Phase 2A Learnings Incorporated into RewinD-LB, a Phase 2B Clinical Trial of Neflamapimod in Dementia with Lewy Bodies.

BACKGROUND: In an exploratory 91-participant phase 2a clinical trial (AscenD-LB, NCT04001517) in dementia with Lewy bodies (DLB), neflamapimod showed improvement over placebo on multiple clinical endpoints. To confirm those results, a phase 2b clinical study (RewinD-LB, NCT05869669 ) that is similar to AscenD-LB has been initiated. OBJECTIVES: To optimize the choice of patient population, primary endpoint, and biomarker evaluations in RewinD-LB. DESIGN: Evaluation of the efficacy results from AscenD-LB, the main results of which, and a re-analysis after stratification for absence or presence of AD co-pathology (assessed by plasma ptau181), have been published. In addition, the MRI data from a prior phase 2a clinical trial in Early Alzheimer's disease (AD), were reviewed. SETTING: 22 clinical sites in the US and 2 in the Netherlands. PARTICIPANTS: Probable DLB by consensus criteria and abnormal dopamine uptake by DaTscan™ (Ioflupane I123 SPECT). INTERVENTION: Neflamapimod 40mg capsules or matching placebo capsules, twice-a-day (BID) or three-times-a-day (TID), for 16 weeks. MEASUREMENTS: 6-test Neuropsychological Test Battery (NTB) assessing attention and executive function, Clinical Dementia Rating Sum-of-Boxes (CDR-SB), Timed Up and Go (TUG), International Shopping List Test (ISLT). RESULTS: Within AscenD-LB, patients without evidence of AD co-pathology exhibited a neflamapimod treatment effect that was greater than that in the overall population and substantial (cohen's d effect size vs. placebo ≥ for CDR-SB, TUG, Attention and ISLT-recognition). In addition, the CDR-SB and TUG performed better than the cognitive tests to demonstrate neflamapimod treatment effect in comparison to placebo. Further, clinical trial simulations indicate with 160-patients (randomized 1:1), RewinD-LB conducted in patients without AD co-pathology has >95% (approaching 100%) statistical power to detect significant improvement over placebo on the CDR-SB. Preliminary evidence of positive treatment effects on beta functional connectivity by EEG and basal forebrain atrophy by MRI were obtained in AscenD-LB and the Early AD study, respectively. CONCLUSION: In addition to use of a single dose regimen of neflamapimod (40mg TID), key distinctions between phase 2b and phase 2a include RewinD-LB (1) excluding patients with AD co-pathology, (2) having CDR-SB as the primary endpoint, and (3) having MRI studies to evaluate effects on basal forebrain atrophy.

Rationale and study design of a randomized, placebo-controlled, double-blind phase 2b trial to evaluate efficacy, safety, and tolerability of an oral glutaminyl cyclase inhibitor varoglutamstat (PQ912) in study participants with MCI and mild AD-VIVIAD.

BACKGROUND: Varoglutamstat (formerly PQ912) is a small molecule that inhibits the activity of the glutaminyl cyclase to reduce the level of pyroglutamate-A-beta (pGluAB42). Recent studies confirm that pGluAB42 is a particular amyloid form that is highly synaptotoxic and plays a significant role in the development of AD. METHODS: This paper describes the design and methodology behind the phase 2b VIVIAD-trial in AD. The aim of this study is to evaluate varoglutamstat in a state-of-the-art designed, placebo-controlled, double-blind, randomized clinical trial for safety and tolerability, efficacy on cognition, and effects on brain activity and AD biomarkers. In addition to its main purpose, the trial will explore potential associations between novel and established biomarkers and their individual and composite relation to disease characteristics. RESULTS: To be expected early 2023 CONCLUSION: This state of the art phase 2b study will yield important results for the field with respect to trial methodology and for the treatment of AD with a small molecule directed against pyroglutamate-A-beta. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04498650.

[Frontotemporal dementia diagnoses within the psychiatric practice: pitfalls and practical tools]. / Diagnostiek van frontotemporale dementie in de psychiatrische praktijk: handvatten en valkuilen.

BACKGROUND: The behavioural variant of frontotemporal dementia (bvFTD) strongly resembles primary psychiatric disorders. Furthermore, a bvFTD mimic may occur, without neurodegenerative aetiology. AIM: To offer psychiatrist clinical tools for making or ruling out a bvFTD diagnosis. METHOD: To present the results of the first prospective cohort study on bvFTD patients and primary psychiatric patients. Results are discussed within the context of the international literature. RESULTS: Frontotemporal atrophy on imaging confirms a suspected bvFTD diagnosis. Merely fulfilling the bvFTD clinical criteria, with or without frontotemporal hypometabolism on functional imaging, may also result from primary psychiatric disorders or the bvFTD-phenocopy syndrome. A high level of stereotypy, hyperorality, a low level of depressive symptoms, impaired social cognition or absent insight increases the probability of bvFTD. Biomarker or genetic tests and follow-up are recommended. CONCLUSIONS A bvFTD diagnosis should be made multidisciplinary. Without the confirmation of atrophy or genetics, great reserve in making the diagnosis is in place and careful analyses for psychiatric aetiologies is advised.

Grey zone amyloid burden affects memory function: the SCIENCe project.

PURPOSE: To determine thresholds for amyloid beta pathology and evaluate associations with longitudinal memory performance with the aim to identify a grey zone of early amyloid beta accumulation and investigate its clinical relevance. METHODS: We included 162 cognitively normal participants with subjective cognitive decline from the SCIENCe cohort (64 ± 8 years, 38% F, MMSE 29 ± 1). Each underwent a dynamic [18F] florbetapir PET scan, a T1-weighted MRI scan and longitudinal memory assessments (RAVLT delayed recall, n = 655 examinations). PET scans were visually assessed as amyloid positive/negative. Additionally, we calculated the mean binding potential (BPND) and standardized uptake value ratio (SUVr50-70) for an a priori defined composite region of interest. We determined six amyloid positivity thresholds using various data-driven methods (resulting thresholds: BPND 0.19/0.23/0.29; SUVr 1.28/1.34/1.43). We used Cohen's kappa to analyse concordance between thresholds and visual assessment. Next, we used quantiles to divide the sample into two to five subgroups of equal numbers (median, tertiles, quartiles, quintiles), and operationalized a grey zone as the range between the thresholds (0.19-0.29 BPND/1.28-1.43 SUVr). We used linear mixed models to determine associations between thresholds and memory slope. RESULTS: As determined by visual assessment, 24% of 162 individuals were amyloid positive. Concordance with visual assessment was comparable but slightly higher for BPND thresholds (range kappa 0.65-0.70 versus 0.60-0.63). All thresholds predicted memory decline (range beta - 0.29 to - 0.21, all p < 0.05). Analyses in subgroups showed memory slopes gradually became steeper with higher amyloid load (all p for trend < 0.05). Participants with a low amyloid burden benefited from a practice effect (i.e. increase in memory), whilst high amyloid burden was associated with memory decline. Memory slopes of individuals in the grey zone were intermediate. CONCLUSION: We provide evidence that not only high but also grey zone amyloid burden subtly impacts memory function. Therefore, in case a binary classification is required, we suggest using a relatively low threshold which includes grey zone amyloid pathology.

Targeting Lifestyle Behavior to Improve Brain Health: User-Experiences of an Online Program for Individuals with Subjective Cognitive Decline.

BACKGROUND: Online programs targeting lifestyle have the potential to benefit brain health. We aimed to develop such a program for individuals with subjective cognitive decline (SCD). These individuals were reported to be at increased risk for dementia, and report both an intrinsic need for brain health information and motivation to participate in prevention strategies. Co-creation and user-evaluation benefits the adherence to and acceptance of online programs. Previously, we developed a prototype of the online program in co-creation with the users . OBJECTIVES: We now aimed to evaluate the user-experiences of our online lifestyle program for brain health. DESIGN: 30-day user test; multi-method. SETTING: Participants were recruited in a memory clinic and (online) research registries in the Netherlands (Alzheimer Center Amsterdam) and Germany (Center for memory disorders, Cologne). PARTICIPANTS: Individuals with SCD (N=137, 65±9y, 57% female). MEASUREMENTS: We assessed user-experiences quantitatively with rating daily advices and usefulness, satisfaction and ease of use questionnaires as well as qualitatively using telephone interviews. RESULTS: Quantitative data showed that daily advices were rated moderately useful (3.5 ±1.5, range 1-5 points). Participants (n=101, 78%) gave moderate ratings on the programs' usability (3.7±1.3, max 7), ease of learning (3.6±1.9) and satisfaction (4.0±1.5), and marginal ratings on the overall usability (63.7±19.0, max 100). Qualitative data collected during telephone interviews showed that participants highly appreciated the content of the program. They elaborated that lower ratings of the program were mainly due to technical issues that hindered a smooth walk through. Participants reported that the program increased awareness of lifestyle factors related to brain health. CONCLUSIONS: Overall user-experience of the online lifestyle program was moderate to positive. Qualitative data showed that content was appreciated and that flawless, easy access technique is essential. The heterogeneity in ratings of program content and in program use highlights the need for personalization. These findings support the use of online self-applied lifestyle programs when aiming to reach large groups of motivated at-risk individuals for brain health promotion.

High occurrence of transportation and logistics occupations among vascular dementia patients: an observational study.

BACKGROUND: Growing evidence suggests a role of occupation in the emergence and manifestation of dementia. Occupations are often defined by complexity level, although working environments and activities differ in several other important ways. We aimed to capture the multi-faceted nature of occupation through its measurement as a qualitative (instead of a quantitative) variable and explored its relationship with different types of dementia. METHODS: We collected occupational information of 2121 dementia patients with various suspected etiologies from the Amsterdam Dementia Cohort (age 67 ± 8, 57% male; MMSE 21 ± 5). Our final sample included individuals with Alzheimer's disease (AD) dementia (n = 1467), frontotemporal dementia (n = 281), vascular dementia (n = 98), Lewy body disease (n = 174), and progressive supranuclear palsy/corticobasal degeneration (n = 101). Within the AD group, we used neuropsychological data to further characterize patients by clinical phenotypes. All participants were categorized into 1 of 11 occupational classes, across which we evaluated the distribution of dementia (sub)types with χ2 analyses. We gained further insight into occupation-dementia relationships through post hoc logistic regressions that included various demographic and health characteristics as explanatory variables. RESULTS: There were significant differences in the distribution of dementia types across occupation groups (χ2 = 85.87, p < .001). Vascular dementia was relatively common in the Transportation/Logistics sector, and higher vascular risk factors partly explained this relationship. AD occurred less in Transportation/Logistics and more in Health Care/Welfare occupations, which related to a higher/lower percentage of males. We found no relationships between occupational classes and clinical phenotypes of AD (χ2 = 53.65, n.s.). CONCLUSIONS: Relationships between occupation and dementia seem to exist beyond the complexity level, which offers new opportunities for disease prevention and improvement of occupational health policy.

Trajectories of cognitive decline in different types of dementia.

BACKGROUND: To investigate trajectories of cognitive decline in patients with different types of dementia compared to controls in a longitudinal study. METHOD: In 199 patients with Alzheimer's disease (AD), 10 with vascular dementia (VaD), 26 with dementia with Lewy bodies (DLB), 20 with behavioural variant frontotemporal dementia (bvFTD), 15 with language variant frontotemporal dementia (lvFTD) and 112 controls we assessed five cognitive domains: memory, language, attention, executive and visuospatial functioning, and global cognition (Mini-Mental State Examination, MMSE). All subjects had at least two neuropsychological assessments (median 2, range 2-7). Neuropsychological data were standardized into z scores using baseline performance of controls as reference. Linear mixed models (LMMs) were used to estimate baseline cognitive functioning and cognitive decline over time for each group, adjusted for age, gender and education. RESULTS: At baseline, patients with dementia performed worse than controls in all cognitive domains (p < 0.05) except visuospatial functioning, which was only impaired in patients with AD and DLB (p < 0.001). During follow-up, patients with AD declined in all cognitive domains (p < 0.001). DLB showed decline in every cognitive domain except language and global cognition. bvFTD showed rapid decline in memory, language, attention and executive functioning (all p < 0.01) whereas visuospatial functioning remained fairly stable. lvFTD declined mostly in attention and executive functioning (p < 0.01). VaD showed decline in attention and executive functioning. CONCLUSIONS: We show cognitive trajectories of different types of dementia. These estimations of natural disease course have important value for the design of clinical trials as neuropsychological measures are increasingly being used as outcome measures.

Disturbed phase relations in white matter hyperintensity based vascular dementia: an EEG directed connectivity study.

OBJECTIVE: White matter hyperintensities (WMH), a feature seen on magnetic resonance imaging (MRI) and regarded to reflect small vessel disease, can lead to vascular dementia (WMH-VaD). In WMH-VaD, cognitive deficits typically consist of executive function disturbances, and reduced information processing speed, regarded as a result of cerebral hypoperfusion. We aimed to investigate whether this patient group has typical functional differences from controls. METHODS: Resting-state encephalography studies of 17 VaD patients and 17 age- and gender matched non-demented controls were analysed in the delta, theta, alpha1 and 2, and beta frequency bands. Undirected functional connectivity between electrodes was established with the Phase Lag Index (PLI) and directed functional connectivity with the directed Phase Lag Index (dPLI). PLI and dPLI were related to performance in cognitive testing. RESULTS: Mean PLI did not differ between patients and controls. In the control group dPLI showed anterior to posterior phase gradients in all bands except the delta band. In the VaD patient group this pattern was significantly different without a clear directional pattern. No relationship with cognition was demonstrated. CONCLUSIONS: This study shows a clear front-to-back direction of connectivity in non-demented controls. In VaD patients with extensive WMH, this pattern is disturbed. SIGNIFICANCE: Structural damage at the regions of long distance white matter tracts may induce changes in the direction of phase relationships of distinct brain regions.

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 3 weeks post-stroke. Patients received 6 months of CLT, comprising semantic and/or phonological training, or communicative treatment for at least 2 h per week. They were assessed before treatment and at 3 and 6 months 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 6 months (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).

MR spectroscopy of brain white matter in the prediction of dementia.

BACKGROUND: Previous 1H-MR spectroscopy (MRS) studies compared biochemical spectra of persons with dementia with those of healthy control subjects. Given the long prodromal period of Alzheimer disease (AD), the authors sought to investigate whether biochemical changes can be observed also in the preclinical period. METHODS: The authors prospectively followed 509 elderly persons (ages 60 to 90), who were free of clinical dementia at baseline, for on average 5.9 years. At baseline, 1H-MRS of the brain (1.5 T) was performed in a plane above the lateral ventricles that comprised mainly white matter voxels. Standard ratios of N-acetyl aspartate (NAA), choline (Cho), and creatine (Cr) were calculated. Structural MRI was administered to assess white matter lesions and hippocampal atrophy. All persons were followed for incident dementia through repeated neuropsychological testing and linkage with medical records. RESULTS: During follow-up, 37 persons developed dementia, of whom 27 fulfilled criteria for AD. Overall, biochemical ratios on 1H-MRS at baseline were not associated with the risk of incident dementia. However, people with higher Cho/Cr ratios had a higher risk to develop dementia or AD within 4 years (hazard ratio for dementia per SD increase 1.55 [95% CI 1.05 to 2.28]). This association attenuated and became nonsignificant after adjustment for white matter lesions on MRI. CONCLUSION: These data suggest that there are biochemical changes on 1H-MR spectroscopy of brains of persons with presymptomatic dementia.

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.

Association between blood pressure, white matter lesions, and atrophy of the medial temporal lobe.

BACKGROUND: Blood pressure level is associated with the risk of clinical Alzheimer disease (AD), yet the underlying mechanisms are unclear. High blood pressure levels may cause cerebral small-vessel pathology, which contributes to cognitive decline in patients with AD. Alternatively, in persons with high blood pressure, increased numbers of neurofibrillary tangles and amyloid plaques at autopsy have also been observed, suggesting direct links between blood pressure and AD. OBJECTIVE: To investigate the association of blood pressure and markers of small-vessel disease (white matter lesions [WMLs] on MRI) with hippocampal and amygdalar atrophy on MRI-potential in vivo indicators of Alzheimer pathology. METHODS: In 1995 to 1996, 511 nondemented elderly subjects (age 60 to 90) underwent MRI. The extent of WMLs was assessed, and volumes of the hippocampus and amygdala were measured. Blood pressure levels were assessed at the time of MRI and 5 years before the MRI. RESULTS: Higher diastolic blood pressure 5 years before MRI predicted more hippocampal atrophy in persons untreated for hypertension (per SD increase -0.10 mL [95% CI -0.19 to -0.02, p = 0.02]). Conversely, in persons treated for hypertension, a low diastolic blood pressure was associated with more severe atrophy. Persons with more WMLs on MRI more often had severe atrophy of the hippocampus and amygdala. CONCLUSION: Blood pressure and indicators of small-vessel disease in the brain may be associated with atrophy of structures affected by Alzheimer pathology.

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.

Measuring progression of cerebral white matter lesions on MRI: visual rating and volumetrics.

OBJECTIVE: To evaluate the concordance of a volumetric method for measuring white matter lesion (WML) change with visual rating scales. METHODS: The authors selected a stratified sample of 20 elderly people (mean age 72 years, range 61 to 88 years) with an MRI examination at baseline and at 3-year follow-up from the community-based Rotterdam Scan Study (RSS). Four raters assessed WML change with four different visual rating scales: the Fazekas scale, the Scheltens scale, the RSS scale, and a new visual rating scale that was designed to measure change in WML. The authors assessed concordance with a volumetric method with scatter plots and correlations, and interobserver agreement with intraclass correlation coefficients. RESULTS: For assessment of change in WML, the Fazekas, Scheltens, and periventricular part of the RSS scale showed little correlation with volumetrics, and low interobserver agreement. The authors' new WML change scale and the subcortical part of the RSS scale showed good correlation with volumetrics. After additional training, the new WML change scale showed good interobserver agreement for measuring WML change. CONCLUSIONS: Commonly used visual rating scales are not well suited for measuring change in white matter lesion severity. The authors' new white matter lesion change scale is more accurate and precise, and may be of use in studies focusing on progression of white matter lesions.

Arterial oxygen saturation, COPD, and cerebral small vessel disease.

OBJECTIVE: To study whether lower arterial oxygen saturation (SaO(2)) and chronic obstructive pulmonary disease (COPD) are associated with cerebral white matter lesions and lacunar infarcts. METHODS: We measured SaO(2) twice with a pulse oximeter, assessed the presence of COPD, and performed MRI in 1077 non-demented people from a general population (aged 60-90 years). We rated periventricular white matter lesions (on a scale of 0-9) and approximated a total subcortical white matter lesion volume (range 0-29.5 ml). All analyses were adjusted for age and sex and additionally for hypertension, diabetes, body mass index, pack years smoked, cholesterol, haemoglobin, myocardial infarction, and left ventricular hypertrophy. RESULTS: Lower SaO(2) was independent of potential confounders associated with more severe periventricular white matter lesions (score increased by 0.12 per 1% decrease in SaO(2) (95% confidence interval 0.01 to 0.23)). Participants with COPD had more severe periventricular white matter lesions than those without (adjusted mean difference in score 0.70 (95% confidence interval 0.23 to 1.16)). Lower SaO(2) and COPD were not associated with subcortical white matter lesions or lacunar infarcts. CONCLUSION: Lower SaO(2) and COPD are associated with more severe periventricular white matter lesions.

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

AIM/HYPOTHESIS: Type 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. METHODS: Data 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. RESULTS: Subjects 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/INTERPRETATION: Type 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.

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.

Homocysteine and cognitive function in the elderly: the Rotterdam Scan Study.

BACKGROUND: Elevated plasma total homocysteine (tHcy) concentrations are associated with AD and vascular dementia, but the relation with cognitive performance in nondemented elderly people is not known. OBJECTIVE: To examine the association of tHcy and cognitive function in the elderly, and assess whether this may be mediated by structural brain changes on MRI. METHODS: The Rotterdam Scan Study is a population-based study of 1,077 nondemented elderly. Cognitive performance was assessed, and compound scores were constructed for psychomotor speed, memory function, and global cognitive function. Cerebral infarcts, white matter lesions, and generalized brain atrophy were measured on MRI. The cross-sectional relationship between tHcy levels and neuropsychological test scores was assessed by multiple regression. RESULTS: Mean tHcy level was 11.5 micro mol/L (SD 4.1). Increasing tHcy levels were associated with lower scores for psychomotor speed, memory function, and global cognitive function, and this was largely due to the association with tHcy levels in the upper quintile (>14 micro mol/L). Adjusted differences between test scores of participants in the upper quintile as compared with the lower four quintiles of tHcy were -0.26 (95% CI: -0.37; -0.14) for psychomotor speed, -0.13 (95% CI: -0.27; 0.01) for memory function, and -0.20 (95% CI: -0.30; -0.11) for global cognitive function. These associations were not mediated by structural brain changes on MRI. CONCLUSION: Elevated tHcy levels are associated with decreased cognitive performance in nondemented elderly people, and the relation was most marked for psychomotor speed. This association was independent of structural brain changes on MRI.