their families are associated with cognitive and behavioural changes post-MND diagnosis, with many occurring independently of MND-FTD and C9orf72 status. These findings support an overlap between MND, frontotemporal dementia and neuropsychiatric disorders, particularly mood disorders.

Functional, cognitive and physical outcomes 3 years after minor lacunar or cortical ischaemic stroke.

OBJECTIVE: Many studies examining stroke outcomes focus on more severe strokes or have short follow-up periods, so the long-term outcomes post-minor ischaemic stroke are unclear. METHODS: We recruited participants from inpatient and outpatient services with a lacunar or minor cortical ischaemic stroke (National Institutes of Health Stroke Scale score <8) and assessed current and premorbid cognitive functioning (Addenbrooke's Cognitive Examination-Revised (ACE-R), National Adult Reading Test (NART)), physical functioning (Timed Get Up and Go (TUG), 9-Hole Peg Test (9HPT)), dependency (modified Rankin Scale (mRS)), depression (Beck's Depression Inventory) in-person and remotely (Stroke Impact Scale). RESULTS: We followed up 224/264 participants at 3 years (mean age at index stroke=67, 126 (56%) men, 25 non-contactable, 15 declined): 66/151 (44%) had cognitive impairment, mean ACE-R 88 (SD 9, range 54-100/100), 61/156 (39%) had depression and 26/223 (12%) were dependent (mRS=3-5). Cognitive impairment at 3 years affected all ACE-R subdomains and was associated with ACE-R 1 year (ß=1.054, p<0.001) and NART (ß=1.023, p<0.05). Poor physical function was associated with stroke severity (TUG, ß=1.064, p<0.01) and recurrent stroke (9HPT, ß=1.130, p<0.05 right, ß=1.214, p<0.05 left). Higher ACE-R scores were associated with faster TUG (ß=-0.279, p<0.05) and 9HPT (right ß=-0.257, p<0.05; left ß=-0.302, p=0.05) and inversely with dependency (mRS=3-5, OR 0.88, 95% CI 0.80 to 0.97). We adjusted analyses for demographic, stroke and known risk factors. In-person and remote assessments were highly correlated. CONCLUSIONS: Cognitive, physical impairments and depression are common and interrelated 3 years after minor stroke. Cognitive and physical impairments require rehabilitation after minor stroke and argue for better integration of stroke and dementia services.

Education, Socioeconomic Status, and Intelligence in Childhood and Stroke Risk in Later Life: A Meta-analysis.

BACKGROUND: Stroke is the second most common cause of death, and a common cause of dependency and dementia. Adult vascular risk factors and socioeconomic status (SES) are associated with increased risk, but less is known about early life risk factors, such as education, childhood SES, or intelligence (IQ). METHODS: We comprehensively searched Medline, PsycINFO, and EMBASE from inception to November 2015. We included all studies reporting data on >50 strokes examining childhood/premorbid IQ, SES, and education. Two reviewers independently screened full texts and extracted and cross-checked data, including available risk factor adjustments. We meta-analyzed stroke risk using hazard ratios (HR), odds ratios (OR), and mean differences (MD). We tested effects of study and participant characteristics in sensitivity analyses and meta-regression, and assessed heterogeneity and publication bias. RESULTS: We identified 90 studies examining stroke risk and education (79), SES (10), or IQ (nine) including approximately 164,683 stroke and over 5 million stroke-free participants. Stroke risk increased with lower education (OR = 1.35, 95% CI = 1.24, 1.48), SES (OR = 1.28, 95% CI = 1.12, 1.46), and IQ (HR = 1.17, 95% CI = 1.00, 1.37) in studies reporting point estimates, with similar associations for MD. We found minimal publication bias. Between-study heterogeneity was partly explained by participant age and case ascertainment method. CONCLUSIONS: Education, childhood SES, and intelligence have modest but important associations with lifetime stroke, and hence dementia, risks. Future studies distinguishing between the individual and combined effects of education, childhood SES and intelligence are needed to determine the independent contribution of each factor to stroke risk. See video abstract at, http://links.lww.com/EDE/B210.

Development, reliability, validity, and acceptability of the remote administration of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS).

BACKGROUND: ALS clinical care and research has changed dramatically since the COVID-19 pandemic, accelerating the need for cognitive assessments to be adapted for remote use. OBJECTIVES: To develop the remote administration method of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS), and determine its reliability and validity. Methods: The validation process consisted of: (1) Two versions of the ECAS (A and B) were administered, one in-person and one remotely via video call in a randomized order to 27 people without ALS; (2) The ECAS was administered remotely to 24 pwALS, with a second rater independently scoring performance; and (3) Acceptability was assessed by gathering feedback from 17 pwALS and 19 clinicians and researchers about their experience of using the ECAS remotely. RESULTS: In the group without ALS, the remote and in-person ECAS total scores were found to be equivalent, and a Bland-Altman plot showed good agreement between the two administration methods. In pwALS, there was excellent agreement between two raters (ICC = 0.99). Positive feedback was gained from pwALS, researchers and clinicians with regards to ease of process, convenience, time, and the environment. CONCLUSIONS: These findings provide evidence of the reliability and validity of the remote administration of the ECAS for pwALS, with clinicians, researchers and pwALS viewing it as a good alternative to face-to-face administration.

The Miami Framework for ALS and related neurodegenerative disorders: an integrated view of phenotype and biology.

Increasing appreciation of the phenotypic and biological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, alongside evolving biomarker evidence for a pre-symptomatic stage of disease and observations that this stage of disease might not always be clinically silent, is challenging traditional views of these disorders. These advances have highlighted the need to adapt ingrained notions of these clinical syndromes to include both the full phenotypic continuum - from clinically silent, to prodromal, to clinically manifest - and the expanded phenotypic spectrum that includes ALS, frontotemporal dementia and some movement disorders. The updated clinical paradigms should also align with our understanding of the biology of these disorders, reflected in measurable biomarkers. The Miami Framework, emerging from discussions at the Second International Pre-Symptomatic ALS Workshop in Miami (February 2023; a full list of attendees and their affiliations appears in the Supplementary Information) proposes a classification system built on: first, three parallel phenotypic axes - motor neuron, frontotemporal and extrapyramidal - rather than the unitary approach of combining all phenotypic elements into a single clinical entity; and second, biomarkers that reflect different aspects of the underlying pathology and biology of neurodegeneration. This framework decouples clinical syndromes from biomarker evidence of disease and builds on experiences from other neurodegenerative diseases to offer a unified approach to specifying the pleiotropic clinical manifestations of disease and describing the trajectory of emergent biomarkers.

Cognitive and neuropsychiatric endophenotypes in amyotrophic lateral sclerosis.

First- and second-degree relatives of people with amyotrophic lateral sclerosis report higher rates of neuropsychiatric disorders, indicating that risk genes may be pleiotropic, causing multiple phenotypes within kindreds. Such phenotypes may constitute a disease endophenotype that associates with disease liability. We have directly investigated cognitive functioning and neuropsychiatric traits among relatives of people with amyotrophic lateral sclerosis to identify potential endophenotypes of the disease. In a family-based, cross-sectional study design, first- and second-degree relatives of people with amyotrophic lateral sclerosis (n = 149) were compared to controls (n = 60) using an in-depth neuropsychological and neuropsychiatric assessment. Subgroup analyses examined the effect of family history and C9orf72 repeat expansion status (n = 16 positive carriers). Relatives of people with amyotrophic lateral sclerosis had lower scores on executive functioning, language and memory tasks compared to controls, with large effect sizes observed on object naming (d = 0.91, P = 0.00001) and phonemic verbal fluency (d = 0.81, P = 0.0003). Relatives also had higher autism quotient attention to detail traits (d = -0.52, P = 0.005), lower conscientiousness (d = 0.57, P = 0.003) and lower openness to experience personality traits (d = 0.54, P = 0.01) than controls. These effects were typically larger in relatives of people with familial, rather than sporadic, amyotrophic lateral sclerosis and were present in both gene carrier and non-carrier relatives of probands with a C9orf72 repeat expansion. Poorer phonemic fluency and object naming, along with autism and personality traits, are more frequent in relatives of people with amyotrophic lateral sclerosis. Among kindreds carrying the C9orf72 repeat expansion, these traits were identified in relatives regardless of their carrier status, suggesting the presence of a disease-associated endophenotype that is not exclusively mediated by the C9orf72 expansion.

Impact of Small Vessel Disease Progression on Long-term Cognitive and Functional Changes After Stroke.

BACKGROUND AND OBJECTIVES: The severity of white matter hyperintensities (WMH) at presentation with stroke is associated with poststroke dementia and dependency. However, WMH can decrease or increase after stroke; prediction of cognitive decline is imprecise; and there are few data assessing longitudinal interrelationships among changing WMH, cognition, and function after stroke, despite the clinical importance. METHODS: We recruited patients within 3 months of a minor ischemic stroke, defined as NIH Stroke Scale (NIHSS) score <8 and not expected to result in a modified Rankin Scale (mRS) score >2. Participants repeated MRI at 1 year and cognitive and mRS assessments at 1 and 3 years. We ran longitudinal mixed-effects models assessing change in Addenbrooke's Cognitive Examination-Revised (ACE-R) and mRS scores. For mRS score, we assessed longitudinal WMH volumes (cube root; percentage intracranial volume [ICV]), adjusting for age, NIHSS score, ACE-R, stroke subtype, and time to assessment. For ACE-R score, we additionally adjusted for ICV, mRS, premorbid IQ, and vascular risk factors. We then used a multivariate model to jointly assess changing cognition/mRS score, adjusted for prognostic variables, using all available data. RESULTS: We recruited 264 patients; mean age was 66.9 (SD 11.8) years; 41.7% were female; and median mRS score was 1 (interquartile range 1-2). One year after stroke, normalized WMH volumes were associated more strongly with 1-year ACE-R score (ß = -0.259, 95% CI -0.407 to -0.111 more WMH per 1-point ACE-R decrease, p = 0.001) compared to subacute WMH volumes and ACE-R score (ß = 0.105, 95% CI -0.265 to 0.054, p = 0.195). Three-year mRS score was associated with 3-year ACE-R score (ß = -0.272, 95% CI -0.429 to -0.115, p = 0.001). Combined change in baseline-1-year jointly assessed ACE-R/mRS scores was associated with fluctuating WMH volumes (F = 9.3, p = 0.03). DISCUSSION: After stroke, fluctuating WMH mean that 1-year, but not baseline, WMH volumes are associated strongly with contemporaneous cognitive scores. Covarying longitudinal decline in cognition and independence after stroke, central to dementia diagnosis, is associated with increasing WMH volumes.

Stability of Estimated Premorbid Cognitive Ability over Time after Minor Stroke and Its Relationship with Post-Stroke Cognitive Ability.

Considering premorbid or "peak" adult intelligence (IQ) is important when examining post-stroke cognition. The stability of estimated premorbid IQ and its relationship to current cognitive ability in stroke is unknown. We investigated changes in estimated premorbid IQ and current cognitive ability up to three years post-stroke. Minor stroke patients (NIHSS < 8) were assessed at one to three months, one and three years' post-stroke. The National Adult Reading Test (NART) and Addenbrooke's Cognitive Examination-Revised (ACE-R) were used to estimate premorbid IQ (NART IQ) and current cognitive ability respectively at each time-point. Baseline demographics, vascular and stroke characteristics were included. Of the 264 patients recruited (mean age 66), 158 (60%), 151 (57%), and 153 (58%) completed cognitive testing at each time-point respectively. NART IQ initially increased (mean difference (MD) = 1.32, 95% CI = 0.54 to 2.13, p < 0.001) before decreasing (MD = -4.269, 95% CI = -5.12 to -3.41, p < 0.001). ACE-R scores initially remained stable (MD = 0.29, 95% CI = -0.49 to 1.07, p > 0.05) before decreasing (MD = -1.05, 95% CI = -2.08 to -0.01, p < 0.05). Adjusting for baseline variables did not change the relationship between NART IQ and ACE-R with time. Increases in NART IQ were associated with more education. For ACE-R, older age was associated with declines, and higher NART IQ and more education was associated with increases. Across 3 years, we observed fluctuations in estimated premorbid IQ and minor changes in current cognitive ability. Future research should aim to identify variables associated with these changes. However, studies of post-stroke cognition should account for premorbid IQ.

Cognitive ability, education and socioeconomic status in childhood and risk of post-stroke depression in later life: A systematic review and meta-analysis.

BACKGROUND: Depression after stroke is common and is associated with poorer recovery. Risk factors such as gender, age and stroke severity are established, but it is unclear whether factors from earlier in life might also contribute. METHODS: We searched MEDLINE, PsycINFO, EMBASE and meta-analysed all available evidence on childhood (premorbid) IQ, socioeconomic status (SES), education and stroke in adulthood. We included all studies reporting data on >50 patients, calculating overall odds ratios (OR), mean difference, correlation, 95% confidence intervals (CI) and 95% predictive intervals (PI) using random effects methods. We quality assessed all studies, performed sensitivity analyses, assessed heterogeneity and publication bias. RESULTS: We identified 33 studies including 2,664 participants with post-stroke depression and 5,460 without (314 participants not classified). Low education (< = 8 years) was associated with post-stroke depression in studies which defined depression as score of mild and above on a depression rating scale (OR 1.47 95% CI 1.10-1.97, p<0.01) but not in studies where depression was defined as severe depressive symptoms or a clinical diagnosis of major depression (OR 1.04 95% CI 0.90-1.31, p = 0.60). Low education was not associated with an increased risk for post-stroke depression in studies that adjusted for age and sex (OR 0.86 95% CI 0.50-1.48 p = 0.58). Those with post-stroke depression had fewer years of education than those without post-stroke depression (MD 0.68 95% CI 0.05-1.31 p = 0.04). Few studies adjusted for vascular risk factors or stroke severity. Heterogeneity between studies was moderate and was partly explained by severity of depression. In the one study identified premorbid IQ did not differ between those with post-stroke depression (mean IQ 10.1.8 SD 9.8) vs those without (mean IQ 104 SD 10.1). There were no studies that examined childhood socioeconomic status and risk of post-stroke depression. CONCLUSIONS: Having less education is associated with an increased risk of post-stroke depressive symptoms but with large confidence intervals and heterogeneity. Future studies should explore the relationship between early and late life risk factors to improve risk identification and to target prevention and treatment strategies.

The relation between total cerebral small vessel disease burden and gait impairment in patients with minor stroke.

Background and aims Individual MRI markers of cerebral small vessel disease are associated with gait impairment. The impact of total cerebral small vessel disease-related brain damage, expressed by a cerebral small vessel disease MRI burden score, on mobility after stroke, has not been considered, although this score gives a better representation of the overall effect of cerebral small vessel disease on the brain. We determined if the total cerebral small vessel disease burden is associated with gait impairment three years after minor stroke. Methods In total, 200 patients with minor lacunar or non-lacunar stroke (NIHSS ≤ 7) underwent a brain MRI at presentation. Presence of lacunes, white matter hyperintensities, cerebral microbleeds, and perivascular spaces were summed in a total cerebral small vessel disease MRI burden score (range 0-4). Gait disturbances, measured by timed-up-and-go test and self-reported stroke impact scale mobility domain were assessed three years after stroke. We tested associations adjusted for key variables by linear regression analysis. Results Total cerebral small vessel disease burden was not associated with gait impairment after minor stroke in all patients, nor in lacunar stroke patients ( n = 87). In non-lacunar stroke patients ( n = 113), total cerebral small vessel disease burden was associated with lower stroke impact scale mobility domain scores, independent of age, vascular risk factors, and stroke severity (unstandardized B -4.61; 95% CI -8.42; -0.79, p < 0.05). Conclusion Patients with non-lacunar stroke and a higher total cerebral small vessel disease burden have more subjective mobility impairment three years after stroke. The total cerebral small vessel disease MRI burden score is a possible marker to identify patients at risk for subjective gait impairment. These findings should be confirmed in larger studies.

Early life risk factors for cerebrovascular disease: A systematic review and meta-analysis.

OBJECTIVE: Cerebrovascular disease (CVD) causes subclinical brain vascular lesions detected using neuroimaging and childhood factors may increase later CVD risk. METHODS: We searched MEDLINE, PsycINFO, and EMBASE, and meta-analyzed all available evidence on childhood (premorbid) IQ, socioeconomic status (SES), education, and subclinical CVD in later life. Overall odds ratios (OR), mean difference or correlation, and 95% confidence intervals (CIs) were calculated using random effects methods. RESULTS: We identified 30 relevant studies (n = 22,890). Lower childhood IQ and lower childhood SES were associated with more white matter hyperintensities (WMH) (IQ: n = 1,512, r = -0.07, 95% CI -0.12 to -0.02, p = 0.007; SES: n = 243, deep WMH r = -0.18, periventricular WMH r = -0.146). Fewer years of education were associated with several CVD markers (n = 15,439, OR = 1.17, 95% CI 1.05 to 1.31, p = 0.003). No studies assessed early life factors combined. CONCLUSIONS: Childhood IQ, SES, and education are associated with increased risk of CVD on neuroimaging in later life. Further studies are required to provide further evidence and thereby inform policy.

Early life characteristics and late life burden of cerebral small vessel disease in the Lothian Birth Cohort 1936.

It is unknown whether relations between early-life factors and overall health in later life apply to burden of cerebral small vessel disease (cSVD), a major cause of stroke and dementia. We explored relations between early-life factors and cSVD in the Lothian Birth Cohort, a healthy aging cohort. Participants were recruited at age 70 (N = 1091); most had completed a test of cognitive ability at age 11 as part of the Scottish Mental Survey of 1947. Of those, 700 participants had brain MRI that could be rated for cSVD conducted at age 73. Presence of lacunes, white matter hyperintensities, microbleeds, and perivascular spaces were summed in a score of 0-4 representing all MRI cSVD features. We tested associations with early-life factors using multivariate logistic regression. Greater SVD score was significantly associated with lower age-11 IQ (OR higher SVD score per SD age-11 IQ = .78, 95%CI 0.65-.95, p=.01). The associations between SVD score and own job class (OR higher job class, .64 95%CI .43-.95, p=.03), age-11 deprivation index (OR per point deprivation score, 1.08, 95%CI 1.00-1.17, p=.04), and education (OR some qualifying education, .60 95%CI .37-.98, p=.04) trended towards significance (p<.05 for all) but did not meet thresholds for multiple testing. No early-life factor was significantly associated with any one individual score component. Early-life factors may contribute to age-73 burden of cSVD. These relations, and the potential for early social interventions to improve brain health, deserve further study.