Prediction of poor clinical outcome in vascular cognitive impairment: TRACE-VCI study

Introduction: Prognostication in memory clinic patients with vascular brain injury (eg possible vascular cognitive impairment [VCI]) is often uncertain. We created a risk score to predict poor clinical outcome. Methods: Using data from two longitudinal cohorts of memory clinic patients with vascular brain injury without advanced dementia, we created (n = 707) and validated (n = 235) the risk score. Poor clinical outcome was defined as substantial cognitive decline (change of Clinical Dementia Rating ≥1 or institutionalization) or major vascular events or death. Twenty-four candidate predictors were evaluated using Cox proportional hazard models. Results: Age, clinical syndrome diagnosis, Disability Assessment for Dementia, Neuropsychiatric Inventory, and medial temporal lobe atrophy most strongly predicted poor outcome and constituted the risk score (C-statistic 0.71; validation cohort 0.78). Of note, none of the vascular predictors were retained in this model. The 2-year risk of poor outcome was 6.5% for the lowest (0-5) and 55.4% for the highest sum scores (10-13). Discussion: This is the first, validated, prediction score for 2-year clinical outcome of patients with possible VCI

Neuropsychiatric symptoms in patients with possible vascular cognitive impairment, does sex matter?

Background: Neuropsychiatric symptoms (NPS) are common in patients with vascular cognitive impairment (VCI). We aimed to establish sex differences in the manifestation of NPS in memory clinic patients with possible VCI and identify which NPS are determinants of clinical progression in women and men separately. Methods: We included 718 memory clinic patients (age 68 ± 8; 45% women) with cognitive complaints and vascular brain lesions on MRI (i.e. possible VCI). NPS were measured using the 12-item Neuropsychiatric Inventory. Clinical progression after two years (women 18%, men 14%) was defined as increase in CDR ≥1 or institutionalization (available n = 589 without advanced dementia at baseline). The association between NPS and clinical progression was assessed with Cox proportional hazard models stratified by sex, adjusted for age and clinical diagnosis and in a second model additionally for manifestations of vascular brain lesions. Results: Men more often presented with agitation (29% versus 17%, p<.05) and irritability (58% versus 45%, p<.05), the other 10 NPS (delusions, hallucinations, depression, anxiety, euphoria, apathy, disinhibition, aberrant motor behavior, nighttime disturbances and appetite & eating abnormalities) did not differ between sexes. In women the presence of apathy (HR 2.1[1.1;4.3]) was associated with higher risk of clinical progression. In men the presence of depression (HR 2.7[1.4;5.1]) and aberrant motor behavior (HR 2.1[1.1;3.8]) were associated with increased risk of clinical progression. Conclusion: Manifestations of NPS in patients with possible VCI differ by sex. Different NPS are associated with future clinical progression in men and women. Management strategies of NPS could benefit from sex-specific approaches

Neuropsychiatric Symptoms as Predictor of Poor Clinical Outcome in Patients With Vascular Cognitive Impairment

OBJECTIVE: Examine the association between neuropsychiatric symptoms (NPS) and clinical outcome in memory clinic patients with vascular brain injury. DESIGN/SETTING: TRACE-VCI prospective memory clinic cohort with follow-up (2.1 ± 0.5 years). PARTICIPANTS: Five hundred and seventy-five memory clinic patients with vascular brain injury on MRI (i.e. possible Vascular Cognitive Impairment [VCI]). Severity of cognitive impairment ranged from no objective cognitive impairment to mild cognitive impairment (MCI) and dementia. MEASUREMENTS: We used Neuropsychiatric Inventory (total score and score on hyperactive, psychotic, affective, and apathetic behavior domains) to measure NPS. We assessed the association between NPS and institutionalization, mortality and cognitive deterioration (increase ≥0.5 on Clinical Dementia Rating scale) with Cox proportional hazards models and logistic regression analyses. RESULTS: NPS were present in 89% of all patients, most commonly in the hyperactive and apathetic behavior domain. Across the whole cohort, affective behavior was associated with institutionalization (HR: 1.98 [1.01-3.87]), mainly driven by the dementia subgroup (HR: 2.06 [1.00-4.21]). Apathetic behavior was associated with mortality and cognitive deterioration (HR: 2.07 [1.10-3.90],OR: 1.67 [1.12-2.49], respectively), mainly driven by the MCI subgroup (HR: 4.93 [1.07-22.86],OR: 3.25 [1.46-7.24], respectively). Conversely, hyperactive behavior was related to lower mortality (HR: 0.54 [0.29-0.98]), again particularly driven by the MCI subgroup (HR:0.17 [0.04-0.75]). Psychotic behavior was associated with cognitive deterioration in patients with no objective cognitive impairment (OR: 3.10 [1.09-8.80]) and with institutionalization in MCI (HR: 12.45 [1.28-121.14]). CONCLUSION: NPS are common and have prognostic value in memory clinic patients with possible VCI. This prognostic value depends on the severity of cognitive impairment

Markers of amyloid-β deposition and burden of enlarged perivascular spaces in patients with cognitive impairment and small vessel disease

MRI-visible enlarged perivascular spaces (EPVS) are common in patients with cognitive impairment and possibly linked to Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). In a study of memory clinic patients (n = 450; mean age 66.5 ± 7.45, 45.8% female), we investigated CSF amyloid-β (Aβ)1–42 (AD biomarker) and strictly lobar microbleeds (CAA marker) in relation to centrum semiovale EPVS (CSO-EPVS). Age-controlled analyses showed that severe CSO-EPVS associated with Aβ status (odds ratio [OR] = 1.51, 95%CI = 1.02–2.24), but not strictly lobar microbleeds (OR = 1.39, 95%CI = 0.92–2.11), with no significant Aβ status and microbleeds interaction. This implies that in this setting, severe CSO-EPVS is not a specific indicator of CAA

Vascular Cognitive Impairment and cognitive decline; a longitudinal study comparing different types of vascular brain injury - The TRACE-VCI study

Background: Little is known about the trajectories of cognitive decline in relation to different types of vascular brain injury in patients presenting at a memory clinic with Vascular Cognitive Impairment (VCI). / Methods: We included 472 memory clinic patients (age 68 (±8.2) years, 44% female, MMSE 25.9 (±2.8), 210 (44.5%) dementia) from the prospective TRACE-VCI cohort study with possible VCI, defined as cognitive complaints and vascular brain injury on MRI and at least 1 follow-up cognitive assessment (follow-up time 2.5 (±1.4) years, n = 1172 assessments). Types of vascular brain injury considered lacune(s) (≥1; n = 108 patients (23%)), non-lacunar infarct(s) (≥1; n = 54 (11%)), white matter hyperintensities (WMH) (none/mild versus moderate/severe (n = 211 patients (45%)) and microbleed(s) (≥1; n = 202 patients (43%)). We assessed cognitive functioning at baseline and follow-up, including the Rey Auditory Verbal Learning Test (RAVLT), Trail Making Test (TMT) A and B, category naming task and MMSE. The association of different types of vascular brain injury with cognitive decline was evaluated with linear mixed models, including one type of vascular brain injury (dichotomized), time and vascular brain injury*time, adjusted for sex, age, dementia status (yes/no), education (Verhage scale) and medial temporal lobe atrophy (MTA) score (dichotomized as ≥ 1.5). / Results: Across the population, performance declined over time on all tests. Linear mixed models showed that lacune(s) were associated with worse baseline TMTA (Beta(SE)) (8.3 (3.8), p = .03) and TMTB (25.6 (10.3), p = .01), albeit with a slower rate of decline on MMSE, RAVLT and category naming. By contrast, patients with non-lacunar infarct(s) showed a steeper rate of decline on TMTB (29.6 (7.7), p = .00), mainly attributable to patients with dementia (62.9 (15.5), p = .00). / Conclusion: Although different types of vascular brain injury have different etiologies and different patterns, they show little differences in cognitive trajectories depending on type of vascular brain injury

Small vessel disease lesion type and brain atrophy: The role of co‐occurring amyloid

Introduction: It is unknown whether different types of small vessel disease (SVD), differentially relate to brain atrophy and if co‐occurring Alzheimer's disease pathology affects this relation. / Methods: In 725 memory clinic patients with SVD (mean age 67 ± 8 years, 48% female) we compared brain volumes of those with moderate/severe white matter hyperintensities (WMHs; n = 326), lacunes (n = 132) and cerebral microbleeds (n = 321) to a reference group with mild WMHs (n = 197), also considering cerebrospinal fluid (CSF) amyloid status in a subset of patients (n = 488). / Results: WMHs and lacunes, but not cerebral microbleeds, were associated with smaller gray matter (GM) volumes. In analyses stratified by CSF amyloid status, WMHs and lacunes were associated with smaller total brain and GM volumes only in amyloid‐negative patients. SVD‐related atrophy was most evident in frontal (cortical) GM, again predominantly in amyloid‐negative patients. / Discussion: Amyloid status modifies the differential relation between SVD lesion type and brain atrophy in memory clinic patients

Cerebral amyloid burden is associated with white matter hyperintensity location in specific posterior white matter regions

White matter hyperintensities (WMHs) are a common manifestation of cerebral small vessel disease. WMHs are also frequently observed in patients with familial and sporadic Alzheimer's disease, often with a particular posterior predominance. Whether amyloid and tau pathologies are linked to WMH occurrence is still debated. We examined whether cerebral amyloid and tau burden, reflected in cerebrospinal fluid amyloid-beta 1-42 (Aβ-42) and phosphorylated tau (p-tau), are related to WMH location in a cohort of 517 memory clinic patients. Two lesion mapping techniques were performed: voxel-based analyses and region of interest-based linear regression. Voxelwise associations were found between lower Aβ-42 and parieto-occipital periventricular WMHs. Regression analyses demonstrated that lower Aβ-42 correlated with larger WMH volumes in the splenium of the corpus callosum and posterior thalamic radiation, also after controlling for markers of vascular disease. P-tau was not consistently related to WMH occurrence. Our findings indicate that cerebral amyloid burden is associated with WMHs located in specific posterior white matter regions, possibly reflecting region-specific effects of amyloid pathology on the white matter

Prediction of poor clinical outcome in vascular cognitive impairment: TRACE-VCI study

INTRODUCTION: Prognostication in memory clinic patients with vascular brain injury (eg possible vascular cognitive impairment [VCI]) is often uncertain. We created a risk score to predict poor clinical outcome. METHODS: Using data from two longitudinal cohorts of memory clinic patients with vascular brain injury without advanced dementia, we created (n = 707) and validated (n = 235) the risk score. Poor clinical outcome was defined as substantial cognitive decline (change of Clinical Dementia Rating ≥1 or institutionalization) or major vascular events or death. Twenty‐four candidate predictors were evaluated using Cox proportional hazard models. RESULTS: Age, clinical syndrome diagnosis, Disability Assessment for Dementia, Neuropsychiatric Inventory, and medial temporal lobe atrophy most strongly predicted poor outcome and constituted the risk score (C‐statistic 0.71; validation cohort 0.78). Of note, none of the vascular predictors were retained in this model. The 2‐year risk of poor outcome was 6.5% for the lowest (0‐5) and 55.4% for the highest sum scores (10‐13). DISCUSSION: This is the first, validated, prediction score for 2‐year clinical outcome of patients with possible VCI

The Clinical Phenotype of Vascular Cognitive Impairment in Patients with Type 2 Diabetes Mellitus

Background: Type 2 diabetes mellitus (T2DM) increases the risk of vascular cognitive impairment (VCI). It is unknown which type of vascular lesions and co-morbid etiologies, in particular Alzheimer’s disease pathology, are associated with T2DM in patients with VCI, and how this relates to cognition and prognosis. Objective: To compare brain MRI and cerebrospinal fluid (CSF) markers, cognition, and prognosis in patients with possible VCI with and without T2DM. Methods: We included 851 memory clinic patients with vascular brain injury on MRI (i.e., possible VCI) from a prospective cohort study (T2DM: n = 147, 68.4±7.9 years, 63% men; no T2DM: n = 704, 67.6±8.5 years, 52% men). At baseline, we assessed between-group differences in brain MRI abnormalities, CSF markers of Alzheimer’s disease, and cognitive profile. After two years follow-up, we compared occurrence of cognitive decline, stroke, and death. Results: The distribution of clinical diagnoses did not differ between patients with and without T2DM. T2DM patients had more pronounced brain atrophy (total and white matter volume), and more lacunar infarcts, whereas microbleeds were less common (all p < 0.05). CSF amyloid-β levels were similar between the groups. T2DM patients performed worse on working memory (effect size: – 0.17, p = 0.03) than those without, whereas performance on other domains was similar. During follow-up, risk of further cognitive decline was not increased in T2DM.∥Conclusion: In patients with possible VCI, presence of T2DM is related to more pronounced brain atrophy and a higher burden of lacunar infarcts, but T2DM does not have a major impact on cognitive profile or prognosis

Clinical relevance of acute cerebral microinfarcts in vascular cognitive impairment

ObjectiveTo determine the occurrence of acute cerebral microinfarcts (ACMIs) in memory clinic patients and relate their presence to vascular risk and cognitive profile, CSF and neuroimaging markers, and clinical outcome.MethodsThe TRACE-VCI study is a memory clinic cohort of patients with vascular brain injury on MRI (i.e., possible vascular cognitive impairment [VCI]). We included 783 patients (mean age 67.6 ± 8.5, 46% female) with available 3T diffusion-weighted imaging (DWI). ACMIs were defined as supratentorial DWI hyperintensities <5 mm with a corresponding hypo/isointense apparent diffusion coefficient signal and iso/hyperintense T2-weighted signal.ResultsA total of 23 ACMIs were found in 16 of the 783 patients (2.0%). Patients with ACMIs did not differ in vascular risk or cognitive profile, but were more often diagnosed with vascular dementia (odds ratio [OR] 5.1; 95% confidence interval [CI] 1.4-18.9, p = 0.014). ACMI presence was associated with lower levels of β-amyloid (p < 0.004) and with vascular imaging markers (lacunar infarcts: OR 3.5, CI 1.3-9.6, p = 0.015; nonlacunar infarcts: OR 4.1, CI 1.4-12.5, p = 0.012; severe white matter hyperintensities: OR 4.8, CI 1.7-13.8, p = 0.004; microbleeds: OR 18.9, CI 2.5-144.0, p = 0.0001). After a median follow-up of 2.1 years, the risk of poor clinical outcome (composite of marked cognitive decline, major vascular event, death, and institutionalization) was increased among patients with ACMIs (hazard ratio 3.0; 1.4-6.0, p = 0.005).ConclusionIn patients with possible VCI, ACMI presence was associated with a high burden of cerebrovascular disease of both small and large vessel etiology and poor clinical outcome. ACMIs may thus be a novel marker of active vascular brain injury in these patients