Is it all in the baseline? Trajectories of chair stand performance over 4 years and their association with grey matter structure in older adults.

Understanding individual variability in response to physical activity is key to developing more effective and personalised interventions for healthy ageing. Here, we aimed to unpack individual differences by using longitudinal data from a randomised-controlled trial of a 12-month muscle strengthening intervention in older adults. Physical function of the lower extremities was collected from 247 participants (66.3 ± 2.5 years) at four time-points. At baseline and at year 4, participants underwent 3 T MRI brain scans. K-means longitudinal clustering was used to identify patterns of change in chair stand performance over 4 years, and voxel-based morphometry was applied to map structural grey matter volume at baseline and year 4. Results identified three groups showing trajectories of poor (33.6%), mid (40.1%), and high (26.3%) performance. Baseline physical function, sex, and depressive symptoms significantly differed between trajectory groups. High performers showed greater grey matter volume in the motor cerebellum compared to the poor performers. After accounting for baseline chair stand performance, participants were re-assigned to one of four trajectory-based groups: moderate improvers (38.9%), maintainers (38.5%), improvers (13%), and decliners (9.7%). Clusters of significant grey matter differences were observed between improvers and decliners in the right supplementary motor area. Trajectory-based group assignments were unrelated to the intervention arms of the study. In conclusion, patterns of change in chair stand performance were associated with greater grey matter volumes in cerebellar and cortical motor regions. Our findings emphasise that how you start matters, as baseline chair stand performance was associated with cerebellar volume 4 years later.

Lack of reproducibility of resting-state functional MRI findings in migraine with aura.

BACKGROUND: Several studies have applied resting-state functional MRI to examine whether functional brain connectivity is altered in migraine with aura patients. These studies had multiple limitations, including small sample sizes, and reported conflicting results. Here, we performed a large, cross-sectional brain imaging study to reproduce previous findings. METHODS: We recruited women aged 30-60 years from the nationwide Danish Twin Registry. Resting-state functional MRI of women with migraine with aura, their co-twins, and unrelated migraine-free twins was performed at a single centre. We carried out an extensive series of brain connectivity data analyses. Patients were compared to migraine-free controls and to co-twins. RESULTS: Comparisons were based on data from 160 patients, 30 co-twins, and 136 controls. Patients were similar to controls with regard to age, and several lifestyle characteristics. We replicated clear effects of age on resting-state networks. In contrast, we failed to detect any differences, and to replicate previously reported differences, in functional connectivity between migraine patients with aura and non-migraine controls or their co-twins in any of the analyses. CONCLUSION: Given the large sample size and the unbiased population-based design of our study, we conclude that women with migraine with aura have normal resting-state brain connectivity outside of migraine attacks.

Midlife perceived stress is associated with cognitive decline across three decades.

BACKGROUND: Research indicates detrimental effects of stress on brain health and cognitive functioning, but population-based studies using comprehensive measures of cognitive decline is lacking. The present study examined the association of midlife perceived stress with cognitive decline from young adulthood to late midlife, controlling for early life circumstances, education and trait stress (neuroticism). METHODS: The sample consisted of 292 members of the Copenhagen Perinatal Cohort (1959-1961) with continued participation in two subsequent follow-up studies. Cognitive ability was assessed in young adulthood (mean age 27 years) and midlife (mean age 56 years) using the full Wechsler Adult Intelligence Scale (WAIS), and perceived stress was measured at midlife using the Perceived Stress Scale. The association of midlife perceived stress with decline in Verbal, Performance and Full-Scale IQ was assessed in multiple regression models based on Full Information Maximum Likelihood estimation. RESULTS: Over a mean retest interval of 29 years, average decline in IQ score was 2.42 (SD 7.98) in Verbal IQ and 8.87 (SD 9.37) in Performance IQ. Mean decline in Full-scale IQ was 5.63 (SD 7.48), with a retest correlation of 0.83. Controlling for parental socio-economic position, education and young adult IQ, higher perceived stress at midlife was significantly associated with greater decline in Verbal (ß = - 0.012), Performance (ß = - 0.025), and Full-scale IQ (ß = - 0.021), all p < .05. Across IQ scales, additionally controlling for neuroticism in young adulthood and change in neuroticism had only minor effects on the association of midlife perceived stress with decline. CONCLUSIONS: Despite very high retest correlations, decline was observed on all WAIS IQ scales. In fully adjusted models, higher midlife perceived stress was associated with greater decline on all scales, indicating a negative association of stress with cognitive ability. The association was strongest for Performance and Full-scale IQ, perhaps reflecting the greater decline on these IQ scales compared to Verbal IQ.

Stress diagnoses in midlife and risk of dementia: a register-based follow-up study.

OBJECTIVES: Previous studies indicated that stress diagnoses increase the risk of dementia. However, previous results may be biased by confounding, reverse causation and misclassification. Therefore, the main aim of this study was to investigate the association between clinically diagnosed stress in midlife and later dementia risk, while addressing limitations of previous studies. METHODS: The study population was selected from all individuals in Denmark born 1935-1956. Individuals diagnosed with stress in midlife (aged 37-58 years) were matched (1:5) with individuals without stress diagnoses based on sex and birthdate (N = 103,484). Data were retrieved from national registers. Cox regression models were adjusted for socio-demographic factors and different morbidities. RESULTS: We found a 2.20 (95% CI: 1.93-2.50) times higher rate of dementia among individuals with any stress diagnosis registered in midlife compared with no stress diagnosis. Hazard rate ratios of dementia were 1.73 (95% CI: 1.13-2.65) among individuals with acute stress reactions, 2.37 (95% CI: 2.05-2.74) among individuals with adjustment disorders, and 2.20 (95% CI: 1.73-2.80) among individuals with unspecified stress reactions. Individuals with PTSD and other stress reactions had non-significantly elevated rates of dementia. Adjustment for confounding only slightly attenuated the association, and reverse causation did not appear to bias the results substantially. CONCLUSION: Our results support the hypothesis that severe stress in midlife is an important risk factor for dementia. This finding emphasizes the importance of identifying and treating severe stress in midlife to reduce potential detrimental consequences for brain health in later life.

Mid- to late-life migraine diagnoses and risk of dementia: a national register-based follow-up study.

BACKGROUND: Previous studies found an association between migraine and dementia, which are two leading causes of disability. However, these studies did not differentiate between migraine types and did not investigate all prevalent dementia subtypes. The main objective of this national register-based study was to investigate whether migraine was a risk factor for dementia. Additionally, we explored potential differences in dementia risk for migraine with and without aura. METHODS: We obtained data on birth cohorts born between 1935 and 1956 (n = 1,657,890) from Danish national registers. Individuals registered with migraine before age 59 (n = 18,135) were matched (1:5) on sex and birthdate with individuals without migraine (n = 1,378,346). Migraine was defined by International Classification of Diseases (ICD) diagnoses and dementia was defined by ICD diagnoses and anti-dementia medication. After matching, 62,578 individuals were eligible for analysis. For the statistical analyses, we used Cox regression models and adjusted for socio-demographic factors and several psychiatric and somatic morbidities. RESULTS: During a median follow-up time of 6.9 (IQR: 3.6-11.2) years, 207 individuals with migraine developed dementia. Compared with individuals without migraine, we found a 50% higher rate of dementia among individuals with migraine (HR = 1.50; 95% CI: 1.28-1.76). Individuals without aura had a 19% higher rate of dementia (HR = 1.19; 95% CI: 0.84-1.70), and individuals with aura had a two times higher rate of dementia (HR = 2.11; 95% CI: 1.48-3.00). CONCLUSIONS: Our findings support the hypothesis that migraine is a midlife risk factor for dementia in later life. The higher rate of dementia in individuals with a hospital-based diagnosis of migraine with aura emphasizes the need for studies on pathological mechanisms and potential preventative measures. Furthermore, given that only hospital-based migraine diagnoses were included in this study, future research should also investigate migraine cases derived from the primary healthcare system to include less severe migraine cases.

Migraine with visual aura associated with thicker visual cortex.

Until recent years it was believed that migraine with aura was a disorder causing intermittent neurological symptoms, with no impact on brain structure. However, recent MRI studies have reported increased cortical thickness of visual and somatosensory areas in patients with migraine with aura, suggesting that such structural alterations were either due to increased neuronal density in the areas involved, or a result of multiple episodes of cortical spreading depression as part of aura attacks. Subsequent studies have yielded conflicting results, possibly due to methodological reasons, e.g. small number of subjects. In this cross-sectional study, we recruited females aged 30-60 years from the nationwide Danish Twin Registry. Brain MRI of females with migraine with aura (patients), their co-twins, and unrelated migraine-free twins (controls) were performed at a single centre and assessed for cortical thickness in predefined cortical areas (V1, V2, V3A, MT, somatosensory cortex), blinded to headache diagnoses. The difference in cortical thickness between patients and controls adjusted for age, and other potential confounders was assessed. Comparisons of twin pairs discordant for migraine with aura were also performed. Comparisons were based on 166 patients, 30 co-twins, and 137 controls. Compared with controls, patients had a thicker cortex in areas V2 [adjusted mean difference 0.032 mm (95% confidence interval 0.003 to 0.061), V3A [adjusted mean difference 0.037 mm (95% confidence interval 0.008 to 0.067)], while differences in the remaining areas examined were not statistically significant [adjusted mean difference (95% confidence interval): V1 0.022 (-0.007 to 0.052); MT: 0.018 (-0.011 to 0.047); somatosensory cortex: 0.020 (-0.009 to 0.049)]. We found no association between the regions of interest and active migraine, or number of lifetime aura attacks. Migraine with aura discordant twin pairs (n = 30) only differed in mean thickness of V2 (0.039 mm, 95% CI 0.005 to 0.074). In conclusion, females with migraine with aura have a thicker cortex corresponding to visual areas and our results indicate this may be an inherent trait rather than a result of repeated aura attacks.

Hearing loss, cognitive ability, and dementia in men age 19-78 years.

Hearing loss in later life has been associated with risk of dementia. The impact of risk factors for dementia may change during life, and it is unknown whether hearing loss early in midlife represents a risk factor for dementia. We examined whether hearing loss diagnosed in midlife was associated with an increased risk of dementia. A cohort comprising 942,567 Danish men enrolled in the mandatory conscription board examination was followed from conscription (age 19). Cognitive ability was measured at conscription, while hearing loss was ascertained either by physicians diagnosis at conscription or by the Danish National Patient Registry from 1977 to 2016 (ICD-8:388; 389; ICD-10:H90; H91). Differences in cognitive ability in relation to hearing loss at conscription were calculated using t test, while the risk of dementia associated with hearing loss was estimated using Cox regression with adjustment for cognitive ability, education, depression, diabetes, hypertension, and cerebrovascular disease. Men with hearing loss at conscription had about 2 points (corresponding to 0.20 SD) lower mean cognitive score than those without hearing loss. During follow-up, 59,834 men had a hearing loss diagnosis, while 9114 were diagnosed with dementia. Midlife hearing loss was associated with an increased rate of dementia diagnosed before age 60 (adjusted Hazard Ratio (HR) = 1.90 [95% CI 1.59-2.76]) or at a later age (adjusted HR = 1.15 [95% CI 1.06-1.25]). Our study supports the evidence that early identification and correction of hearing loss holds promise for prevention of dementia later in life.

Parental socioeconomic position and midlife allostatic load: a study of potential mediators.

BACKGROUND: The mechanisms underlying the association of parental socioeconomic position with later life allostatic load remain unclear. The present study aims to examine potential pathways underlying this association: personality, social relations, intelligence and education. METHODS: The study comprised 361 members of the Copenhagen Perinatal Cohort who participated in two subsequent follow-ups: the Prenatal Development Project (mean age 27 years) and the Copenhagen Aging and Midlife Biobank study (mean age 50 years). Allostatic load was based on 14 biomarkers representing the inflammatory, metabolic and cardiovascular system measured at midlife. Information on potential mediators was collected in young adulthood, and their role in the association of parental socioeconomic position with midlife allostatic load were examined in linear regression path analyses. RESULTS: Parental socioeconomic position at one year was inversely associated with midlife allostatic load (ß = - 0.238, p < .001). No mediation effects were found for personality or social relations. In a model including intelligence and education, a significant indirect effect was found for education (ß = - 0.151, p < .001). A significant direct effect remained (ß = - 0.111, p = .040). CONCLUSIONS: Parental socioeconomic position was inversely associated with allostatic load in midlife. Results suggest that part of this association was mediated by education. A better understanding of the non-cognitive pathways related to education is an important prerequisite for the development of effective intervention strategies.

High-dose erythropoietin in patients with progressive multiple sclerosis: A randomized, placebo-controlled, phase 2 trial.

BACKGROUND: Erythropoietin (EPO) is a part of an endogenous neuroprotective system in the brain and may address pathophysiological mechanisms in progressive multiple sclerosis (MS). OBJECTIVE: To evaluate a treatment effect of EPO on progressive MS. METHODS: This was a single-center, randomized, double-blind, placebo-controlled phase 2 trial, in which 52 patients with secondary or primary progressive MS were allocated to treatment with recombinant EPO (48,000 IU) or placebo, administered intravenously 17 times during 24 weeks. Patients had an Expanded Disability Status Score (EDSS) from 4 to 6.5 and clinical progression without relapses in the 2 preceding years. The primary outcome was the change in a composite measure of maximum gait distance, hand dexterity, and cognition from baseline to 24 weeks. RESULTS: A total of 50 patients completed the study. Venesection was performed often but no thromboembolic events occurred. We found no difference in the primary outcome between the EPO and the placebo group using the intention-to-treat principle ( p = 0.22). None of the secondary outcomes, neither clinical nor magnetic resonance imaging (MRI) measures showed any significant differences. CONCLUSION: This study provides class II evidence that treatment with high-dose EPO is not an effective treatment in patients with moderately advanced progressive MS.

Migraine with aura and risk of silent brain infarcts and white matter hyperintensities: an MRI study.

A small number of population-based studies reported an association between migraine with aura and risk of silent brain infarcts and white matter hyperintensities in females. We investigated these relations in a population-based sample of female twins. We contacted female twins ages 30-60 years identified through the population-based Danish Twin Registry. Based on questionnaire responses, twins were invited to participate in a telephone-based interview conducted by physicians. Headache diagnoses were established according to the International Headache Society criteria. Cases with migraine with aura, their co-twins, and unrelated migraine-free twins (controls) were invited to a brain magnetic resonance imaging scan performed at a single centre. Brain scans were assessed for the presence of infarcts, and white matter hyperintensities (visual rating scales and volumetric analyses) blinded to headache diagnoses. Comparisons were based on 172 cases, 34 co-twins, and 139 control subjects. Compared with control subjects, cases did not differ with regard to frequency of silent brain infarcts (four cases versus one control), periventricular white matter hyperintensity scores [adjusted mean difference (95% confidence interval): -0.1 (-0.5 to 0.2)] or deep white matter hyperintensity scores [adjusted mean difference (95% confidence interval): 0.1 (-0.8 to 1.1)] assessed by Scheltens' scale. Cases had a slightly higher total white matter hyperintensity volume compared with controls [adjusted mean difference (95% confidence interval): 0.17 (-0.08 to 0.41) cm(3)] and a similar difference was present in analyses restricted to twin pairs discordant for migraine with aura [adjusted mean difference 0.21 (-0.20 to 0.63)], but these differences did not reach statistical significance. We found no evidence of an association between silent brain infarcts, white matter hyperintensities, and migraine with aura.

Cognitive ability in young adulthood and risk of dementia in a cohort of Danish men, brothers, and twins.

INTRODUCTION: We examined the association between cognitive ability in young adulthood and dementia in Danish men, brothers, and male twins. METHODS: In total, 666,986 men born between 1939 and 1959 were identified for dementia diagnosis in national registries from 1969 to 2016. The association between cognitive ability from draft board examination and dementia was examined using Cox regression. RESULTS: During a 44-year follow-up, 6416 (0.96%) men developed dementia, 1760 (0.26%) and 970 (0.15%) of which were classified as Alzheimer's and vascular dementia, respectively. Low cognitive ability was associated with increased risk of dementia (hazard ratio [HR]per SD decrease 1.33 [95% confidence interval {CI} = 1.30-1.35]) with the strongest associations for vascular dementia (HRper SD decrease 1.47 [95% CI = 1.31-1.56]) and a weaker for Alzheimer's disease (HRper SD decrease 1.07 [95% CI = 1.03-1.13]). The intrabrother and twin analyses (taking shared family factors into account) showed attenuated risk estimates but with wide CIs. DISCUSSION: Low early-life cognitive ability increases the risk of dementia before the age of 78 years. The association is partly explained by shared family factors.

Training shortest-path tractography: Automatic learning of spatial priors.

Tractography is the standard tool for automatic delineation of white matter tracts from diffusion weighted images. However, the output of tractography often requires post-processing to remove false positives and ensure a robust delineation of the studied tract, and this demands expert prior knowledge. Here we demonstrate how such prior knowledge, or indeed any prior spatial information, can be automatically incorporated into a shortest-path tractography approach to produce more robust results. We describe how such a prior can be automatically generated (learned) from a population, and we demonstrate that our framework also retains support for conventional interactive constraints such as waypoint regions. We apply our approach to the open access, high quality Human Connectome Project data, as well as a dataset acquired on a typical clinical scanner. Our results show that the use of a learned prior substantially increases the overlap of tractography output with a reference atlas on both populations, and this is confirmed by visual inspection. Furthermore, we demonstrate how a prior learned on the high quality dataset significantly increases the overlap with the reference for the more typical yet lower quality data acquired on a clinical scanner. We hope that such automatic incorporation of prior knowledge and the obviation of expert interactive tract delineation on every subject, will improve the feasibility of large clinical tractography studies.

Monthly oral methylprednisolone pulse treatment in progressive multiple sclerosis.

BACKGROUND: There is a large unmet need for treatments for patients with progressive multiple sclerosis (MS). Phase 2 studies with cerebrospinal fluid (CSF) biomarker outcomes may be well suited for the initial evaluation of efficacious treatments. OBJECTIVE: To evaluate the effect of monthly oral methylprednisolone pulse treatment on intrathecal inflammation in progressive MS. METHODS: In this open-label phase 2A study, 15 primary progressive and 15 secondary progressive MS patients received oral methylprednisolone pulse treatment for 60 weeks. Primary outcome was changes in CSF concentrations of osteopontin. Secondary outcomes were other CSF biomarkers of inflammation, axonal damage and demyelination; clinical scores; magnetic resonance imaging measures of disease activity, magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI); motor evoked potentials; and bone density scans. RESULTS: We found no change in the CSF concentration of osteopontin, but we observed significant improvement in clinical scores, MTR, DTI and some secondary CSF outcome measures. Adverse events were well-known side effects to methylprednisolone. CONCLUSION: Monthly methylprednisolone pulse treatment was safe, but had no effect on the primary outcome. However, improvements in secondary clinical and MRI outcome measures suggest that this treatment regimen may have a beneficial effect in progressive MS.

White Matter Lesions, Carotid and Coronary Atherosclerosis in Late-Onset Depression and Healthy Controls.

BACKGROUND: Cerebral white matter lesions (WMLs) are more common in individuals with late-onset or late-life depression. It has been proposed that carotid atherosclerosis may predispose to WMLs by inducing cerebral hypoperfusion. This hemodynamic effect of carotid atherosclerosis could be important for the formation of WMLs in depression. METHODS: The case-control study included 29 patients with late-onset major depressive disorder and 27 controls matched for sex, age, and tobacco use. WML volume, carotid intima-media thickness, and coronary plaque volume were assessed using magnetic resonance imaging, ultrasound scan, and coronary computed tomography (CT) angiography, respectively. RESULTS: The mean age for the total sample was 59.7 ± 4.7 years. There was no difference in carotid intima-media thickness between patients and controls (p = 0.164), whereas a higher WML volume in the patients was found (p = 0.051). In both patients and controls, WML volume was associated with carotid but not with coronary atherosclerosis. In adjusted multiple linear regression, a 0.1mm increase in averaged carotid intima-media thickness was associated with a 52% (95% CI: 8.4-112, p = 0.032) increase in WML volume. The association between carotid intima-media thickness and WML volume was, however, similar in patients and controls. CONCLUSIONS: In older persons aged between 50 and 70 years, WMLs do not seem to be a part of generalized atherosclerotic disease, but seem to be dependent on atherosclerosis in the carotid arteries. Carotid atherosclerosis, however, could not explain the higher WML load observed in the depressed patients, and thus, studies are needed to establish the mechanisms linking depression and WMLs.

Shape abnormalities of the caudate nucleus correlate with poorer gait and balance: results from a subset of the LADIS study.

OBJECTIVE: Functional deficits seen in several neurodegenerative disorders have been linked with dysfunction in frontostriatal circuits and with associated shape alterations in striatal structures. The severity of visible white matter hyperintensities (WMHs) on magnetic resonance imaging has been found to correlate with poorer performance on measures of gait and balance. This study aimed to determine whether striatal volume and shape changes were correlated with gait dysfunction. METHODS: Magnetic resonance imaging scans and clinical gait/balance data (scores from the Short Physical Performance Battery [SPPB]) were sourced from 66 subjects in the previously published LADIS trial, performed in nondisabled individuals older than age 65 years with WMHs at study entry. Data were obtained at study entry and at 3-year follow-up. Caudate nuclei and putamina were manually traced using a previously published method and volumes calculated. The relationships between volume and physical performance on the SPPB were investigated with shape analysis using the spherical harmonic shape description toolkit. RESULTS: There was no correlation between the severity of WMHs and striatal volumes. Caudate nuclei volume correlated with performance on the SPPB at baseline but not at follow-up, with subsequent shape analysis showing left caudate changes occurred in areas corresponding to inputs of the dorsolateral prefrontal, premotor, and motor cortex. There was no correlation between putamen volumes and performance on the SPPB. CONCLUSION: Disruption in frontostriatal circuits may play a role in mediating poorer physical performance in individuals with WMHs. Striatal volume and shape changes may be suitable biomarkers for functional changes in this population.

Visual processing speed in old age.

Mental speed is a common concept in theories of cognitive aging, but it is difficult to get measures of the speed of a particular psychological process that are not confounded by the speed of other processes. We used Bundesen's (1990) Theory of Visual Attention (TVA) to obtain specific estimates of processing speed in the visual system controlled for the influence of response latency and individual variations of the perception threshold. A total of 33 non-demented old people (69-87 years) were tested for the ability to recognize briefly presented letters. Performance was analyzed by the TVA model. Visual processing speed decreased approximately linearly with age and was on average halved from 70 to 85 years. Less dramatic aging effects were found for the perception threshold and the visual apprehension span. In the visual domain, cognitive aging seems to be most clearly related to reductions in processing speed.

Plasma NT-proBNP and white matter hyperintensities in type 2 diabetic patients.

UNLABELLED: Elevated plasma N-terminal (NT)-proBNP from the heart as well as white matter hyperintensities (WMH) in the brain predict cardiovascular (CV) mortality in the general population. The cause of poor prognosis associated with elevated P-NT-proBNP is not known but WMH precede strokes in high risk populations. We assessed the association between P-NT-proBNP and WMH or brain atrophy measured with magnetic resonance imaging (MRI) in type 2 diabetic patients, and age-matched controls. METHODS AND RESULTS: We measured P-NT-proBNP(ng/l) in 20 diabetic patients without prior stroke but with(n=10) or without(n=10) asymptomatic coronary artery disease(CAD) in order to include patients with a wide-ranging CV risk profile. All patients and 26 controls had a 3D MRI and brain volumes(ml) with WMH and brain parenchymal fraction(BPF), an indicator of brain atrophy, were determined.P-NT-proBNP was associated with WMH in linear regression analysis adjusted for CV risk factors(r=0.94, p=0.001) and with BPF in univariate analysis(r=0.57, p=0.009). Patients divided into groups of increased P-NT-proBNP levels were paralleled with increased WMH volumes(geometric mean[SD];(2.86[5.11] ml and 0.76[2.49] ml compared to patients with low P-NT-proBNP 0.20[2.28] ml, p=0.003)) and also when adjusted for age, sex and presence of CAD(p=0.017). The association was strengthened by CV risk factors and we did not find a common heart or brain specific driver of both P-NT-proBNP and WMH. Patients and particular patients with CAD had higher WMH, however no longer after adjustment for age and sex. CONCLUSION: P-NT-proBNP was associated with WMH in type 2 diabetic patients, suggesting a linkage between heart and brain disease.

An ex vivo imaging pipeline for producing high-quality and high-resolution diffusion-weighted imaging datasets.

Diffusion tensor (DT) imaging and related multifiber reconstruction algorithms allow the study of in vivo microstructure and, by means of tractography, structural connectivity. Although reconstruction algorithms are promising imaging tools, high-quality diffusion-weighted imaging (DWI) datasets for verification and validation of postprocessing and analysis methods are lacking. Clinical in vivo DWI is limited by, for example, physiological noise and low signal-to-noise ratio. Here, we performed a series of DWI measurements on postmortem pig brains, which resemble the human brain in neuroanatomical complexity, to establish an ex vivo imaging pipeline for generating high-quality DWI datasets. Perfusion fixation ensured that tissue characteristics were comparable to in vivo conditions. There were three main results: (i) heat conduction and unstable tissue mechanics accounted for time-varying artefacts in the DWI dataset, which were present for up to 15 h after positioning brain tissue in the scanner; (ii) using fitted DT, q-ball, and persistent angular structure magnetic resonance imaging algorithms, any b-value between ∼2,000 and ∼8,000 s/mm(2) , with an optimal value around 4,000 s/mm(2) , allowed for consistent reconstruction of fiber directions; (iii) diffusivity measures in the postmortem brain tissue were stable over a 3-year period. On the basis of these results, we established an optimized ex vivo pipeline for high-quality and high-resolution DWI. The pipeline produces DWI data sets with a high level of tissue structure detail showing for example two parallel horizontal rims in the cerebral cortex and multiple rims in the hippocampus. We conclude that high-quality ex vivo DWI can be used to validate fiber reconstruction algorithms and to complement histological studies.

Corpus callosum tissue loss and development of motor and global cognitive impairment: the LADIS study.

OBJECTIVE: To examine the impact of corpus callosum (CC) tissue loss on the development of global cognitive and motor impairment in the elderly. METHODS: This study was based on the Leukoaraiosis and Disability (LADIS) study. Assessment of cognitive and motor functions and magnetic resonance imaging (MRI) were done at baseline and at a 3-year follow-up in nondemented elderly subjects. RESULTS: 328 of 639 LADIS subjects had MRIs at baseline and at the 3-year follow-up, which allowed for assessment of CC. Logistic regression revealed differential tissue loss rates in posterior CC in subjects converting to dementia, compared to nonconverters (p < 0.05). Anterior and posterior CC tissue loss was significantly correlated with self-perceived memory impairment in nonconverters (p < 0.05). CC tissue loss was also significantly associated with impaired single leg stance time (p < 0.01). CONCLUSION: The present longitudinal study on CC supports the role of callosal tissue loss in the development of global cognitive as well as motor impairment.

White matter hyperintensities and prepulse inhibition in a mixed elderly population.

Prepulse inhibition (PPI) of the startle response, a measure for sensorimotor gating, exhibits a relatively high inter-individual variability in elderly subjects. The aim of this study was to investigate whether white matter hyperintensities (WMH), frequently identified on cranial magnetic resonance imaging (MRI) in elderly subjects with and without cognitive impairment, may contribute to variations in PPI. A passive acoustic PPI paradigm was applied in 92 human subjects (53 healthy and 39 patients with Alzheimer's disease or mild cognitive impairment) between 60 and 85years of age. WMH were rated visually on craniel MRI FLAIR images using the Fazekas scale. WMH were identified in 70% of all subjects. The latency to peak of the startle response increased significantly with increasing WMH load, whereas the inhibition of the startle response (PPI) was neither significantly related to the degree of WMH nor to cognitive performance. We conclude that the presence of WMH in the fronto-striatal brain circuit may affect the latency of the startle response, but not information processing in elderly subjects.