Niels D. Prins

Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI

Aim/hypothesisType 2 diabetes increases the risk not only of vascular dementia but also of Alzheimer’s disease. The question remains whether diabetes increases the risk of Alzheimer’s disease by diabetic vasculopathy or whether diabetes influences directly the development of Alzheimer neuropathology. In vivo, hippocampal and amygdalar atrophy on brain MRI are good, early markers of the degree of Alzheimer neuropathology. We investigated the association between diabetes mellitus, insulin resistance and the degree of hippocampal and amygdalar atrophy on magnetic resonance imaging (MRI) accounting for vascular pathology.MethodsData was obtained in a population-based study of elderly subjects without dementia between 60 to 90 years of age. The presence of diabetes mellitus and, in non-diabetic subjects, insulin resistance was assessed for 506 participants in whom hippocampal and amygdalar volumes on MRI were measured. We assessed the degree of vascular morbidity by rating carotid atherosclerosis, and brain white matter lesions and infarcts on MRI.ResultsSubjects with diabetes mellitus had more hippocampal and amygdalar atrophy on MRI compared to subjects without diabetes mellitus. Furthermore, increasing insulin resistance was associated with more amygdalar atrophy on MRI. The associations were not due to vascular morbidity being more pronounced in persons with diabetes mellitus.Conclusions/interpretationType 2 diabetes is associated with hippocampal and amygdalar atrophy, regardless of vascular pathology. This could suggest that Type 2 diabetes directly influences the development of Alzheimer neuropathology.

Progression of Cerebral Small Vessel Disease in Relation to Risk Factors and Cognitive Consequences Rotterdam Scan Study

Background and Purpose— Cerebral white matter lesions and lacunar infarcts are small vessel disease-related lesions, which are associated with cognitive decline and dementia. We aimed to assess the relationship between risk factors, effect modifiers, and progression of these lesions. Furthermore, we studied the cognitive consequences of lesion progression. Methods— Six hundred sixty-eight people, aged 60 to 90 years, underwent repeated MRI scanning and neuropsychological testing within 3-year follow-up. We rated incident lacunar infarcts and change in periventricular and subcortical white matter lesion severity with a semiquantitative scale. We assessed the relationships between age, sex, baseline lesion load, risk factors, lesion progression, and change in cognitive function by multivariate regression analyses and additional stratified analyses. Results— Baseline lesion load, higher age, high blood pressure, and current smoking were independently associated with progression of white matter lesions. Women had more marked progression of subcortical white matter lesions and incident lacunar infarcts compared with men. Carotid atherosclerosis was associated with incident lacunar infarcts. Higher blood pressure did not contribute to lesion progression in people with already severe lesions at baseline nor in the very old. Lesion progression was associated with a paralleled decline in general cognitive function and in particular with a decreased information processing speed. Conclusions— Higher age, female sex, cigarette smoking, elevated blood pressure, and baseline lesion load were associated with small vessel disease progression. Age and baseline lesion load influenced the risk relations with blood pressure. Progression of small vessel disease was related to a paralleled decline in cognitive function.

C-Reactive Protein and Cerebral Small-Vessel Disease: The Rotterdam Scan Study

Background—Inflammatory processes are involved in the development and consequences of atherosclerosis. Whether these processes are also involved in cerebral small-vessel disease is unknown. Cerebral white matter lesions and lacunar brain infarcts are caused by small-vessel disease and are commonly observed on MRI scans in elderly people. These lesions are associated with an increased risk of stroke and dementia. We assessed whether higher C-reactive protein (CRP) levels were related to white matter lesion and lacunar infarcts. Methods and Results—We based our study on 1033 participants of the population-based Rotterdam Scan Study for whom complete data on CRP levels were available and who underwent brain MRI scanning. Subjects were 60 to 90 years of age and free of dementia at baseline. Six hundred thirty-six subjects had a second MRI scan on average 3.3 years later. We used multivariate regression models to assess the associations between CRP levels and markers of small-vessel disease. Higher CRP levels were associated with presence and progression of white matter lesions, particularly with marked lesion progression (ORs for highest versus lowest quartile of CRP 3.1 [95% CI 1.3 to 7.2] and 2.5 [95% CI 1.1 to 5.6] for periventricular and subcortical white matter lesion progression, respectively). These associations persisted after adjustment for cardiovascular risk factors and carotid atherosclerosis. Persons with higher CRP levels tended to have more prevalent and incident lacunar infarcts. Conclusions—Inflammatory processes may be involved in the pathogenesis of cerebral small-vessel disease, in particular, the development of white matter lesions.

White matter hyperintensities, cognitive impairment and dementia: an update

White matter hyperintensities (WMHs) in the brain are the consequence of cerebral small vessel disease, and can easily be detected on MRI. Over the past three decades, research has shown that the presence and extent of white matter hyperintense signals on MRI are important for clinical outcome, in terms of cognitive and functional impairment. Large, longitudinal population-based and hospital-based studies have confirmed a dose-dependent relationship between WMHs and clinical outcome, and have demonstrated a causal link between large confluent WMHs and dementia and disability. Adequate differential diagnostic assessment and management is of the utmost importance in any patient, but most notably those with incipient cognitive impairment. Novel imaging techniques such as diffusion tensor imaging might reveal subtle damage before it is visible on standard MRI. Even in Alzheimer disease, which is thought to be primarily caused by amyloid, vascular pathology, such as small vessel disease, may be of greater importance than amyloid itself in terms of influencing the disease course, especially in older individuals. Modification of risk factors for small vessel disease could be an important therapeutic goal, although evidence for effective interventions is still lacking. Here, we provide a timely Review on WMHs, including their relationship with cognitive decline and dementia.

Operational definitions for the NINDS-AIREN criteria for vascular dementia: an interobserver study.

Background and Purpose— Vascular dementia (VaD) is thought to be the most common cause of dementia after Alzheimer’s disease. The commonly used International Workshop of the National Institute of Neurological Disorders and Stroke (NINDS) and the Association Internationale pour la Recherche et l’Enseignement en Neurosciences (AIREN) criteria for VaD necessitate evidence of vascular disease on CT or MRI of the brain. The purposes of our study were to operationalize the radiological part of the NINDS-AIREN criteria and to assess the effect of this operationalization on interobserver agreement. Methods— Six experienced and 4 inexperienced observers rated a set of 40 MRI studies of patients with clinically suspected VaD twice using the NINDS-AIREN set of radiological criteria. After the first reading session, operational definitions were conceived, which were subsequently used in the second reading session. Interobserver reproducibility was measured by Cohen’s &kgr;. Results— Overall agreement at the first reading session was poor (&kgr;=0.29) and improved slightly after application of the additional definitions (&kgr;=0.38). Raters in the experienced group improved their agreement from almost moderate (&kgr;=0.39) to good (0.62). The inexperienced group started out with poor agreement (&kgr;=0.17) and did not improve (&kgr;=0.18). The experienced group improved in both the large- and small-vessel categories, whereas the inexperienced group improved generally in the extensive white matter hyperintensities categories. Conclusions— Considerable interobserver variability exists for the assessment of the radiological part of the NINDS-AIREN criteria. Use of operational definitions improves agreement but only for already experienced observers.

Plasma amyloid beta, apolipoprotein E, lacunar infarcts, and white matter lesions.

Lacunar brain infarcts and cerebral white matter lesions are frequently observed on magnetic resonance imaging scans in elderly subjects. These lesions are also frequent in patient with cerebral amyloid angiopathy. We examined whether plasma amyloid β peptide (Aβ) levels are associated with lacunar infarcts and white matter lesions in the general population, and whether the apolipoprotein E (APOE) genotype modifies these associations. We studied 1,077 participants within the population‐based Rotterdam Scan Study, who were 60 to 90 years of age and free of dementia. Cross‐sectional associations were analyzed by regression models with adjustments for age, sex, creatinine levels, and hypertension. In APOE ε4 carriers, plasma Aβ levels were positively associated with lacunar infarcts and white matter lesions, whereas in noncarriers no associations were observed. Per standard deviation increase in Aβ1‐40 and Aβ1‐42 levels the odds ratios for lacunar infarcts were 1.72 (95% confidence interval [CI] = 1.22–2.43) and 1.93 (95% CI = 1.31–2.85), the periventricular white matter lesion grade increased by 0.32 (95% CI = 0.08–0.57) and 0.29 (95% CI = 0.00–0.57), and the subcortical white matter lesion volume increased by 0.48ml (95% CI = 0.04–0.91) and 0.24ml (95% CI = −0.27–0.75). Higher Aβ levels are associated with more lacunar infarcts and white matter lesions in elderly subjects who carry an APOE ε4 allele. Ann Neurol 2004

Neuroanatomical localisation and clinical correlates of white matter lesions in the elderly

Background: White matter lesions (WML) in elderly people co-occur with hypertension, depression, and cognitive impairment. Little is known about the density and distribution of WML in normal elderly people, whether they occur randomly in the aging brain or tend to cluster in certain areas, or whether patterns of WML aggregation are linked to clinical symptoms. Objectives: To describe patterns of WML distribution in a large representative population of elderly people using non-inferential cluster analysis; and to determine the extent to which such patterns are associated with clinical symptomatology. Method: A population sample of 1077 elderly people was recruited. Multiple analysis of correspondence followed by automatic classification methods was used to explore overall patterns of WML distribution. Correspondence was then sought between these patterns and a range of cerebrovascular, psychiatric, and neurological symptoms. Results: Three distinct patterns of spatial localisation within the brain were observed, corresponding to distinct clusters of clinical symptoms. In particular WML aggregation in temporal and occipital areas was associated with greater age, hypertension, late onset depressive disorder, poor global cognitive function, and overall WML frequency. Conclusions: WML localisation is not random in the aging brain, and their distribution is associated with age and the presence of clinical symptoms. Age differences suggest there may be patterns of progression across time; however, this requires confirmation from longitudinal imaging studies.

Frequency of white matter lesions and silent lacunar infarcts.

White matter lesions and silent lacunar infarcts are related to and may result from cerebral small vessel disease. Reported frequencies of these lesions vary largely among studies. Differences in imaging techniques, rating scales, cut-off points in lesion severity grading and study populations contribute to the variation, in addition to differences in risk factor profiles across studies. In this paper, we will firstly discuss general methodological issues that may influence reported frequencies of white matter lesions and silent lacunar infarctions, and then review published data. We will focus on the results from population-based studies and only briefly comment on patient series of stroke and dementia.

Efficacy of early cognitive–linguistic treatment and communicative treatment in aphasia after stroke: a randomised controlled trial (RATS-2)

Background The two main approaches in aphasia treatment are cognitive–linguistic treatment (CLT), aimed at restoring the linguistic levels affected, semantics, phonology or syntax, and communicative treatment, aimed at optimising information transfer by training compensatory strategies and use of residual language skills. The hypothesis that CLT is more effective than communicative treatment in the early stages after stroke was tested in this study. Methods In this multicentre, randomised, parallel group trial with blinded outcome assessment, 80 patients with aphasia after stroke were included within 3u2005weeks post-stroke. Patients received 6u2005months of CLT, comprising semantic and/or phonological training, or communicative treatment for at least 2u2005h per week. They were assessed before treatment and at 3 and 6u2005months with the Amsterdam–Nijmegen Everyday Language Test (ANELT-A, primary outcome) and semantic and phonological tests (secondary outcomes). The intervention effect was evaluated by means of analysis of covariance, with adjustment for baseline scores. Results There was no difference between the mean ANELT-A score of the CLT group (n=38) and the communicative treatment group (n=42), at 3 months (adjusted difference 1.5, 95% CI −2.6 to 5.6) or at 6u2005months (adjusted difference 1.6, 95% CI −2.3 to 5.6) post-stroke. On two of six specific semantic and phonological tests, the mean scores differed significantly, both in favour of CLT. Conclusion This study does not confirm the hypothesis that patients with aphasia after stroke benefit more from CLT, aimed at activation of the underlying semantic and phonologic processes, than from general, non-specific communicative treatment (ISRCTN67723958 Current Controlled Trials).

Glucocorticoid receptor variant and risk of dementia and white matter lesions

OBJECTIVEnElevated glucocorticoid levels are associated with dementia. A glucocorticoid receptor gene variant (ER22/23EK) is related to relative glucocorticoid resistance. We investigated whether the ER22/23EK allele is associated with dementia and structural brain abnormalities.nnnMETHODSnThis study was performed in two prospective population-based cohort studies among elderly. The first study included 6034 participants who were screened for dementia (mean follow-up 5.8 years). The second study included 1011 elderly subjects with an MRI at baseline and follow-up. The ER22/23EK allele was assessed for association with dementia, cognitive function and white matter lesions.nnnRESULTSnThe ER22/23EK allele was associated with a decreased risk of dementia. Among non-demented participants, ER22/23EK-carriers had a better performance on psychomotor speed tests than non-carriers. No differences were found in memory function between genotypes. In addition, both presence and progression of white matter lesions was lower in ER22/23EK-carriers. No association was found with brain atrophy on MRI.nnnCONCLUSIONSnOur findings suggest a protective effect of the ER22/23EK allele on the risk of dementia and white matter lesions.