Multiple biochemical deficits in both gray and white matter of Alzheimer brains

A biochemical investigation of 21 brains from patients with dementia of Alzheimer type (AD/SDAT) and 22 brains from controls was made. In the normal brains 5-hydroxytryptamine (5-HT), noradrenaline (NA) and dopamine (DA) were reduced with age while their metabolites were not reduced. In the brains from the Alzheimer patients the examination of gray matter (caudate nucleus and hippocampus) showed a significant reduced activity of choline-acetyl transferase (CAT) and a reduction of acetylcholinesterase (AChE) that bordered significance in the hippocampus. In the brains from the Alzheimer patients a disturbance was found in the 5-HT system in the form of reduced levels of 5-HT and 5-hydroxyindolacetic acid (5-HIAA). The catecholamine systems were also disturbed but to a less extent. In the 5-HT and DA systems the active amines as well as the metabolites were reduced in the brains from patients with AD/SDAT indicating not only a possible neuronal loss but also an incapacity of the remaining neurons to compensate for the loss by an increased turnover. The lipid content was slightly reduced in gray matter of the demented brains. In white matter there was a more severe reduction of the lipids and in this tissue also the cerebrosides and sulfatides were reduced. It is concluded that in brains from patients with AD/SDAT there are multiple biochemical deficits in gray as well as in white matter. The changes in white matter may be of pathogenetic importance in subgroups of AD/SDAT.     

A quantitative study of the pathological changes in white matter in multiple system atrophy

The density and spatial distribution of the vacuoles, glial cell nuclei and glial cytoplasmic inclusions (GCI) were studied in the white matter of various cortical and subcortical areas in 10 cases of multiple system atrophy (MSA). Vacuolation was more prevalent in subcortical than cortical areas and especially in the central tegmental tract. Glial cell nuclei widespread in all areas of the white matter studied; overall densities of glial cell nuclei being significantly greater in the central tegmental tract and frontal cortex compared with areas of the pons. The GCI were present most consistently in the external and internal capsules, the central tegmental tract and the white matter of the cerebellar cortex. The density of the vacuoles was greater in the MSA brains than in the control brains but glial cell density was similar in both groups. In the majority of areas, the pathological changes were distributed across the white matter randomly, uniformly, or in large diffuse clusters. In most areas, there were no spatial correlations between the vacuoles, glial cell nuclei and GCI. These results suggest: (i) there is significant degeneration of the white matter in MSA characterized by vacuolation and GCI; (ii) the central tegmental tract is affected significantly more than the cortical tracts; (iii) pathological changes are diffusely rather than topographically distributed across the white matter; and (iv) the development of the vacuoles and GCI appear to be unrelated phenomena.     

Postmortem MRI changes of the brains of the rats of different ages

Brain degenerative changes were studied in the rats of different ages after cervical dislocation by T(2) MRI and histology. Appearance of dark spots in the T(2) images increased with increased duration after death. Quantitative analysis of the density of these spots revealed that the neonatal (1 week) and the old (9 months) animals had accelerated degenerative changes when compared with the young adult (1 month). The degenerative changes correlated with the accumulation of vacuoles or spaces in the brain tissue histologically. This study pointed out not only brain degenerative changes after death were associated with age, it also revealed that the MRI T(2) evaluations could be used as a way in postmortem investigation.     

CT and MRI rating of white matter changes

The impact of white matter changes (WMC) detectable on CT or MRI on various diseases like ischemic stroke and intracerebral hemorrhage and their association with cognitive impairment was and still is under debate. To assess WMC in a qualitative and/or semiquantitative fashion rating scales have been developed. For MRI most widely used scales are the scales of Manolio, Fazekas, Schmidt, and Scheltens. Most recently a new scale extending earlier suggestions has been introduced by Wahlund et al. applicable for both CT and MRI. This article will review strengths and weaknesses of these rating scales and will discuss further requirements and future perspectives.     

Microglial activation in white matter lesions and nonlesional white matter of ageing brains

White matter lesions (WML), a common feature in brain ageing, are classified as periventricular (PVL) or deep subcortical (DSCL), depending on their anatomical location. Microglial activation is implicated in a number of neurodegenerative diseases, but the microglial response in WML is poorly characterized and its role in pathogenesis unknown. We have characterized the microglial response in WML and control white matter using immunohistochemistry to markers of microglial activation and of proliferation. WML of brains from an unbiased population-based autopsy cohort (Medical Research Council's Cognitive Function and Ageing Study) were identified by post mortem magnetic resonance imaging and sampled for histology. PVL contain significantly more activated microglia, expressing major histocompatibility complex (MHC) class II and the costimulatory molecules B7-2 and CD40, than either control white matter (WM) or DSCL. Furthermore, we show that significantly more microglia express the replication licensing protein minichromosome maintenance protein 2 within PVL, suggesting this is a more proliferation-permissive environment than DSCL. Although microglial activation occurs in both PVL and DSCL, our findings suggest a difference in pathogenesis between these lesion-types: the ramified, activated microglia associated with PVL may reflect immune activation resulting from disruption of the blood brain barrier, while the microglia within DSCL may reflect an innate, amoeboid phagocytic phenotype. We also show that microglia in control WM from lesional cases express significantly more MHC II than control WM from nonlesional ageing brain, suggesting that WML occur in a 'field-effect' of abnormal WM.     

Comparison of MRI white matter changes with neuropsychologic impairment in Cockayne syndrome.

The neuropsychologic function and white matter changes observed on magnetic resonance imaging (MRI) in Cockayne syndrome were studied. MRI with T2-weighted sequences revealed periventricular hyperintensity and white matter hyperintensity in all 3 Cockayne syndrome patients examined; in contrast, 8 age-matched controls had no periventricular or white matter hyperintensity. MRI scans were graded according to the severity of periventricular or white matter hyperintensity using a scale applied to an elderly patient population. There was no difference in the severity of MRI white matter changes in these 3 Cockayne syndrome patients, 2 of whom had severe neuropsychologic functions and one a relatively milder one. There was no correlation between neuropsychologic impairment and MRI white matter changes.     

MRI signal changes in the white matter after corpus callosotomy

Magnetic resonance imaging (MRI) changes reported after corpus callosotomy include hyperintensity in the corpus callosum, perifalcine hyperintensity caused by surgical retraction, and acute changes associated with surgical complications. The authors have observed MRI signal changes in the cerebral white matter of corpus callosotomy patients that are separate from the sectioned callosum and not clearly related to surgical manipulation or injury. Brain MRI scans were retrospectively reviewed in 25 of 38 patients who underwent anterior, posterior, or total callosotomy for refractory seizures between 1988 and 1995. Nine patients had signal changes in the cerebral white matter on postoperative MRI. Six of these patients had preoperative MRI studies available for comparison, and none of the white matter signal abnormalities were evident preoperatively. T2 prolongation or hyperintensity on proton-density images was observed in areas including the centrum semiovale, forceps major, and forceps minor. Three patients had signal changes that had distinct borders extending only to the posterior limit of the callosotomy. MRI signal changes in the cerebral white matter after corpus callosotomy have not been previously reported and may represent distant effects of callosal section. Wallerian degeneration occurring in the neuronal processes cut during surgery could account for the signal changes.     

MRI study of white matter diffusion anisotropy in schizophrenia

Diffusion tensor imaging (DTI) can provide information about brain white matter integrity. The results of DTI studies in schizophrenia are somewhat variable and could benefit from standardized image processing methods. Fourteen patients with schizophrenia or schizoaffective disorder and 14 healthy volunteers underwent DTI. Scans were analyzed using a rigorous voxelwise approach. The key dependent variable, fractional anisotropy, was lower for patients in the corpus callosum, left superior temporal gyrus, parahippocampal gyri, middle temporal gyri, inferior parietal gyri, medial occipital lobe, and the deep frontal perigenual region. Regions showing reduced white matter fractional anisotropy are known to be abnormal in schizophrenia. The voxelwise method used in the current study can provide the basis for hypothesis-driven research.     

Cerebral white matter perfusion in dementia of Alzheimer type.

Local cerebral blood flow was measured in 19 patients with probable dementia of Alzheimer type (DAT) by using xenon-enhanced computerized tomography (CT) and CT densitometry to accurately differentiate white from gray matter. Patients met standard diagnostic criteria for probable DAT and results were compared with similar measures in 26 age-matched, neurologically and cognitively normal volunteers. Perfusions of frontal and occipital white matter as well as frontal, parietal, temporal, and occipital cortex were reduced in DAT compared with age-matched normals. White matter perfusion differences were not observed among DAT patients with and without risk factors for stroke. Reduced perfusion of frontal white matter correlated significantly with reduced perfusion of thalamus and putamen in patients with DAT. Results confirm the frequent association of white matter abnormalities in patients with DAT that are possibly caused by amyloid angiopathy and may contribute to cognitive impairments.     

A white matter disorder in dementia of the Alzheimer type: a pathoanatomical study

In cases of Alzheimer's presenile and senile dementia, Alzheimer's disease (AD) and senile dementia of the Alzheimer type (SDAT), respectively, we have observed, in addition to the gray matter degeneration, a lesion that has the character of an incomplete infarction confined to the white matter. It is encountered in 60% of both groups, with mild changes in two thirds and moderate or severe changes in one third. It involves the deep white matter symmetrically, tapering off toward the cortex. It is characterized by partial loss of myelin, axons, and oligodendroglial cells; mild reactive astrocytic gliosis; and sparsely distributed macrophages as well as stenosis resulting from hyaline fibrosis of arterioles and smaller vessels. No complete or cavitating infarctions and no hypertensive vascular changes were observed. The white matter changes are thought to be due to hypoperfusion of the concerned white matter territories since, in addition to the white matter hyaline vascular stenosis, these cases show signs of cardiovascular disease, usually with hypotension. The white matter disorder also occurs independent of the gray matter process of AD and SDAT and may be seen as the sole brain lesion in non-AD subjects. Its occurrence is thus neither regularly related to the severity nor to the regional appearance and accentuation of the cortical Alzheimer process and is thus not likely to be just the result of a wallerian degeneration. Histologically it is similar in several respects to Binswanger's disease, although with some distinct differences. It is thus related to the cerebrovascular group of disorders in addition to AD and SDAT. In view of its frequency and severity, this white matter lesion is important to define, to diagnose, and ultimately to prevent or cure.     

Normal-appearing white matter in ischemic leukoaraiosis: a diffusion tensor MRI study.

Ischemic leukoaraiosis is a consistent concomitant of vascular dementia. Conventional MRI provides little information about underlying white matter tract disruption and correlates poorly with cognitive dysfunction. Diffusion tensor MRI may provide better markers of tract integrity. Changes in the normal-appearing white matter were demonstrated in 30 patients with ischemic leukoaraiosis compared with 17 age-matched control subjects. These changes correlated with executive dysfunction assessed by the Wisconsin Card Sorting Test.     

Evidence of white matter tract disruption in MRI hyperintensities.

BACKGROUND: Diffusion tensor imaging (DTI) of brain tissue measures the apparent diffusion coefficient (ADC), or isotropic diffusion, and anisotropy, or diffusion as influenced by tissue structure. We hypothesized that hyperintensities, when compared with normal tissue by DTI, would show evidence of damage through an increased ADC and decreased anisotropy. We also hypothesized that DTI changes in hyperintensities would be similar between depressed subjects and control subjects. METHODS: Fourteen depressed geriatric patients and nineteen control subjects received DTI. The ADC and aniso-tropy of normal tissue from standard regions were compared with hyperintensities from these regions. The Students' t test compared individual regions and averaged white matter results. RESULTS: Hyperintensities showed higher ADC and lower anisotropy than normal regions. Gray matter exhibited similar trends. There was no significant difference in diffusion characteristics of hyperintensities between subjects and control subjects. CONCLUSIONS: Hyperintensities damage the structure of brain tissue, and do so comparably in depressed subjects and control subjects.     

Morphological spectrum, distribution and clinical correlation of white matter lesions in AIDS brains

This paper analyses the histopathological characteristics and the topographical distribution of 'pure' HIV-associated white matter lesions of the brain in 18 AIDS patients at autopsy; it includes a time-controlled correlation of neuropathology to clinical staging of the AIDS dementia complex. Three distinct lesion types can be delineated: 1 Vacuolar myelin damage (n = 15) in the hemispheric and interhemispheric white matter, in projection fibre tracts, and in intracerebral segments of cranial nerves III, VII, and VIII; 2 Angiocentric foci (n = 14), disseminated randomly in the white matter; 3 HIV leukoencephalopathy (n = 14), as previously defined, seen predominantly in the hemispheric white matter. As a sole lesion type, HIV leukoencephalopathy is found in two cases, while vacuolar myelin damage and angiocentric foci always occur in combination with one or both other types of pathology. Patients with advanced AIDS-dementia complex consistently show severe and combined white matter pathologies at autopsy. We conclude that, in addition to the previously defined features of diffuse HIV leukoencephalopathy, vacuolar myelin damage and angiocentric foci are significant and frequent components of white matter pathology in AIDS autopsies. This reflects the multitude of pathogenetic factors which co-operate in damaging the brain in AIDS. The advanced AIDS dementia complex correlates with the combined and severe white matter lesions.     

Absence of pestivirus antigen in brains with white matter damage

We previously suggested that antenatal pestivirus infection might play a role in the pathogenesis of perinatal brain white matter damage (WMD) in preterm infants. We have now examined 22 brains from stillborns and deceased newborns (both preterm and term) for the presence of bovine virus diarrhoea virus (BVDV) antigen. The brains of five females and five males with WMD (median gestational age 36.5wks), and nine female and three male controls (median gestational age 36.5wks) were used in the study. No BVDV antigen was detected in any of the 22 brains. We conclude that brain infection with BVDV is unlikely to play a role in WMD pathogenesis among preterm or term newborns. Further research is needed to test the hypothesis that intrauterine exposure to pestivirus antigen elicits a fetal inflammatory response which then contributes to WMD.     

Regressive changes of astroglia in white matter lesions in cerebrovascular disease and Alzheimer’s disease patients

The pathogenesis of white matter lesions, which are frequently found in ischemic cerebrovascular disease and Alzheimer’s disease, remains unclear. Using light and electron microscopic immunohistochemistry for glial fibrillary acidic protein (GFAP) as a marker, the present study focused on the role of astroglia which show characteristic morphological alterations. Of 29 brains of patients with cerebrovascular disease and Alzheimer’s disease, 4 brains showed extensive swelling and vacuolation of white matter astroglia with their processes disintegrated and beaded (termed clasmatodendrosis). No such cells were observed in 6 control patients. Clasmatodendritic astroglia were not intensely eosinophilic using hematoxylin and eosin staining and included large lipophilic granules in their perikarya. These astroglia were immunoreactive for serum proteins such as immunoglobulins, fibrinogen and complement C3, C1q and C3d, as well as for proteins which are known to increase in reactive astroglia, such as vimentin, α-B crystallin, apolipoprotein-E and laminin. Double labeling for GFAP and microglial cell markers indicated that these cells were of astroglial lineage. Immunoelectron microscopy for GFAP revealed that clasmatodendritic astroglia had condensed chromatin, lysosomes and large membrane-bound osmiophilic cytoplasmic inclusions, which corresponded to the lipophilic granules observed with light microscopy. These cytochemical features collectively suggest that clasmatodendritic astroglia incorporate edema fluid and phagocytose cellular debris, and eventually degenerate as a result of cerebral edema. Received: 3 December 1996 / Revised, accepted: 24 January 1997     

Migraine with aura and white matter lesions: an MRI study

Several studies report the presence of white matter lesions on brain magnetic resonance imaging in patients with migraine. The aim of our study was to detect the entity of white matter T2-hyperintensities in 90 high selected patients affected by migraine with aura, compared to a group of 90 healthy controls. We found no significant difference of incidence of white matter alterations comparing these two groups.     

A quantitative MRI study of vascular dementia.

We studied the MRI and clinical factors associated with dementia following stroke by quantifying ventricle-to-brain ratio (VBR), anatomic region of infarction, and cortical, subcortical, and white matter areas of infarction in 24 stroke patients with dementia and 29 nondemented stroke patients. The factors that most strongly correlated with dementia were total white matter lesion (WML) area, left WML, VBR, right WML, age, left cortical infarction area, left parietal infarction area, and total infarction area. Using discriminant analysis, these factors correctly classified 28 of 29 nondemented patients and 18 of 24 demented patients. Both cortical and white matter total infarction area measurements were strongly associated with dementia in stroke patients, suggesting that these factors strongly influenced the development of dementia following stroke. There was a strong association between dementia and left- but not right-hemisphere infarction area. The only demographic factor that strongly associated with dementia was age.