Extensive White Matter Lesions Research Articles

Cerebral blood flow in nondemented elderly subjects with extensive deep white matter lesions on magnetic resonance imaging

Our previous study showed that deep white matter lesions (DWML) were associated with subtle cognitive decline in community-dwelling elderly people. However, even extensive (EXT)-DWML, found in 7 (4%) of 178 subjects aged 60 years or older, did not cause dementia. The purpose of the present study was to investigate brain circulation in nondemented elderly subjects with EXT-DWML. We compared cerebral blood flow in the deep white matter and frontal cortex between 5 subjects with EXT-DWML and 5 without such lesions, using a xenon-enhanced computed tomography (CT) method. Although the difference of deep white matter findings on magnetic resonance imaging (MRI) was the greatest possible (i.e., extensive v no or minimum lesions), cerebral blood flow values in anterior deep white matter and frontal cortex were 21.4 ± 5.3 standard deviation (SD) mL/100 g/minute and 42.7 ± 4.1, respectively, in subjects with extensive lesions, which were not significantly different from 24.3 ± 4.3 and 44.0 ± 7.1 in subjects without DWML. The present study suggests that EXT-DWML in nondemented elderly individuals do not necessarily indicate apparent hypoperfusion or marked cognitive decline.

Limitations of clinical criteria for the diagnosis of vascular dementia in clinical trials. Is a focus on subcortical vascular dementia a solution?

Vascular dementia (VaD) includes several different vascular mechanisms and changes in the brain, and has different causes and clinical manifestations. Critical to its conceptualization and diagnosis are definitions of the cognitive syndrome, vascular etiologies, and changes in the brain. Variation in these has resulted in different definitions of VaD, estimates of prevalence, and types and distribution of brain lesions. This definitional heterogeneity may have been a factor for negative results in prior clinical trials on VaD. We propose that the division of VaD into subtypes can identify a more homogeneous group of patients for drug trials. A so-called "subcortical" VaD could incorporate two old clinical entities "Binswanger's disease" and "the lacunar state." Small vessel disease is the primary vascular etiology, lacunar infarcts and ischemic white matter lesions are the primary type of brain lesions, the subcortical areas and frontal connections are the primary location of lesions, and a subcortical syndrome as the primary clinical manifestation. The clinical syndromes are likely more variable, and urgently need to be categorized. Selection of these patients for clinical trials could mainly be based on brain imaging features, where the essential changes and the main aspects of the lesions include extensive ischemic white matter lesions and lacunar infarcts in the deep gray and white matter structures. Subcortical VaD is expected to show a more predictable clinical picture, natural history, outcomes, and treatment responses.

Mechanism for decreased cortical oxygen metabolism in patients with leukoaraiosis: Is disconnection the answer?

Cerebral blood flow and metabolism are decreased in the cerebral cortex in patients with dementia of the Binswanger type. Decreased cortical metabolism may be explained by a disconnection of neuronal fibers in the cerebral deep white matter. This theory, however, has not been tested. Cerebral circulation and oxygen metabolism were measured by positron-emission tomography (PET) to examine mechanisms underlying decreased cortical oxygen metabolism in patients with extensive deep white matter lesions. Examinations with the use of PET were performed on 6 patients with dementia of the Binswanger type and 9 control subjects with hypertension. Cerebral cortex oxygen extraction fraction (OEF) was compared between the 2 groups of patients. Cortical OEF was higher in patients with dementia of the Binswanger type than in hypertensive control subjects. The result is consistent with the view that primary cortical hypoperfusion plays a role, at least in part, as a pathogenesis of impaired cortical metabolism in hypertensive patients with extensive deep white matter lesions

Imaging of Static Brain Lesions in Vascular Dementia: Implications for Clinical Trials

Vascular dementia (VaD) relates to different vascular mechanisms and changes in the brain and has different causes and clinical manifestations, reflecting complex interactions between vascular etiologies, changes in the brain, host factors, and cognition. Critical elements to the concept and diagnosis of VaD are defining the vascular causes, the vascular etiologies, and changes in the brain. Verifying the relation between brain lesions and cognition (i.e., the extent to which brain changes cause, compound, or coexist with cognitive impairment) and establishing the types, extent, side, site, and tempo of brain lesions that relate to incident cognitive impairment are major diagnostic challenges. Previous work on interactions between brain lesion and cognition in to cerebrovascular disease (CVD) have shown variation in the definitions and measures of cognitive impairment, in the techniques and methods used to reveal different brain changes, and in the selection of patient populations. Furthermore, small sample sizes and the absence of multivariate statistics have been design limitations. Accordingly, the different sets of criteria used and methods applied identify different numbers and clusters of subjects and different distribution of brain changes. Furthermore, this heterogeneity is reflected in variation in natural history such as the rate of progression of decline in different cognitive domains over time. All these factors have hampered optimal designs of clinical drug trials. A summary of generalizations regarding lesion and cognition interaction in VaD can be made. (1) Not a single feature, but a combination of infarct features--extent and type of white matter lesions (WMLs), degree and site of atrophy, and host factor characteristics--constitues correlates of VaD. (2) Infarct features favoring VaD include bilaterality, multiplicity (>1), location in the dominant hemisphere, and location in the limbic structures (fronto- and mediolimbic). (3) WML features favoring VaD are extensive WMLs (extensive periventricular WMLs and confluent to extensive WMLs in the deep WM). (4) It is doubtful that only a single small lesion could provide imaging evidence for a diagnosis of VaD. (5) Absence of CVD lesions on computed tomography or magnetic resonance imaging is strong evidence against a diagnosis of VaD. In forthcoming protocols on CVD-associated cognitive impairment, the following brain imaging features should be specified: detailed characterization of brain changes; use of possible predefined subtypes based on brain imaging; use of rating of vascular burden; defining the type and extent of WMLs favoring a diagnosis of VaD; defining the extent of medial temporal lobe atrophy disfavoring a diagnosis of VaD; and technical harmonization of methods of scanning and analysis.

Nimodipine in Subcortical Vascular Dementia Trial

Vascular dementia (VaD) is a heterogeneous pathology currently regarded as the result of a variety of causes. Different types of VaD can be identified according to different criteria. This heterogeneity might be one of the causes of the controversial results observed, up to now, in clinical trials. Recently, the 10th revision of the International Classification of Diseases (ICD-10) explicitly identified subcortical VaD as a well-defined subgroup. Abnormalities of white matter are clearly detectable with computed tomography or magnetic resonance scans. The clinicoradiological association of dementia, blood hypertension, and other vascular risk factors, extensive white matter lesions, and small subcortical infarcts might be considered as a clinical univocal entity. Following the encouraging results of a preliminary pilot study, the above-mentioned criteria were followed to define a population of patients to be enrolled in a double-blind, parallel-groups, placebo-controlled clinical trial with nimodipine, which has been proposed as a drug that can improve cognitive functions in patients with VaD. The paper discusses the protocol design of this ongoing trial and its main entry criteria, with particular emphasis on the definition of the population to be enrolled. Implication for future trials in subcortical VaD are discussed further.

RETROVIRAL CO-INFECTIONS IN NEW ORLEANS.

P191 HIV/HTLV-I and HIV/HTLV-II co-infections are recognized with increasing frequency in many urban areas. To characterize the clinical, immunologic and virologic features associated with retroviral co-infections, a longitudinal study of HIV/HTLV co-infections was initiated in 1992 through the present at the Charity Hospital HIV Outpatient Clinic in New Orleans, Louisiana. 172 HTLV-I/II infections have been diagnosed in 2,339 HIV-infected patients (7.3%). From this group, we studied 1271 individuals with HIV only (group 1), 41 individuals with HIV/HTLV-I co-infection (group 2) and 65 individuals with HIV/HTLV-II coinfection (group 3). In bivariate analysis, age at time of HTLV-I/II test, African American race, and history of IVDA were highly associated with HIV/HTLV-I as well as HIV/HTLV-II co-infections (p<0.001). After adjusting for these factors, we determined the adjusted odds ratios (95% CI) for having a CD4>500 as follows: Group 1 (OR 1.00), Group 2 (OR 2.22, 1.02-4.84), Group 3 (OR 2.07, 1.07-4.02). For CD8>800: Group 1 (OR 1.00), Group 2 (OR 2.52, 1.28-4.95), Group 3 (1.88, 1.05-3.12). One case of ATLL was seen in Group 2. Also, patients in group 2 were more likely to have a diagnosis of myelopathy than group 1 (n=4 or 9.7%, p<0.01). All four patients had HAM/TSP-like features as well as elevated creatine phosphokinase levels. One also had extensive white matter lesions in the brain. All four had CD4 and CD8 > 1,000 at time of diagnosis, and had detectable HTLV-I tax/rex mRNA in uncultured peripheral blood mononuclear cells by reverse transcription polymerase chain reaction. These results confirm that retroviral co-infections are associated with higher CD4 and CD8 counts even after adjusting for unique demographic parameters. Also, HAM/TSP during HIV/HTLV-I co-infection is associated with high CD4 and CD8 counts and HTLV-I virus expression is increased.

White Matter Lesions in Alzheimer Patients Are Influenced by Apolipoprotein E Genotype

To analyse the influence of apolipoprotein E (APOE) genotype on the extent of white matter lesions (WMLs) in Alzheimer’s disease (AD), we examined 60 AD patients with magnetic resonance imaging. The WMLs were rated visually in different brain regions. The patients with the APOE genotype σ4/4 had more extensive WMLs in the deep white matter than patients with genotypes σ3/3 and σ3/4. There was a correlation with age for WMLs in the deep white matter in patients with the APOE σ3/3 genotype. In patients carrying at least one σ4 allele, the WMLs showed no age correlation. The results could imply that in APOE allele σ4 carriers, the WMLs represent a pathological process related to the aetiology of the disease.

Cognitive deficits of mild dementia: A comparison between dementia of the Alzheimer's type and vascular dementia.

This study was designed to examine the profiles of cognitive deficits in 11 mildly demented patients with dementia of Alzheimer's type (DAT), five with vascular dementia with multiple subcortical lacunar infarcts (VDS), and seven with vascular dementia with extensive white matter lesions (VDW) in comparison with 23 aged individuals without dementia. Memory, attention, abstract thinking, and visuospatial function were assessed using the Japanese translation of the Wechsler Memory Scale-Revised (WMS-R) and the Japanese version of the Wechsler Adult Intelligence Scale-Revised (WAIS-R). Compared with normal aged individuals, three dementia groups were significantly impaired in the memory and abstract thinking. However, the performances on several tests on attention (i.e. Mental Control and Visual Memory Span Backward from WMS-R) and visuospatial function (i.e. Object Assembly from WAIS-R) differed significantly between the DAT and VDS groups, with VDS being the worst in terms of performance than was DAT. This study suggests that, in the mildly demented stage, the patients with DAT have few problems in the attention and visuospatial function, but those with VDS have impairments in these cognitive abilities.

Developmental neuropathology and impact of perinatal brain damage. II: white matter lesions of the neocortex.

The neuropathology and developmental impact of acute, subacute, and chronic white matter lesions has been studied in infants who survived (days, weeks, months, or years) this type of perinatal brain damage. The study emphasizes the survival of the developing gray matter overlying extensive white matter lesions (multicystic encephalopathy, porencephaly, and hydranencephaly ex-vacuo). Although partially isolated from afferent inputs (corticipetal fiber destruction) and unable to reach other cortical centers (corticofugal fiber destruction), this overlying gray matter is able to survive because neither its independent leptomeningeal blood supply nor its intrinsic anastomotic vasculature are affected by the underlying lesion. Moreover, the postinjury structural and functional development of this partially isolated gray matter is altered. Some of its axotomized pyramidal neurons are transformed into local-circuit interneurons, some of its interneurons are structurally and functionally enlarged (hypertrophy), and its intracortical neuropil (deprived of afferent synaptic terminals) increases by an expansion of intrinsic terminals (hypertrophy). An attempt has been made to correlate these postinjury alterations with the pathogenesis of the ensuing neurologic sequelae (7 infants develop epilepsy). The study proposes that neurological sequelae (e.g. epilepsy and cerebral palsy) following perinatal white matter lesions are a direct consequence of the postinjury gray matter transformations.

Vascular mechanisms in the pathophysiology of human spinal cord injury

Vascular injury plays an important role in the primary and secondary injury mechanisms that cause damage to the acutely traumatized spinal cord. To understand the pathophysiology of human spinal cord injury, the authors investigated the vascular system in three uninjured human spinal cords using silicone rubber microangiography and analyzed the histological findings related to vascular injury in nine acutely traumatized human spinal cords obtained at autopsy. The interval from spinal cord injury to death ranged from 20 minutes to 9 months. The microangiograms of the uninjured human cervical cords demonstrated new information about the sulcal arterial system and the pial arteries. The centrifugal sulcal arterial system was found to supply all of the anterior gray matter, the anterior half of the posterior gray matter, approximately the inner half of the anterior and lateral white columns, and the anterior half of the posterior white columns. Traumatized spinal cord specimens in the acute stage (3-5 days postinjury) showed severe hemorrhages predominantly in the gray matter, but also in the white matter. The white matter surrounding the hemorrhagic gray matter showed a variety of lesions, including decreased staining, disrupted myelin, and axonal and periaxonal swelling. The white matter lesions extended far from the injury site, especially in the posterior columns. There was no evidence of complete occlusion of any of the larger arteries, including the anterior and posterior spinal arteries and the sulcal arteries. However, occluded intramedullary veins were identified in the degenerated posterior white columns. In the chronic stage (3-9 months postinjury), the injured segments showed major tissue loss with large cavitations, whereas both rostral and caudal remote sites showed well-demarcated necrotic areas indicative of infarction mainly in the posterior white columns. Obstruction of small intramedullary arteries and veins by the initial mechanical stress or secondary injury mechanisms most likely produced these extensive white matter lesions. Our studies implicate damage to the anterior sulcal arteries in causing the hemorrhagic necrosis and subsequent central myelomalacia at the injury site in acute spinal cord injury in humans.

Vascular mechanisms in the pathophysiology of human spinal cord injury

Vascular injury plays an important role in the primary and secondary injury mechanisms that cause damage to the acutely traumatized spinal cord. To understand the pathophysiology of human spinal cord injury, the authors investigated the vascular system in three uninjured human spinal cords using silicone rubber microangiography and analyzed the histological findings related to vascular injury in nine acutely traumatized human spinal cords obtained at autopsy. The interval from spinal cord injury to death ranged from 20 minutes to 9 months. The microangiograms of the uninjured human cervical cords demonstrated new information about the sulcal arterial system and the pial arteries. The centrifugal sulcal arterial system was found to supply all of the anterior gray matter, the anterior half of the posterior gray matter, approximately the inner half of the anterior and lateral white columns, and the anterior half of the posterior white columns. Traumatized spinal cord specimens in the acute stage (3-5 days postinjury) showed severe hemorrhages predominantly in the gray matter, but also in the white matter. The white matter surrounding the hemorrhagic gray matter showed a variety of lesions, including decreased staining, disrupted myelin, and axonal and periaxonal swelling. The white matter lesions extended far from the injury site, especially in the posterior columns. There was no evidence of complete occlusion of any of the larger arteries, including the anterior and posterior spinal arteries and the sulcal arteries. However, occluded intramedullary veins were identified in the degenerated posterior white columns. In the chronic stage (3-9 months postinjury), the injured segments showed major tissue loss with large cavitations, whereas both rostral and caudal remote sites showed well-demarcated necrotic areas indicative of infarction mainly in the posterior white columns. Obstruction of small intramedullary arteries and veins by the initial mechanical stress or secondary injury mechanisms most likely produced these extensive white matter lesions. Our studies implicate damage to the anterior sulcal arteries in causing the hemorrhagic necrosis and subsequent central myelomalacia at the injury site in acute spinal cord injury in humans.

Preservation of normal cognitive functioning in elderly subjects with extensive white-matter lesions of long duration

Preservation of normal cognitive functioning in elderly subjects with extensive white-matter lesions of long duration

Preservation of Normal Cognitive Functioning in Elderly Subjects With Extensive White-Matter Lesions of Long Duration

Although deep white-matter brain lesions are seen on magnetic resonance imaging in about one third of elderly subjects, their clinical significance is not known. In 1984, we studied three retired teachers who had extensive deep white-matter brain lesions on magnetic resonance imaging, yet functioned cognitively at an above-average level. Blinded review of 1981 computed tomographic scans revealed patchy white-matter lucencies for two of the subjects. Repeated magnetic resonance imaging in 1987 showed that the deep white-matter brain lesions were at least as extensive as in the initial study. One subject had developed renal failure, while the other two continued to function at a high level with no evidence of cognitive decline or psychiatric or neurologic impairment. The presence of extensive deep white-matter brain lesions for up to 7 years in two subjects whose cognitive, behavioral, and neurologic functioning is unimpaired suggests that deep white-matter brain lesions do not necessarily indicate a clinically significant central nervous system disease process.

A radiologic study of dynamic processes in lacunar dementia.

Using magnetic resonance imaging and digitized brain computed tomography, we evaluated 33 elderly patients with documented lacunar stroke and divided them into three groups (nondemented, n = 15; borderline, n = 9; and demented, n = 9) by neuropsychological assessments and DSM III criteria. We evaluated the extent of white matter lesions and the degree of atrophy of specific anatomic structures, such as the corpus callosum, using magnetic resonance imaging and quantified the volumes of the ventricles, the subarachnoid spaces, and the brain parenchyma using digitized brain computed tomography. Our results show that both borderline and demented patients had significantly more extensive white matter lesions than nondemented patients, indicating a significant relation between the extent of white matter lesions and intellectual decline. In addition, borderline and demented patients had significantly larger ventricles and more brain atrophy than nondemented patients; demented patients also had significantly larger subarachnoid spaces than nondemented patients and more brain atrophy than borderline patients. Our findings suggest that in most patients with lacunar stroke, periventricular and subcortical white matter lesions with subsequent white matter atrophy first induce ventricular enlargement, followed by generalized brain atrophy, resulting in dementia.

Infantile multiple sclerosis with extensive white matter lesions

A boy developed a right hemiparesis at 13 months of age which disappeared spontaneously at 19 months. Computed tomography and magnetic resonance imaging revealed extensive low-density areas with left-sided predominance in the white matter at age 17 months. The flash visual evoked potential revealed abnormal findings of wave V. At 20 months of age, paraplegia developed; as it receded 3 months later, a left hemiparesis developed. At that time, computed tomography demonstrated a new low-density area in the right centrum semiovale which disappeared at 28 months of age concomitant with the recovery of the left hemiparesis. Overall, he had experienced 3 independent episodes, 2 of which corresponded to each of the lesions depicted by computed tomography and magnetic resonance imaging. Multiple sclerosis was diagnosed at 23 months of age which is earlier than in any previously reported patient. Unlike most typical findings of multiple sclerosis on computed tomography and magnetic resonance imaging studies, our patient demonstrated extensive white matter lesions.

Severe nonfluency in aphasia. Role of the medial subcallosal fasciculus and other white matter pathways in recovery of spontaneous speech.

The relationship between location and extent of lesion on CT scan and limitation in spontaneous speech was examined. The severity of spontaneous speech ranged from cases with no speech or only verbal stereotypies (first major group) to those with reduced, hesitant, poorly articulated, agrammatic speech (nonfluent Broca's aphasia, second major group). CT scan analysis revealed no single neuroanatomical area that contained an extensive lesion which could be used to discriminate the most severe cases from the least severe. The two groups were separable, however, on the basis of the CT scan when the extent of the lesion in two subcortical white matter areas were combined: (1) the most medial and rostral portion of the subcallosal fasciculus plus (2) the periventricular white matter near the body of the lateral ventricle, deep to the lower motor/sensory cortex area for the mouth. The most rostral portion of the medial subcallosal fasciculus, located in the lateral angle of the frontal horn (extremely deep to Broca's area), contains projections from the cingulate gyrus (area 24) and the supplementary motor area, to the caudate nucleus. We suggest that one explanation for the more severe limitation in spontaneous speech in the first group is the extensive white matter lesion in these two subcortical pathways had interrupted a large number of connections for (1) initiation and preparation of speech movements, and limbic aspects of speech (lesions in the medial subcallosal fasciculus), and (2) motor execution and sensory feedback for spontaneous speech (lesions in periventricular white matter deep to the motor/sensory cortex area for the mouth). Extensive lesion in only one of these two white matter pathway areas, alone was not sufficient to produce long-lasting severe limitation in spontaneous speech and could not be used to discriminate the two groups on the basis of the CT scans. The patients with less severe limitation in spontaneous speech (nonfluent Broca's aphasia) had less extensive lesion within these two white matter areas combined, and had interrupted a smaller number of these subcortical connections. The sites of the lesions in subcortical white matter in CT scans in Broca's original case who could only produce a verbal stereotypy are similar to those in our first group with the most severe limitation in spontaneous speech. The presence or absence of hemiplegia was not related to severity or recovery of spontaneous speech. Careful examination of lesion extent in these two areas of subcortical white matter on CT scanning appears to be relevant in predicting potential for recovery of spontaneous speech in some stroke patients.

Magnetic resonance imaging in multiple sclerosis: decreased signal in thalamus and putamen.

High-field strength (1.5 Tesla) magnetic resonance imaging in 15 patients with multiple and extensive white-matter lesions and clinically definite multiple sclerosis delineated a previously undescribed finding of abnormally decreased signal intensity on T2-weighted images in the thalamus and putamen. The decreased signal intensity (preferential decreased T2 relaxation time) is most likely to be related to abnormally increased iron accumulation causing local magnetic field heterogeneities.