Saartje Burgmans

Multiple Indicators of Age-related Differences in Cerebral White Matter and the Modifying Effects of Hypertension

We investigated differences associated with age and hypertension, a common risk factor for vascular disease, in three aspects of white matter integrity--gross regional volumes of the white matter, volume of the white matter hyperintensities (WMH) and diffusion properties. We acquired MRI scans on 93 adult volunteers (age 50-77 years; 36 with diagnosis of hypertension or elevated blood pressure), and obtained all measures in seven brain regions: frontal, temporal, parietal and occipital white matter, and the genu, body and splenium of the corpus callosum. The results demonstrated robust age-related differences in diffusion-based indices of cerebral white matter integrity and age-related increase in the WMH volume, but no age differences in the gross regional volumes of the white matter. Hypertension was associated with decline in fractional anisotropy, and exacerbated age differences in fractional anisotropy more than those in the volume of WMH. These findings indicate that of all examined measures, diffusion-based indices of white matter integrity may be the most sensitive indicators of global and regional declines and vascular damage in the aging brain.

Age differences in speed of processing are partially mediated by differences in axonal integrity

Advanced age is associated with declines in brain structure and in cognitive performance, but it is unclear which aspects of brain aging mediate cognitive declines. We inquired if individual differences in white matter integrity contribute to age differences in two cognitive domains with established vulnerability to aging: executive functioning and speed of processing. The participants were healthy volunteers aged 50-81, some of whom had elevated blood pressure, a known vascular risk factor. Using latent variable analyses, we examined whether age differences in regional white matter integrity mediated age-related differences in executive functions and speed of processing. Although diffusion-related latent variables showed stronger age differences than white matter volumes and white matter hyperintensity volumes, only one of them was significantly associated with cognitive performance. Smaller linear anisotropy partially mediated age-related reduction in speed of processing. The effect was significant in posterior (temporal-parietal-occipital) but not anterior (frontal) region, and appeared stronger for cognitive rather than reaction time measures of processing speed. The presence of hypertensive participants did not affect the results. We conclude that in healthy adults, deterioration of axonal integrity and ensuing breech of connectivity may underpin age-related slowing of information processing.

Blood–brain barrier impairment in dementia: Current and future in vivo assessments

Increasing evidence indicates that blood-brain barrier (BBB) impairment may play a role in the pathophysiology of cognitive decline and dementia. In vivo imaging studies are needed to quantify and localize the BBB defects during life, contemplating the circulatory properties. We reviewed the literature for imaging studies investigating BBB impairment in patients suffering from dementia. After selection, 11 imaging studies were included, of which 6 used contrast-enhanced magnetic resonance imaging (MRI), 2 used contrast-enhanced computed tomography (CT), and 3 positron emission tomography (PET). Primarily the MRI studies hint at a subtle increasing permeability of the BBB, particularly in patients already exhibiting cerebrovascular pathology. More elaborate studies are required to provide convincing evidence on BBB impairment in patients with various stages of dementia with and without obvious cerebrovascular pathology. In the future, dynamic contrast enhanced MRI techniques and transport specific imaging using PET may further detail the research on the molecular nature of BBB defects.

Neurovascular unit impairment in early Alzheimer's disease measured with magnetic resonance imaging

The neurovascular unit, which protects neuronal cells and supplies them with essential molecules, plays an important role in the pathophysiology of Alzheimers Disease (AD). The aim of this study was to noninvasively investigate 2 linked functional elements of the neurovascular unit, blood-brain barrier (BBB) permeability and cerebral blood flow (CBF), in patients with early AD and healthy controls. Therefore, both dynamic contrast-enhanced magnetic resonance imaging and arterial spin labeling magnetic resonance imaging were applied to measure BBB permeability and CBF, respectively. The patients with early AD showed significantly lower CBF and local blood volume in the gray matter, compared with controls. In the patients, we also found that a reduction in CBF is correlated with an increase in leakage rate. This finding supports the hypothesis that neurovascular damage, and in particular impairment of the neurovascular unit constitutes the pathophysiological link between CBF reduction and BBB impairment in AD.

Co-occurrence of Different Pathologies in Dementia: Implications for Dementia Diagnosis

The standard for differentiating between dementia subtypes is currently based on neuropathological changes and follows traditional nosological classifications. However, the high incidence of comorbid neuropathologies complicates the differentiation between dementia diagnoses in the clinic. The aim of this study was to investigate the grades of agreement between clinical and neuropathological diagnoses in neurodegenerative disorders, to compare them with rates found in previous studies, and to propose implications for dementia diagnostics. Patients, who donated their brains to the Brain Bank of Navarre (Pamplona, Spain), had been diagnosed with a neurodegenerative disorder during life (clinical diagnosis) and postmortem (neuropathological diagnosis). We studied a sample of patients with a short average time interval between the last clinical assessment and death (4.6 months). Overall, there was a mean grade of agreement of 44.0% between the clinical diagnosis and the pure neuropathological diagnosis (i.e., without co-morbid neuropathological disorders). This grade of agreement differed between dementia subtypes: e.g., 85% for prion disease, 49% for Alzheimers disease, and 0% for Lewy body dementia. Our data confirm that co-occurrence of multiple neuropathological disorders is very common in individuals with dementia, and that the underlying neuropathology often differs from the neuropathology implied by the clinical diagnosis. These findings support a multidimensional approach to diagnosing dementia, in which dementia syndromes are not categorized into diagnostic subtypes, but are seen as syndromes characterized by a combination of various neuropathological dimensions.

Amyloid-β interacts with blood-brain barrier function in dementia: a systematic review.

To date, the exact pathogenesis of dementia is still unknown. The most frequently hypothesized initiating factor is an accumulation of the protein amyloid-β in the brain, which has been associated with dementia of the Alzheimer type. Another potentially important initiating factor is a disrupted blood-brain barrier. This can initiate cerebral microangiopathy, which has frequently been associated with vascular dementia. Although amyloid-β and blood-brain barrier dysfunction have both been associated with one particular type of dementia (Alzheimers disease and vascular dementia, respectively), they co-exist in most demented patients. In fact, increasing evidence indicates that amyloid-β and blood-brain barrier disruption may interact and facilitate each other in their effect on neurodegeneration. The present systematic analysis describes the available evidence for a significant interplay between amyloid-β and blood-brain barrier function in dementia.

The posterior parahippocampal gyrus is preferentially affected in age-related memory decline.

Atrophy in the medial temporal lobe is generally considered to be highly associated with age-related memory decline. Volume loss in the hippocampus and entorhinal cortex has extensively been investigated, but the posterior parts of the parahippocampal gyrus have received little attention. The present MRI study investigated whether volume differences in medial temporal lobe areas are differentially related to age-related memory decline. Thirty-nine subjects from a longitudinal study on cognitive aging (the Maastricht Aging Study) have been examined: 20 participants (mean age=67 years, range 52-80) with memory decline over a period of 12 years were matched to 19 participants without memory decline. Manual tracing was performed on 3T MR images to measure the volumes of the anterior, middle and posterior parts of the hippocampus and parahippocampal gyrus. A robust group difference and a significant association with memory decline were observed only in the posterior part of the parahippocampal gyrus. Our results may suggest that the posterior parahippocampal gyrus plays a key role in age-related memory decline.

Increased neural activation during picture encoding and retrieval in 60-year-olds compared to 20-year-olds

Brain aging has been associated with both reduced and increased neural activity during task execution. The purpose of the present study was to investigate whether increased neural activation during memory encoding and retrieval is already present at the age of 60 as well as to obtain more insight into the mechanism behind increased activity. Eighteen young (mean age 21.3) and 18 older (mean age 59.9) right-handed male participants were administered two picture memory tasks in an fMRI environment. Neural activation was measured during encoding and retrieval of pictures of natural scenes (landscapes) and physical objects. Results indicated reduced medial temporal activity during encoding in older participants and increased activity during both encoding and retrieval in several other areas in the brain, including the inferior and dorsolateral prefrontal cortices. This increased activation was not related to better memory performance. The present findings indicate that increased neural activation during memory tasks is present in individuals near the age of 60 compared to individuals near the age of 20, which extends findings from studies of more-advanced age groups. Also, increased activation was present even though cognitive performance at 60 was not as impaired as is generally found in more-advanced age groups. Although compensation is a plausible explanation of the increased activation at this age, we suggest that other mechanisms like disinhibition, dedifferentiation, or the recruitment of less-efficient cognitive strategies may be more likely.

Sensitivity of Different MRI-Techniques to Assess Gray Matter Atrophy Patterns in Alzheimer’s Disease is Region-Specific

The present study compares four different structural magnetic resonance imaging techniques used to measure gray matter (GM) atrophy in Alzheimers disease (AD): manual and automated volumetry, cortical thickness (CT) and voxel-based morphometry (VBM). These techniques are used interchangeably in AD research and thus far it is unclear which technique is superior in detecting abnormalities early in the disease process. 18 healthy participants without any memory impairment, 18 patients with MCI, and 17 patients with mild AD were included and between-group differences were investigated in AD signature regions (areas in the prefrontal cortex (PFC), medial temporal lobe (MTL) and posterior parietal cortex (PPC)). Both manual volumetric measurements and VBM were able to detect GM atrophy in the early stages (differentiation controls and MCI), mainly in the MTL. In the early phase, automated volumetric measurements showed GM differences in the PPC but not in the MTL. In our sample, CT measurements were not sensitive for group differences in the early stages. PFC regions showed abnormalities in the later stages (controls vs AD) when manual volumetric measurements or VBM are employed. Manual volumetric measurements together with VBM are preferred techniques for assessing GM differences showing abnormalities in most of the investigated regions, with a predominance of the MTL in the early phase. Automated FreeSurfer volumetric measurements show similar performances in the early phase, displaying group differences in the PPC but not in MTL regions. Measurements of CT are less sensitive in the MCI stage and its sensitivity is restricted to the MTL and PPC regions in later stages of the disease (AD).

A time-saving and facilitating approach for segmentation of anatomically defined cortical regions: MRI volumetry

In this study, we present an accurate, reliable, robust, and time-efficient technique for a semi-automatic segmentation of neuroanatomically defined cortical structures in Magnetic Resonance Imaging (MRI) scans. It involves manual drawing of the border of a region of interest (ROI), supported by three-dimensional (3D) visualization techniques (rendering), and a subsequent automatic tracing of the gray matter voxels inside the ROI by means of an automatic tissue classifier. The approach has been evaluated on a set of MRI scans of 75 participants selected from the Maastricht Aging Study (MAAS) and applied to cortical brain structures for both the left and right hemispheres, viz., the inferior prefrontal cortex (PFC); the orbital PFC; the dorsolateral PFC; the anterior cingulate cortex; and the posterior cingulate cortex. The use of a 3D surface-rendered brain can be rotated in any direction was invaluable in identifying anatomical landmarks on the basis of gyral and sulcal topography. This resulted in a high accuracy (anatomical correctness) and reliability: the intra-rater intra-class correlation coefficient (ICC) was between 0.96 and 0.99. Furthermore, the obtained time savings were substantial, i.e., up to a factor of 7.5 compared with fully manual segmentations.