Small vessel pathology and microvascular lesions are no longer considered as minor players in the fields of cognitive impairment and mood regulation. Although frequently found in cognitively intact elders, both neuroimaging and neuropathological data revealed the negative impact on cognitive performances of their presence within neocortical association areas, thalamus and basal ganglia. Unlike cognition, the relationship between these lesions and mood dysregulation is still a matter of intense debate. Early studies focusing on the role of macroinfarct location in the occurrence of post-stroke depression (PSD) led to conflicting data. Later on, the concept of vascular depression proposed a deleterious effect of subcortical lacunes and deep white matter demyelination on mood regulation in elders who experienced the first depressive episode. More recently, the chronic accumulation of lacunes in thalamus, basal ganglia and deep white matter has been considered as a strong correlate of PSD. We provide here a critical overview of neuroimaging and neuropathological sets of evidence regarding the affective repercussions of vascular burden in the aging brain and discuss their conceptual and methodological limitations. Based on these observations, we propose that the accumulation of small vascular and microvascular lesions constitutes a common neuropathological platform for both cognitive decline and depressive episodes in old age.
Vascular burden; Cognitive impairment; Aging; Mood; Microvascular pathology; Lacunes
is a common psychiatric disorder in late life and it may be associated
with vascular disease processes. Although there are clinical and
neuroimaging studies lending support to such a "vascular
depression" hypothesis there have been no neuropathological studies
to directly test this. Postmortem tissue was investigated to determine
whether late life depression was associated with atheromatous change in
large and medium vessels and microvascular disease in the brain.
tissue wae obtained from 20 patients with a history of at least one
episode of DSM-IV major depression and 20 control subjects. Standard
procedures were carried out to analyze and quantify Alzheimer type
pathology (plaques, tangles, Braak staging) and cortical Lewy bodies.
Coronary arteries, cerebral vessels, and aorta were rated for
atheromatous disease on a 0-3 scale and the four neocortical areas
were rated for microvascular disease.
RESULTS—The two groups
showed no significant differences in age, sex, or postmortem delay.
There was a significant increase in atheromatous disease in the
depressed group (p=0.023). No differences were found for microvascular
disease, either in the brain generally or locally in the frontal lobes.
No subject had any significant Alzheimer type or Lewy body pathology.
evidence was found for an excess of atheromatous disease, related to
the aortic and cerebral vessels, in late life depression. However,
there was no evidence of an increase in microvascular disease. The
findings broadly support the vascular depression hypothesis.
Background and purpose
Most of the neuropathological studies in brain aging were based on the assumption of a symmetric right-left hemisphere distribution of both Alzheimer's disease (AD) and vascular pathology. To explore the impact of asymmetric lesion formation on cognition, we performed a clinicopathological analysis of 153 cases with mixed pathology except macroinfarcts.
Cognitive status was assessed prospectively using the Clinical Dementia Rating (CDR) scale; neuropathological evaluation included assessment of Braak neurofibrillary tangle (NFT) and Aß-deposition staging, microvascular pathology and lacunes. The right-left hemisphere differences in neuropathological scores were evaluated using the Wilcoxon signed rank test. The relationship between the interhemispheric distribution of lesions and CDR scores was assessed using ordered logistic regression.
Unlike Braak NFT and Aß deposition staging, vascular scores were significantly higher in the left hemisphere for all CDR scores. A negative relationship was found between Braak NFT, but not Aß, staging and vascular scores in cases with moderate to severe dementia. In both hemispheres, Braak NFT staging was the main determinant of cognitive decline followed by vascular scores and Aß deposition staging. The concomitant predominance of AD and vascular pathology in the right hemisphere was associated with significantly higher CDR scores.
Our data show that the cognitive impact of AD and vascular lesions in mixed cases may be assessed unilaterally without major information loss. However, interhemispheric differences and, in particular, increased vascular and AD burden in the right hemisphere may increase the risk for dementia in this group.
Alzheimer; cerebral infarct; cognition; white matter disease
Current studies suggest an interaction between vascular mechanisms and neurodegenerative processes that leads to late-onset Alzheimer disease (AD). We tested whether AD pathology was associated with white matter hyperintensities (WMH) or cerebral infarcts in the oldest old individuals.
Brains from 132 subjects over 85 years old, who came to autopsy from the Vantaa 85+ population-based cohort, were scanned by postmortem MRI and examined for neuropathologic changes. Coronal images were analyzed to determine the degree of frontal and parietal periventricular WMH (PVWMH) and deep WMH (DWMH) and cerebral infarcts. Neuropathologic variables included Consortium to Establish a Registry for Alzheimer's Disease scores for neuritic plaques and Braak staging among subjects in 5 groups: normal aging (NA), borderline with insufficient AD pathology, AD, AD plus other pathology, and other primary degenerative diseases.
Frontal DWMH were detected in >50% of the sample. Both frontal PVWMH and DWMH were significantly more extensive in the AD group compared to the NA group or the NA and borderline groups combined. Frontal PVWMH and DWMH were also associated with increased Braak staging (p = 0.03) and the neuritic plaque load (p = 0.01). Further analysis revealed there were a greater number of cerebral infarcts associated with frontal DWMH (p = 0.03) but not with frontal PVWMH.
Our study showed an association between neurofibrillary pathology and frontal PVWMH and DWMH (rather than parietal), as a surrogate of small vessel disease, particularly in very old community-dwelling individuals.
= Alzheimer disease;
= argyrophilic grain disease;
= Consortium to Establish a Registry for Alzheimer's Disease;
= cerebrovascular disease;
= dementia with Lewy bodies;
= diffusion tensor imaging;
= deep white matter hyperintensities;
= magnetic resonance;
= normal aging;
= periventricular white matter hyperintensities;
= vascular dementia;
= white matter;
= white matter hyperintensities.
To examine whether the association between clinical Alzheimer disease (AD) diagnosis and neuropathology and the precision by which neuropathology differentiates people with clinical AD from those with normal cognition varies by age.
We conducted a cross-sectional analysis of 2,014 older adults (≥70 years at death) from the National Alzheimer's Coordinating Center database with clinical diagnosis of normal cognition (made ≤1 year before death, n = 419) or AD (at ≥65 years, n = 1,595) and a postmortem neuropathologic examination evaluating AD pathology (neurofibrillary tangles, neuritic plaques) and non-AD pathology (diffuse plaques, amyloid angiopathy, Lewy bodies, macrovascular disease, microvascular disease). We used adjusted logistic regression to analyze the relationship between clinical AD diagnosis and neuropathologic features, area under the receiver operating characteristic curve (c statistic) to evaluate how precisely neuropathology differentiates between cognitive diagnoses, and an interaction to identify effect modification by age group.
In a model controlling for coexisting neuropathologic features, the relationship between clinical AD diagnosis and neurofibrillary tangles was significantly weaker with increasing age (p < 0.001 for interaction). The aggregate of all neuropathologic features more strongly differentiated people with clinical AD from those without in younger age groups (70–74 years: c statistic, 95% confidence interval: 0.93, 0.89–0.96; 75–84 years: 0.95, 0.87–0.95; ≥85 years: 0.83, 0.80–0.87). Non-AD pathology significantly improved precision of differentiation across all age groups (p < 0.004).
Clinical AD diagnosis was more weakly associated with neurofibrillary tangles among the oldest old compared to younger age groups, possibly due to less accurate clinical diagnosis, better neurocompensation, or unaccounted pathology among the oldest old.
In a prospective study of primary care patients with diabetes we determined whether macrovascular or microvascular events or coronary, cerebrovascular or peripheral vascular procedures during follow-up were associated with meeting criteria for major depression at 5-year follow-up.
Design, Patients and Measurements
A total of 2759 patients with diabetes mellitus were followed over a 5-year period. Evidence of macrovascular and microvascular events and coronary, cerebrovascular and peripheral vascular procedures was assembled from automated data using ICD-9 and CPT codes and was verified by chart review. Depression was measured using the Patient Health Questionnaire.
After controlling for baseline severity of depression symptoms and history of depression, having 1 or more coronary procedures during follow-up, and baseline severity of diabetes symptoms were strong predictors of having major depression at 5-year follow-up.
The risk of major depression among persons with diabetes is increased by prior depression history, baseline diabetes symptoms, and cardiovascular procedures.
OBJECTIVES—To better define the neuropathology of
METHODS—The neuropathological findings in 18 elderly, undemented subjects free of cerebrovascular disease were
compared with 19 elderly undemented subjects who had cerebrovascular
disease (many of whom had had a "stroke") and 24 elderly demented
subjects who had cerebrovascular disease, but no other pathology to
account for dementia. Cases in all groups were selected for absence or
no more than very mild Alzheimer type pathology.
RESULTS—Microvascular brain damage in the form of
severe cribriform change and associated subcortical white matter damage
and microinfarction were correlated with a history of dementia. Severe
cribriform change was much more common and microinfarction somewhat
more common in the demented group with vascular disease than the
undemented group with vascular disease (P=0.0006 and P=0.031
respectively). Other findings of note were that congophilic angiopathy
had a greater prevalence in the vascular dementia group than the
control group, single cerebral infarcts were more common in the group who were undemented with vascular disease than in the group with dementia and vascular disease (P=0.0028), and the last group lacked evidence of macroscopic infarction more often than the first (P=0.034). There was a non-significant trend for the ratio of
infarcted:uninfarcted tissue in one cerebral hemisphere to be higher in
the group with dementia and vascular disease than in the group with
vascular disease but no dementia.
CONCLUSIONS—Microvascular disease, not macroscopic
infarction, was the chief substrate of vascular dementia in this series
Background: Microangiopathic brain lesions can be separated in diffuse lesions – leukoaraiosis – and focal lesions – lacunes. Leukoaraiosis and lacunes are caused by common cerebrovascular risk factors, but whether they represent a common entity is not sufficiently investigated. The present study aimed to determine the clinical profiles associated with the extent of leukoaraiosis and lacunes. Methods: Sixty-four consecutive patients with acute microangiopathic stroke were studied. Leukoaraiosis and lacunes were stratified according to their MRI-based extent. Standardized clinical assessment included clinical syndromes, cerebrovascular risk factors, cognitive performance, retinal imaging, ultrasonography, blood, and urine parameters. Results: Different clinical profiles for leukoaraiosis and lacunes were found. Regarding leukoaraiosis, the cognitive scores (SISCO, mini mental score examination, mental examination) and the presence of hyperlipidemia decreased as the severity of leukoaraiosis increased. Univariate and multivariate analysis revealed that these cognitive score values as well as the presence of hyperlipidemia correlated significantly with no or only mild leukoaraiosis. Regarding lacunes, the percentage of migraine, previous stroke events, hydrocephalus, left ventricular hypertrophy, and a higher National Institutes of Health Stroke Scale increased as the number of lacunar lesions increased. Statistical analysis revealed that these parameters correlated not significantly with the number of lacunes. Conclusions: The findings suggests that leukoaraiosis and lacunes are different microangiopathic entities potentially requiering different treatment concepts.
microangiopathic brain lesions; leukoaraiosis; lacunar lesion; cardiovascular risk factor
Previous reports showed that patients with Alzheimer disease (AD) frequently have coexisting vascular-related pathologies, such as cerebral infarcts and white matter lesions. The aim of this study was to determine the effects of subcortical lacunar infarcts on brain structure in patients with AD. Semi-automated tissue segmentation and volumetry of magnetic resonance imaging data were performed in 38 AD patients without lacunes (AD-L), 24 AD patients with subcortical lacunes (AD+L), and 40 age-matched cognitively healthy subjects without lacunes. The following tissue volumes were quantified, expressed as percentage of total intracranial volume: ventricular cerebrospinal fluid (CSF), sulcal CSF, cortical gray matter (GM), subcortical GM, white matter (WM), white matter signal hyperintensities (WMSH), lacunes, and hippocampus. There was no difference in the Mini-Mental State Examination between the two AD groups. AD+L patients compared with AD-L subjects had significantly greater volumes of WMSH and ventricular CSF spaces (as expected) but smaller sulcal CSF spaces and no significant increase in cortical GM atrophy (both unexpected). In the AD groups, ventricular CSF correlated inversely with cortical GM but not with WM; sulcal CSF correlated inversely with cortical GM and WM. Cognitive impairment was associated with sulcal CSF volume but not with volumes of WMSH or lacunes. In conclusion, the presence of subcortical lacunes in those with AD is associated with more WM lesions and ventriculomegaly but not with cortical atrophy.
Alzheimer disease; Cerebral infarcts; Magnetic resonance imaging
Depression is found in 30–40% of all patients with Parkinson’s disease (PD), but its etiology is unclear. Using neuropathology as a signpost for neurotransmitter function, we investigated the prevalence of pathological features found at postmortem and sought to uncover differences between depressed (n = 11) and non-depressed (n = 9) elderly PD patients. The results indicate a higher prevalence of pathological features in depressed compared to non-depressed PD patients, particularly in catecholamine areas of the brain; the locus coeruleus (neuronal loss: odds ratio = 7.2, p = 08; gliosis: odds ratio = 18.0, p = 008); dorsal vagus nerve (gliosis: odds ratio = 7.63, p < 0.05), and substantia nigra pars compacta (gliosis: odds ratio 2.85, ns). However, neuropathological differences were absent in the dorsal raphe nuclei, amygdala, and cortical regions. Our evidence suggests that depression in PD is related more to catecholaminergic than serotonergic system dysfunction.
Depression; Parkinson’s disease; Clinical-neuropathological
Subcortical ischemic vascular dementia (SIVD) has been proposed as a subtype of vascular cognitive impairment (VCI). The syndrome is defined clinically by cognitive impairment and evidence of subcortical vascular brain injury, including lacunar infarcts and deep white matter changes. SIVD has been traditionally recognized as lacunar state, strategic infarct dementia, and Binswanger syndrome, but these clinical syndromes represent the tip of the iceberg. Proton density magnetic resonance (MRI) often discloses “silent” hyperintensities in 20-40% of community dwelling elderly. Efforts to relate MRI-measured lacunes and white matter changes to cognitive impairment have not been straightforward. The hidden possibility that concomitant Alzheimer disease pathology contributes significantly to cognitive impairment increases with age. Nonetheless, new knowledge is being gained from longitudinal MRI and systematic neuropathological studies. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukencephalopathy (CADASIL), a rare genetic disorder, provides an opportunity to study pure SIVD in the absence of AD. Dysexecutive syndrome characterized by slowing of mental processing speed, decreased working memory, and impairment of abstract reasoning are associated with lacunes and deep white matter changes. But data related to sensitivity and specificity which would support dysexecutive syndrome as diagnostic criteria are limited. Hypertension, by far the leading risk factor for sporadic SIVD, is eminently treatable. High priority must be given to reducing vascular risk profiles.
vascular dementia; subcortical; ischemia; lacunes; white matter changes
Vascular cognitive impairment is an umbrella term for cognitive dysfunction associated with and presumed to be caused by vascular brain damage. Autopsy studies have identified microinfarcts as an important neuropathological correlate of vascular cognitive impairment that escapes detection by conventional magnetic resonance imaging (MRI). As a frame of reference for future high-resolution MRI studies, we systematically reviewed the literature on neuropathological studies on cerebral microinfarcts in the context of vascular disease, vascular risk factors, cognitive decline and dementia. We identified 32 original patient studies involving 10,515 people. The overall picture is that microinfarcts are common, particularly in patients with vascular dementia (weighted average 62%), Alzheimer's disease (43%), and demented patients with both Alzheimer-type and cerebrovascular pathology (33%) compared with nondemented older individuals (24%). In many patients, multiple microinfarcts were detected. Microinfarcts are described as minute foci with neuronal loss, gliosis, pallor, or more cystic lesions. They are found in all brain regions, possibly more so in the cerebral cortex, particularly in watershed areas. Reported sizes vary from 50 μm to a few mm, which is within the detection limit of current high-resolution MRI. Detection of these lesions in vivo would have a high potential for future pathophysiological studies in vascular cognitive impairment.
cerebral microinfarct; cerebrovascular disease; dementia; MRI; neuropathology
Introduction. Late onset depressive symptoms (LODSs) frequently occur in elderly with cerebral small vessel disease (SVD). SVD cannot fully explain LODS; a contributing factor could be amygdala volume. We investigated the relation between amygdala volume and LODS, independent of SVD in 503 participants with symptomatic cerebral SVD. Methods. Patients underwent FLAIR and T1 scanning. Depressive symptoms were assessed with structured questionnaires; amygdala and WML were manually segmented. The relation between amygdala volume and LODS/EODS was investigated and adjusted for age, sex, intracranial volume, and SVD. Results. Patients with LODS had a significantly lower left amygdala volume than those without (P = 0.02), independent of SVD. Each decrease of total amygdala volume (by mL) was related to an increased risk of LODS (OR = 1.77; 95% CI 1.02–3.08; P = 0.04).
Conclusion. Lower left amygdala volume is associated with LODS, independent of SVD. This may suggest differential mechanisms, in which individuals with a small amygdala might be vulnerable to develop LODS.
Formalin-fixed brain slices from four cases of subcortical arteriosclerotic encephalopathy in which a firm diagnosis could be made both clinically and pathologically have been studied by magnetic resonance imaging (MRI). The slices were subsequently embedded in paraffin-wax or celloidin and sections were cut in the same plane as the MRI slices. There was a good correlation between the extent and severity of the abnormal MRI signal and the pathological changes. Areas of diffuse MRI abnormality corresponded with areas of axonal and myelin loss with gliosis, and small "lacune"-like lesions corresponded with lacunar infarcts histologically. Sparing of the subcortical U-fibres was seen histologically and on MRI. The abnormal signal probably originates from increased tissue water attributable to gliosis and an expanded extracellular space.
The association between small but still visible lacunar infarcts and cognitive decline has been established by multiple population-based radiological and pathological studies. Microscopic examination of brain sections reveals even smaller but substantially more numerous microinfarcts, the focus of the current review. These lesions often result from small vessel pathologies such as arteriolosclerosis or cerebral amyloid angiopathy. They typically go undetected in clinical-radiological correlation studies that rely on conventional structural MRI, though the largest acute microinfarcts may be detectable by diffusion-weighted imaging. Given their high numbers and widespread distribution, microinfarcts may directly disrupt important cognitive networks and thus account for some of the neurologic dysfunction seen in association with lesions visible on conventional MRI such as lacunar infarcts and white matter hyperintensities. Standardized neuropathological assessment criteria and development of non-invasive means of detection during life would be major steps towards understanding the causes and consequences of the otherwise macroscopically invisible microinfarct.
We examined the magnetic resonance imaging (MRI) correlates of depressed mood, apathy, anhedonia, and anergia in older adults with and without cognitive impairment or dementia.
This analysis included 270 community-dwelling older adults (59% male; 79% Caucasian; mean age 74.4 years) who were recruited into a multi-center longitudinal observational study of subcortical ischemic vascular disease (SIVD).The distribution of cognitive status included: cognitively intact (38%), cognitively impaired (27%), or demented (35%). All subjects underwent MRI and 41% were classified as having subcortical lacunes. MRI measures included cortical gray and white matter volumes, lacunar volumes in subcortical white and gray matter structures, volume of white matter hyperintensities, and total hippocampal volume. Depressed mood, anhedonia, anergia, and apathy apparent at the time of assessment were assessed using a behavioral assessment Associations between neuropsychiatric symptoms and MRI variables were evaluated using logistic regression.
Subjects with neuropsychiatric symptoms were more likely to be cognitively impaired or demented than those without neuropsychiatric symptoms. In multivariate models controlling for cognitive status, age, gender, and education, higher lacunar volume in white matter was independently associated with the presence of all four neuropsychiatric symptoms.
We report an association between the lacunar volumes in the white matter and depressed mood, anhedonia, apathy, and anergia, thus supporting the role of subcortical ischemic vascular disease in the pathogenesis of late-life neuropsychiatric disorders.
late-life neuropsychiatric symptoms; depression; apathy; anhedonia; anergia; subcortical ischemic vascular disease; hippocampal volume; magnetic resonance imaging (MRI)
Studies suggest early onset depression (EOD) is associated with a more severe course of the depressive disorder, while late onset depression (LOD) is associated with more cognitive and neuroimaging changes. This study examined if older adults with EOD, compared with those with LOD, would exhibit more severe symptoms of depression and, consistent with the glucocorticoid cascade hypothesis, have more hippocampal volume loss. A second goal was to determine if LOD, compared with EOD, would demonstrate more cognitive and neuroimaging changes.
At regular intervals over a four year period non-demented, older, depressed adults were assessed on the Mini Mental Status Examination (MMSE) and the Montgomery-Asberg Depression Rating Scale (MADRS). They were also assessed on Magnetic Resonance Imaging (MRI).
Compared with LOD, EOD had more depressive symptoms, more suicidal thoughts, and less social support. Growth curve analyses indicated that EOD demonstrated higher levels of residual depressive symptoms over time. The LOD group exhibited a greater decrement in cognitive scores. Contrary to the glucocorticoid cascade hypothesis, participants with EOD lost right hippocampal volume at a slower rate than did participants with LOD. Right cerebrum gray matter was initially smaller among participants with LOD.
EOD is associated with greater severity of depressive illness. LOD is associated with more severe cognitive and neurological changes. These differences are relevant to understanding cognitive impairment in geriatric depression.
late-onset depression; early-onset depression; cognition; hippocampus
To test the hypothesis that microvascular brain pathology is associated with late-life motor impairment.
More than 2,500 persons participating in the Religious Orders Study or the Memory and Aging Project agreed to annual motor assessment and autopsy. Brains from 850 deceased participants were assessed for microvascular pathology including microinfarcts, cerebral amyloid angiopathy, and arteriolosclerosis, and we examined their association with global motor scores proximate to death.
Mean age at death was 88.5 years. More than 60% of cases had evidence of 1 or more microvascular pathologies and of these more than half did not have observed macroinfarcts. In separate regression models adjusted for age, sex, and education, microinfarcts and arteriolosclerosis were associated with level of motor function proximate to death (arteriolosclerosis, estimate, −0.027, SE 0.005, p < 0.001; microinfarcts, estimate, −0.017, SE 0.008, p = 0.026). These associations were not attenuated when controlling for vascular risk factors and diseases, postmortem interval, or interval from last clinical examination, and did not vary with level of cognition or presence of dementia proximate to death. When the 3 microvascular pathologies, macroinfarcts, and atherosclerosis were considered together in a single model, more severe arteriolosclerosis (estimate, −0.021, SE 0.005, p < 0.001) and macroinfarcts (estimate, −0.019, SE 0.006, p < 0.001) showed separate effects with the level of motor function proximate to death.
Microvascular brain pathology is common in older adults and may represent an under-recognized, independent cause of late-life motor impairment.
Cerebellar ataxia is a prominent clinical symptom in patients with mitochondrial DNA (mtDNA) disease. Often this is progressive with onset in young adulthood. Here, we performed a detailed neuropathological investigation of the olivary-cerebellum in 14 genetically and clinically well-defined patients with mtDNA disease. Quantitative neuropathological investigation showed varying levels of loss of Purkinje cells, and neurons of the dentate nucleus and inferior olivary nuclei. Typically, focal Purkinje cell loss was present in patients with the m.3243A>G mutation due to the presence of microinfarcts with relative preservation of neuronal cell populations in olivary and dentate nuclei. In contrast, patients with the m.8344A>G mutation or recessive POLG mutations showed extensive and global neuronal cell loss in all 3 olivary-cerebellum areas examined. Molecular analysis of mutated mtDNA heteroplasmy levels revealed that neuronal cell loss occurred independently of the level of mutated mtDNA present within surviving neurons. High levels of neuronal respiratory chain deficiency, particularly of complex I, were detected in surviving cells; levels of deficiency were greater in regions with extensive cell loss. We found a relationship between respiratory deficiency and neuronal cell density, indicating that neuronal cell death correlates with respiratory deficiency. These findings highlight the vulnerability of the olivary-cerebellum to mtDNA defects.
Cerebellar ataxia; Mitochondrial DNA; Mitochondrial disease; Neurodegeneration; Olivo-Cerebellum
Depression is a common psychiatric complication of diabetes, but little is known about the natural course and the consequences of depressive symptoms in primary care patients with type 2 diabetes. While depression has been related to poor glycemic control and increased risk for macrovascular disease, its association with microvascular complications remains understudied. The predictive role of other psychological risk factors such as Type D (distressed) personality and the mechanisms that possibly link depression and Type D personality with poor vascular outcomes are also still unclear.
This prospective cohort study will examine: (1) the course of depressive symptoms in primary care patients with type 2 diabetes; (2) whether depressive symptoms and Type D personality are associated with the development of microvascular and/or macrovascular complications and with the risk of all-cause or vascular mortality; and (3) the behavioral and physiological mechanisms that may mediate these associations. The DiaDDZoB Study is embedded within the larger DIAZOB Primary Care Diabetes study, which covers a comprehensive cohort of type 2 diabetes patients treated by over 200 primary care physicians in South-East Brabant, The Netherlands. These patients will be followed during their lifetime and are assessed annually for demographic, clinical, lifestyle and psychosocial factors. Measurements include an interviewer-administered and self-report questionnaire, regular care laboratory tests and physical examinations, and pharmacy medication records. The DiaDDZoB Study uses data that have been collected during the original baseline assessment in 2005 (M0; N = 2,460) and the 2007 (M1; N = 2,225) and 2008 (M2; N = 2,032) follow-up assessments.
The DiaDDZoB Study is expected to contribute to the current understanding of the course of depression in primary care patients with type 2 diabetes and will also test whether depressed patients or those with Type D personality are at increased risk for (further) development of micro- and cardiovascular disease. More knowledge about the mechanisms behind this association is needed to guide new intervention studies.
Transverse myelopathy is an uncommon complication of systemic lupus erythematosus (SLE). Three patients with SLE are reported who developed transverse myelopathy, including the neuropathological findings in one patient on whom necropsy was performed. Paraparesis was present in all three cases, but definite sensory changes were present in only one patient. In two patients, the CSF findings were remarkable for elevated protein and depressed glucose concentrations. Microscopic examination of the brain demonstrated small, scattered foci of recent necrosis consistent with microinfarctions. Striking abnormalities were found in the spinal cord at all levels, including multiple foci of vacuolar spongy degeneration in the peripheral white matter, as well as ballooning of myelin sheaths, swollen axons, myelin pallor, and loss of glial nuclei. The pathological findings in previously reported cases of SLE-related transverse myelopathy are reviewed, and the possible pathogenesis of the findings in our case are discussed.
Lacunar (small deep cerebral infarcts) infarction is described in association with raised packed cell volumes. Two patients had polycythaemia vera, one stress polycythaemia. They presented with transient ischaemic episodes and were shown by computed tomography to have lacunes deep in the basal ganglia and internal capsule. Such lesions may be caused by small vessel occlusions related to increased viscosity and impaired oxygen consumption by adjacent tissues. Finding a raised packed cell volume in patients with lacunes and transient ischaemic attacks offers a further possibility of treatment.
Cerebral small vessel disease (CSVD, cerebral microangiopathy) leads to dementia and stroke-like symptoms. Lacunes, white matter lesions (WML) and microbleeds are the main pathological correlates depicted in in-vivo imaging diagnostics. Early studies described segmental arterial wall disorganizations of small penetrating cerebral arteries as the most pronounced underlying histopathology of lacunes. Luminal narrowing caused by arteriolosclerosis was supposed to result in hypoperfusion with WML and infarcts.
We have used the model of spontaneously hypertensive stroke-prone rats (SHRSP) for a longitudinal study to elucidate early histological changes in small cerebral vessels. We suggest that endothelial injuries lead to multiple sites with blood brain barrier (BBB) leakage which cause an ongoing damage of the vessel wall and finally resulting in vessel ruptures and microbleeds. These microbleeds together with reactive small vessel occlusions induce overt cystic infarcts of the surrounding parenchyma. Thus, multiple endothelial leakage sites seem to be the starting point of cerebral microangiopathy. The vascular system reacts with an activated coagulatory state to these early endothelial injuries and by this induces the formation of stases, accumulations of erythrocytes, which represent the earliest detectable histological peculiarity of small vessel disease in SHRSP.
In this review we focus on the meaning of the BBB breakdown in CSVD and finally discuss possible consequences for clinicians.
Animal model; Blood brain barrier; Cerebral microbleeds; Cerebral small vessel disease; SHRSP
Cerebral small vessel disease-related brain lesions such as white matter lesions and lacunes are common findings of magnetic resonance imaging in the elderly. These lesions are thought to be major contributors to disability in old age, and risk factors that include age and hypertension have been established. The radiological, histopathologic and clinical phenotypes of age-related cerebral small vessel disease remarkably resemble autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy, which is caused by mutations in NOTCH3. We hypothesized that genetic variations in NOTCH3 also play a role in age-related cerebral small vessel disease. We directly sequenced all 33 exons, the promoter and 3′-untranslated region of NOTCH3 in 195 participants with either coalescent white matter lesions or lacunes and compared the results to 82 randomly selected participants with no focal changes on magnetic resonance images in the Austrian Stroke Prevention Study. We detected nine common and 33 rare single nucleotide polymorphisms, of which 20 were novel. All common single nucleotide polymorphisms were genotyped in the entire cohort (n = 888), and four of them, rs1043994, rs10404382, rs10423702 and rs1043997, were associated significantly with both the presence and progression of white matter lesions. The association was confined to hypertensives, a result which we replicated in the Cohorts for Heart and Ageing Research in Genomic Epidemiology Consortium on an independent sample of 4773 stroke-free hypertensive elderly individuals of European descent (P = 0.04). The 33 rare single nucleotide polymorphisms were scattered over the NOTCH3 gene with three being located in the promoter region, 24 in exons (18 non-synonymous), three in introns and three in the 3′-untranslated region. None of the single nucleotide polymorphisms affected a cysteine residue. Sorting Intolerant From Tolerant, PolyPhen2 analyses and protein structure simulation consistently predicted six of the non-synonymous single nucleotide polymorphisms (H170R, P496L, V1183M, L1518M, D1823N and V1952M) to be functional, with four being exclusively or mainly detected in subjects with severe white matter lesions. In four individuals with rare non-synonymous single nucleotide polymorphisms, we noted anterior temporal lobe hyperintensity, hyperintensity in the external capsule, lacunar infarcts or subcortical lacunar lesions. None of the observed abnormalities were specific to cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy. This is the first comprehensive study investigating (i) the frequency of NOTCH3 variations in community-dwelling elderly and (ii) their effect on cerebral small vessel disease related magnetic resonance imaging phenotypes. We show that the NOTCH3 gene is highly variable with both common and rare single nucleotide polymorphisms spreading across the gene, and that common variants at the NOTCH3 gene increase the risk of age-related white matter lesions in hypertensives. Additional investigations are required to explore the biological mechanisms underlying the observed association.
NOTCH3; cerebral small vessel disease; genetics; MRI; ageing
Neuropathologic change underlying primary progressive aphasia (PPA) most commonly includes one of the frontotemporal lobar degenerations, such as FTLD-tau or FTLD-ubiquitin. The next most frequent etiology of PPA is Alzheimer’s disease (AD). We describe 5 subjects with clinical diagnoses of semantic dementia, who underwent longitudinal clinical evaluation and postmortem neuropathology examination of the central nervous system. This case series examines retrospectively which clinical parameters might have pointed to the neuropathological diagnosis of AD.
Family history of late onset dementia, APOEε4 status, combined features of semantic dementia and progressive non-fluent aphasia present early in illness, or generalized seizures, may indicate AD as the underlying pathology of semantic dementia.