Degeneration Of Cerebral White Matter Research Articles

Association between brain amyloid deposition and longitudinal changes of white matter hyperintensities

BackgroundGrowing evidence suggests that not only cerebrovascular disease but also Alzheimer’s disease (AD) pathological process itself cause cerebral white matter degeneration, resulting in white matter hyperintensities (WMHs). Some preclinical evidence also indicates that white matter degeneration may precede or affect the development of AD pathology. This study aimed to clarify the direction of influence between in vivo AD pathologies, particularly beta-amyloid (Aβ) and tau deposition, and WMHs through longitudinal approach.MethodsTotal 282 older adults including cognitively normal and cognitively impaired individuals were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s Disease (KBASE) cohort. The participants underwent comprehensive clinical and neuropsychological assessment, [11C] Pittsburgh Compound B PET for measuring Aβ deposition, [18F] AV-1451 PET for measuring tau deposition, and MRI scans with fluid-attenuated inversion recovery image for measuring WMH volume. The relationships between Aβ or tau deposition and WMH volume were examined using multiple linear regression analysis. In this analysis, baseline Aβ or tau were used as independent variables, and change of WMH volume over 2 years was used as dependent variable to examine the effect of AD pathology on increase of WMH volume. Additionally, we set baseline WMH volume as independent variable and longitudinal change of Aβ or tau deposition for 2 years as dependent variables to investigate whether WMH volume could precede AD pathologies.ResultsBaseline Aβ deposition, but not tau deposition, had significant positive association with longitudinal change of WMH volume over 2 years. Baseline WMH volume was not related with any of longitudinal change of Aβ or tau deposition for 2 years. We also found a significant interaction effect between baseline Aβ deposition and sex on longitudinal change of WMH volume. Subsequent subgroup analyses showed that high baseline Aβ deposition was associated with increase of WMH volume over 2 years in female, but not in male.ConclusionsOur findings suggest that Aβ deposition accelerates cerebral WMHs, particularly in female, whereas white matter degeneration appears not influence on longitudinal Aβ increase. The results also did not support any direction of influence between tau deposition and WMHs.

Tau pathology relates to regional microstructural alterations of cerebral white matter in older adults with diverse cognitive spectrum

AbstractBackgroundGrowing evidences suggest that degeneration of cerebral white matter (WM) occurs in Alzheimer’s disease (AD) independently of cerebrovascular risks or injury. Previous studies using diffusion tensor imaging (DTI) have reported a loss of WM microstructural integrity in the corpus callosum (CC) and cingulum (CG) in AD dementia and mild cognitive impairment (MCI). However, only limited information is available for the relationship of in vivo AD‐specific pathologies including beta‐amyloid (Aβ) and tau accumulation with WM microstructal alterations. Thus, we aimed to examine the association between in vivo AD pathologies and microstructural integrity of the CC and CG through cross‐sectional and longitudinal approaches.MethodA total of 170 (74 cognitively normal, 58 MCI, and 38 AD dementia) older adults from the Korean Brain Aging Study for the Early diagnosis and prediction of Alzheimer’s disease cohort were included. All participants underwent comprehensive clinical assessment and multi‐modal brain imaging including [11C]‐Pittsburgh‐Compound‐B‐positron emission tomography (PET), 18F‐AV‐1451 PET, and DTI. The mean fractional anisotropy (FA) values were obtained for 2 regions of interests, the CC and CG on DTI. The data was analyzed using linear regression model adjusted for age, sex, APOE4 positivity, and vascular risk factor score. Regression‐based mediation analysis was also conducted to assess the mediation of tau for the relationship between Aβ and FA.ResultIn cross‐sectional analyses for baseline data, global tau deposition had a significant negative association with both CC and CG FA (β = ‐0.013, p = 0.004 and β = ‐0.011, p = 0.002), while global Aβ retention showed a negative association with only CG FA (β = ‐0.015, p = 0.004). Longitudinal analyses revealed that higher tau deposition at baseline was associated with both greater reduction of both CC and CG FA over 2 years (β = ‐0.010, p = 0.001 and β = ‐0.005, p = 0.046), whereas Aβ was associated with neither CC nor CG FA change over the period. Additional mediation analysis demonstrated that the cross‐sectional association between Aβ and CG FA was mediated by tau deposition, while there was no direct relationship between the two.ConclusionOur findings suggest that regional alterations of WM microstructural integrity in MCI and AD dementia, which occurs independently of vascular risks, are mainly related with tau pathology rather than amyloid pathology.

Predicting post-stroke cognitive impairment using machine learning: A prospective cohort study

BackgroundPost-stroke cognitive impairment (PSCI) is a serious complication of stroke that warrants prompt detection and management. Consequently, the development of a diagnostic prediction model holds clinical significance. Objective: Machine learning algorithms were employed to identify crucial variables and forecast PSCI occurrence within 3–6 months following acute ischemic stroke (AIS). MethodsA prospective study was conducted on a developed cohort (331 patients) utilizing data from the Affiliated Zhongda Hospital of Southeast University between January 2022 and August 2022, as well as an external validation cohort (66 patients) from December 2022 to January 2023. The optimal model was determined by integrating nine machine learning classification models, and personalized risk assessment was facilitated by a Shapley Additive exPlanations (SHAP) interpretation. ResultsAge, education, baseline National Institutes of Health Scale (NIHSS), Cerebral white matter degeneration (CWMD), Homocysteine (Hcy), and C-reactive protein (CRP) were identified as predictors of PSCI occurrence. Gaussian Naïve Bayes (GNB) model was determined to be the optimal model, surpassing other classifier models in the validation set (area under the curve [AUC]: 0.925, 95 % confidence interval [CI]: 0.861 - 0.988) and achieving the lowest Brier score. The GNB model performed well in the test sets (AUC: 0.919, accuracy: 0.864, sensitivity: 0.818, and specificity: 0.932). ConclusionsThe present study involved the development of a GNB model and its elucidation through employment of the SHAP method. These findings provide compelling evidence for preventing PSCI, which could serve as a guide for high-risk patients to undertake appropriate preventive measures.

Incidence and risk factors of post-stroke cognitive impairment in convalescent elderly patients with first-episode acute ischemic stroke.

A total of 350 first-time AIS elderly patients (aged ≥60 years) were collected and analyzed. Multivariate Logistic regression analysis showed that the lesion site, frontal temporal, cerebral white matter degeneration, age ≥75 years, BMI ≥28, onset in autumn/winter, hospitalization expenses >20,000 yuan/month, high DBPV, high NIHSS score, and high HAMD score were risk factors for PSCI. Higher education level was a protective factor. In conclusion, the incidence of PSCI in elderly AIS patients was relatively high and related to the several factors, which indicated that more attention should be paid for such patients to prevent PSCI.

A prospective harmonized multicenter DTI study of cerebral white matter degeneration in ALS.

To evaluate progressive white matter (WM) degeneration in amyotrophic lateral sclerosis (ALS). Sixty-six patients with ALS and 43 healthy controls were enrolled in a prospective, longitudinal, multicenter study in the Canadian ALS Neuroimaging Consortium (CALSNIC). Participants underwent a harmonized neuroimaging protocol across 4 centers that included diffusion tensor imaging (DTI) for assessment of WM integrity. Three visits were accompanied by clinical assessments of disability (ALS Functional Rating Scale-Revised [ALSFRS-R]) and upper motor neuron (UMN) function. Voxel-wise whole-brain and quantitative tract-wise DTI assessments were done at baseline and longitudinally. Correction for site variance incorporated data from healthy controls and from healthy volunteers who underwent the DTI protocol at each center. Patients with ALS had a mean progressive decline in fractional anisotropy (FA) of the corticospinal tract (CST) and frontal lobes. Tract-wise analysis revealed reduced FA in the CST, corticopontine/corticorubral tract, and corticostriatal tract. CST FA correlated with UMN function, and frontal lobe FA correlated with the ALSFRS-R score. A progressive decline in CST FA correlated with a decline in the ALSFRS-R score and worsening UMN signs. Patients with fast vs slow progression had a greater reduction in FA of the CST and upper frontal lobe. Progressive WM degeneration in ALS is most prominent in the CST and frontal lobes and, to a lesser degree, in the corticopontine/corticorubral tracts and corticostriatal pathways. With the use of a harmonized imaging protocol and incorporation of analytic methods to address site-related variances, this study is an important milestone toward developing DTI biomarkers for cerebral degeneration in ALS. NCT02405182.

Predictors of cognitive impairment in multiple system atrophy

ObjectiveTo determine predictors of cognitive impairment and frontal dysfunction in patients with multiple system atrophy (MSA). MethodsWe recruited 59 patients with MSA and determined the predictors of a decline in the Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB) scores. ResultsThe MMSE scores negatively correlated with disease duration, Unified MSA Rating Scale (UMSARS) part 1 and 4 scores, and residual urine volume, and positively correlated with the coefficient of variation of electrocardiographic RR intervals. The FAB scores negatively correlated with the UMSARS part 2 score, periventricular hyperintensity grade, and deep white matter hyperintense signal grade. A significant predictor of rapidly progressive cognitive impairment was a high residual urine volume. ConclusionsImpairment of global cognitive function correlates with the long-term disease duration, global disability due to the disease, and autonomic dysfunction, whereas frontal dysfunction correlates with motor function and degeneration of cerebral white matter.

A mouse model of subcortical vascular dementia reflecting degeneration of cerebral white matter and microcirculation

Subcortical vascular dementia(SVaD) is associated with white matter damage, lacunar infarction, and degeneration of cerebral microcirculation. Currently available mouse models can mimic only partial aspects of human SVaD features. Here, we combined bilateral common carotid artery stenosis (BCAS) with a hyperlipidaemia model in order to develop a mouse model of SVaD; 10- to 12-week-old apolipoprotein E (ApoE)-deficient or wild-type C57BL/6J mice were subjected to sham operation or chronic cerebral hypoperfusion with BCAS using micro-coils. Behavioural performance (locomotion, spatial working memory, and recognition memory), histopathological findings (white matter damage, microinfarctions, astrogliosis), and cerebral microcirculation (microvascular density and blood–brain barrier (BBB) integrity) were investigated. ApoE-deficient mice subjected to BCAS showed impaired locomotion, spatial working memory, and recognition memory. They also showed white matter damage, multiple microinfarctions, astrogliosis, reduction in microvascular density, and BBB breakdown. The combination of chronic cerebral hypoperfusion and ApoE deficiency induced cognitive decline and cerebrovascular pathology, including white matter damage, multiple microinfarctions, and degeneration of cerebral microcirculation. Together, these features are all compatible with those of patients with SVaD. Thus, the proposed animal model is plausible for investigating SVaD pathophysiology and for application in preclinical drug studies.

White Matter Integrity Declined Over 6-Months, but Dance Intervention Improved Integrity of the Fornix of Older Adults

Degeneration of cerebral white matter (WM), or structural disconnection, is one of the major neural mechanisms driving age-related decline in cognitive functions, such as processing speed. Past cross-sectional studies have demonstrated beneficial effects of greater cardiorespiratory fitness, physical activity, cognitive training, social engagement, and nutrition on cognitive functioning and brain health in aging. Here, we collected diffusion magnetic resonance (MRI) imaging data from 174 older (age 60–79) adults to study the effects of 6-months lifestyle interventions on WM integrity. Healthy but low-active participants were randomized into Dance, Walking, Walking + Nutrition, and Active Control (stretching and toning) intervention groups (NCT01472744 on ClinicalTrials.gov). Only in the fornix there was a time × intervention group interaction of change in WM integrity: integrity declined over 6 months in all groups but increased in the Dance group. Integrity in the fornix at baseline was associated with better processing speed, however, change in fornix integrity did not correlate with change in processing speed. Next, we observed a decline in WM integrity across the majority of brain regions in all participants, regardless of the intervention group. This suggests that the aging of the brain is detectable on the scale of 6-months, which highlights the urgency of finding effective interventions to slow down this process. Magnitude of WM decline increased with age and decline in prefrontal WM was of lesser magnitude in older adults spending less time sedentary and more engaging in moderate-to-vigorous physical activity. In addition, our findings support the anterior-to-posterior gradient of greater-to-lesser decline, but only in the in the corpus callosum. Together, our findings suggest that combining physical, cognitive, and social engagement (dance) may help maintain or improve WM health and more physically active lifestyle is associated with slower WM decline. This study emphasizes the importance of a physically active and socially engaging lifestyle among aging adults.

Clinical and genetic characterization of leukoencephalopathies in adults.

Leukodystrophies and genetic leukoencephalopathies are a rare group of disorders leading to progressive degeneration of cerebral white matter. They are associated with a spectrum of clinical phenotypes dominated by dementia, psychiatric changes, movement disorders and upper motor neuron signs. Mutations in at least 60 genes can lead to leukoencephalopathy with often overlapping clinical and radiological presentations. For these reasons, patients with genetic leukoencephalopathies often endure a long diagnostic odyssey before receiving a definitive diagnosis or may receive no diagnosis at all. In this study, we used focused and whole exome sequencing to evaluate a cohort of undiagnosed adult patients referred to a specialist leukoencephalopathy service. In total, 100 patients were evaluated using focused exome sequencing of 6100 genes. We detected pathogenic or likely pathogenic variants in 26 cases. The most frequently mutated genes were NOTCH3, EIF2B5, AARS2 and CSF1R. We then carried out whole exome sequencing on the remaining negative cases including four family trios, but could not identify any further potentially disease-causing mutations, confirming the equivalence of focused and whole exome sequencing in the diagnosis of genetic leukoencephalopathies. Here we provide an overview of the clinical and genetic features of these disorders in adults.

Sporadic hereditary diffuse leukoencephalopathy with axonal spheroids showing numerous lesions with restricted diffusivity caused by a novel splice site mutation in the CSF1R gene

AbstractHereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal dominant disease characterized by cerebral white matter degeneration with axonal spheroids. The disease is caused by mutations in the protein tyrosine kinase domain of colony‐stimulating factor 1 receptor (CSF1R), encoded by the CSF1R gene on chromosome 5q34. Because of a preferential involvement of the frontal white matter, HDLS usually presents as presenile dementia. Here, we report an atypical case of HDLS mimicking primary progressive multiple sclerosis (PPMS). A 22‐year‐old woman had difficulty moving her left leg and hand in April 2011 and January 2012, respectively. These symptoms worsened, resulting in spastic quadriplegia and dysarthria. At first admission to Kyushu University hospital, Fukuoka, Japan, in January 2013, she had forced laughter, dysarthria, and rigidospasticity and hyperreflexia in all four limbs, and bilateral extensor plantar response, whereas her Mini‐Mental State Examination score was 26 out of 30. Blood and cerebrospinal fluid tests were all normal, except for an elevated myelin basic protein level (294 pg/mL). Brain T2/fluid‐attenuated inversion recovery‐weighted magnetic resonance imaging showed bilateral high‐signal intensity lesions in the parietal and posterior frontal deep white matter. Remarkably, numerous magnetic resonance imaging lesions showed restricted diffusion. Biopsied specimens from the right cerebral deep white matter showed decreased myelin, severe loss of axons with axonal spheroid,s and infiltration of CD68+ macrophages and CD45+ lymphocytes. She had a heterozygous mutation, c.2,442+1G>A in CSF1R. The present case emphasizes that diagnosis of HDLS should be considered as part of the differential diagnosis of PPMS. The presence of periventricular lesions with restricted diffusivity might favor a diagnosis of HDLS.

The Relationship between Cortical Blood Flow and Sub-Cortical White-Matter Health across the Adult Age Span

Degeneration of cerebral white matter is commonly observed in aging, and the associated degradation in neural connectivity contributes to cognitive decline in older adults. Vascular dysfunction has been implicated as a potential mechanism for general age-related neural tissue deterioration; however, no prior study has examined the direct relationship between cortical vascular health and subcortical white-matter integrity. In this work, we aimed to determine whether blood supply to the brain is associated with microstructural integrity of connective tissue, and whether such associations are regionally specific and mainly accounted for by aging. We examined the association between cerebral blood flow (CBF) in the cortical mantle, measured using arterial spin labeling (ASL), and subcortical white-matter integrity, measured using diffusion tensor imaging (DTI), in a group of healthy adults spanning early to late adulthood. We found cortical CBF to be significantly associated with white-matter integrity throughout the brain. In addition, these associations were only partially tied to aging, as they remained even when statistically controlling for age, and when restricting the analyses to a young subset of the sample. Furthermore, vascular risk was not a prominent determinant of these effects. These findings suggest that the overall blood supply to the brain is an important indicator of white-matter health in the normal range of variations amongst adults, and that the decline in CBF with advancing age may potentially exacerbate deterioration of the connective anatomy of the brain.

Supranuclear ophthalmoparesis and vacuolar degeneration of the cerebral white matter in amyotrophic lateral sclerosis: A clinicopathological study

Possible clinicopathological relationship between vacuolar degeneration of cerebral white matter and clinical manifestation, especially of supranuclear ophthalmoparesis, both infrequent in amyotrophic lateral sclerosis (ALS) patients, was tested. Of 104 ALS sequential series, cases with vacuolar degeneration of the cerebral white matter were selected to yield 14 cases pathologically surveyed in this study. Clinical features were retrospectively assessed in their clinical records. Microscopic examination clarified vacuolar changes with fibrous gliosis, infiltration of macrophages, axonal degeneration with segmental dilatation and partial loss of myelin on electron microscopy. This histological change was extended into the cerebral white matter just under the cortices but sometimes accentuated as restricted areas along the pyramidal tract and precentral regions. In a patient with the most extensive focal lesion, these white matter vacuolar changes were detected with magnetic resonance imaging. The clinical manifestations linked to this focal vacuolar degeneration were disturbance of vertical ocular movements and shorter duration of the illness, compared with patients without vacuolar degeneration. In conclusion, histological demonstration of characteristic vacuolar degeneration in the white matter of ALS and its focal accentuation along precentral-pyramidal tracts are mutually related and possibly linked to clinical manifestations such as supranuclear ophthalmoparesis, an exceptional but possible manifestation of ALS.

Adult Onset Leukodystrophy with Neuroaxonal Spheroids: Clinical, Neuroimaging and Neuropathologic Observations

Pigmented orthochromatic leukodystrophy and hereditary diffuse leukoencephalopathy with spheroids are two adult onset leukodystrophies with neuroaxonal spheroids presenting with prominent neurobehavioral, cognitive and motor symptoms. These are familial or sporadic disorders characterized by cerebral white matter degeneration including myelin and axonal loss, gliosis, macrophages and axonal spheroids. We report clinical, neuroimaging and pathological correlations of four women ages 34-50 years with adult onset leukodystrophy. Their disease course ranged from 1.5-8 years. Three patients had progressive cognitive and behavioral changes; however, one had acute onset. Neuroimaging revealed white matter abnormalities characterized by symmetric, bilateral, T2 hyperintense and T1 hypointense Magnetic Resonance Imaging signal involving frontal lobe white matter in all patients. Extensive laboratory investigations were negative apart from abnormalities in some mitochondrial enzymes and immunologic parameters. Autopsies demonstrated severe leukodystrophy with myelin and axonal loss, axonal spheroids and macrophages with early and severe frontal white matter involvement. The extent and degree of changes outside the frontal lobe appeared to correlate with disease duration. The prominent neurobehavioral deficits and frontal white matter disease provide clinical-pathologic support for association pathways linking distributed neural circuits sub-serving cognition. These observations lend further support to the notion that white matter disease alone can account for dementia.

CT and MR Characteristics of Cerebral Sparganosis

Sparganosis is a rare parasitic infection in humans by a larval cestode of the genus Spirometra. Preoperative diagnosis of cerebral sparganosis in the past has been very difficult. Our objective was to evaluate the CT and MR features of cerebral sparganosis in order to make a definite diagnosis. We retrospectively reviewed 25 patients (13 male and 12 female; age range, 9-83 years) who proved to have cerebral sparganosis. Fifteen patients underwent MR imaging: 2 patients had CT scanning, and the remaining 8 had both CT and MR scanning. We focused on evaluating the imaging features on CT and MR. All patients showed edema and degeneration of cerebral white matter. All but 1 had a unilateral lesion. Twenty-two patients had ipsilateral ventricular dilation. The new finding was a tunnel sign, approximately 4 cm in length and 0.8 cm in width, column or fusiform shaped on postcontrast coronal and sagittal MR images (n = 10). Thirteen patients showed bead-like enhancement, but solitary ring enhancement was common on the CT images (n = 2). The wall of the ring and tunnel appeared isointense or slightly hyperintense on T2-weighted images. Punctate calcifications were seen in 6 patients on CT images but only in 3 patients on the MR images. Hemorrhage was seen in 4 patients on the MR images. An intact whitish, stringlike, living worm was found (n = 5). The most characteristic finding was a tunnel sign on postcontrast MR images. The most common finding was bead-shaped enhancement. MR is superior to CT in demonstrating the extent and number of lesions, except punctate calcifications. Combined with clinical data and enzyme-linked immunosorbent assay, the preoperative diagnosis of cerebral sparganosis could be established on MR imaging.

Pyramidal tract degeneration in sporadic Creutzfeldt‐Jakob disease

We investigated the neuropathologic features of pyramidal tract degeneration in 27 cases of sporadic Creutzfeldt-Jakob disease (sCJD). The present study included 13 cases of subacute spongiform encephalopathy (SSE), 13 cases of panencephalopathic-type (PE-type) sCJD and one case of thalamic-type sCJD. Pyramidal tract degeneration was observed in PE-type sCJD cases with disease duration of more than 13 months. Cases of SSE, PE-type sCJD of relatively short duration and thalamic-type sCJD showed no pyramidal tract degeneration. All cases with pyramidal tract degeneration showed severe cerebral neocortical involvement with widespread cerebral white matter degeneration. The loss of myelin and axons and macrophage infiltration and fibrillary gliosis seen in these pyramidal tract lesions is consistent with secondary tract degeneration due to cerebral neocortical involvement. Interestingly, some cases with pyramidal tract degeneration showed a distal-dominant pathology that we believe indicates retrograde degeneration or a "dying-back" phenomenon of the pyramidal tract. Our results indicate that pyramidal tract degeneration is a late pathologic event in sCJD. Investigation of pyramidal tract degeneration may help clarify the mechanisms underlying the development of sCJD white matter pathology, particularly that of PE-type sCJD.

Hereditary diffuse leukoencephalopathy with spheroids: clinical, pathologic and genetic studies of a new kindred

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a rare autosomal dominant disorder characterized by cerebral white matter degeneration with axonal spheroids leading to progressive cognitive and motor dysfunction. We report clinical and pathological features, as well as molecular genetic analysis, of a family with HDLS. A pedigree consisting of 27 persons in 5 generations contained 6 affected individuals. Dementia and depression were common; two individuals presented with a syndrome resembling corticobasal degeneration (CBD). Postmortem neuropathologic evaluation of three affected individuals revealed enlargement of the lateral ventricles and marked attenuation of cerebral white matter, but preservation of white matter in brainstem and cerebellum, except for the corticospinal tract. Histopathologic studies showed a loss of myelinated fibers, lipid-laden macrophages and bizarre astrocytes, as well as abundant axonal spheroids that were immunoreactive for phosphorylated neurofilament protein and amyloid precursor protein (APP), but not alphaB-crystallin and variably with ubiquitin. By electron microscopy, axonal spheroids contained aggregates of intermediate filaments or of organelles that were predominantly vesicular and lamellar. The cerebral cortex had focal neuronal degeneration with alphaB-crystallin-immunoreactive ballooned neurons. In summary, the present report describes a previously unreported kindred with HDLS with individuals presenting as CBD. Immunohistochemistry for APP and alphaB-crystallin demonstrates distinctive neurodegeneration in cerebral axons and perikarya.

Late Infantile Onset Krabbe Disease in Siblings with Cortical Degeneration and Absence of Cerebral Globoid Cells

Krabbe disease, a disorder caused by the deficiency of lysosomal galactosylceramidase, is typically associated with cerebral white matter degeneration, cortical sparing, accumulation of macrophages ("globoid cells"), and ultrastructural needle-shaped inclusions. Two sisters presented with progressive neurological deterioration beginning before the age of 2.5 years. The first, who died at the age of 9 years, exhibited profound destruction of cerebral white matter with sparing of subcortical fibers but no globoid cells. The brain of the second, who died at the age of 15 years and who had a proven galactosylceramidase deficiency, exhibited white matter destruction, previously undescribed circumscribed spongiform cortical degeneration (postcentral, inferior temporal, cingulate), and cerebellar atrophy, but no globoid cells. The peripheral nerve biopsies from both girls exhibited typical needle-shaped inclusions in Schwann cells. These observations confirm the rare reports that Krabbe disease is not always associated with globoid cells in the brain. Psychosine, which accumulates in the brain, might be toxic to cortical neurons following prolonged survival. The reason for the regional susceptibility in the cerebral cortex is unknown.

Late onset white matter disease in peroxisome biogenesis disorder.

To report late onset cerebral white matter disease as a distinctive phenotype in peroxisome biogenesis disorder (PBD). There is phenotypic and genetic overlap among the PBD known as Zellweger syndrome (ZS), infantile Refsum disease (IRD), and neonatal adrenoleukodystrophy (NALD). Distinctive external features are variable among these three disorders, and neurologic deficit has its onset at birth or in infancy. In a structured follow-up cohort of 25 patients with PBD, not including ZS, three patients had an unusual pattern of cerebral white matter disease with onset past the age of 1, not conforming to any of the classic PBD phenotypes. Clinical phenotyping and follow-up, peroxisomal biochemical determinations in body fluids and fibroblasts, identification of affected PEX gene by genetic complementation in fibroblasts, and MRI studies. Two unrelated patients with PBD without distinctive external features had normal neurodevelopmental milestones during their first year, followed by rapid deterioration including severe hypotonic pareses, seizures, retinopathy, and deafness. A third patient initially diagnosed with IRD developed cerebral white matter degeneration in the third year of life, complicating the original diagnosis. MRI in all three patients showed cerebral demyelination with sparing of subcortical fibers and pronounced central cerebellar demyelination. Late-onset cerebral white matter disease may occur in PBD, either following IRD or following normal early development and in the absence of distinctive external features. Peroxisome biogenesis disorder should be included in the differential diagnosis of post-infantile onset of cerebral white matter disease

Spongiform encephalopathy with extensive involvement of white matter

We report a proven case of CJD with a prolonged clinical course and white matter involvement which consisted of severe, widespread myelin damage in the forebrain and cerebellum but with sparing of the internal capsule. Histologically, there was status spongiosus of the involved white matter with axonal loss, proliferation of hypertrophic astrocytes and scattered and perivascular foamy macrophages. White matter lesions have not been considered to be a significant feature of CJD. In the last few years, however, a few cases have been described with prominent degeneration of cerebral white matter. We believe that our findings corroborate the existence of an entitythat at present may only be defined as spongiform panencephalopathy.

The role of plasma hyperviscosity in subcortical arteriosclerotic encephalopathy (Binswanger's disease).

Five haemorheological variables (haematocrit, plasma viscosity, red cell aggregation, red cell deformability and yield shear stress) and the plasma fibrinogen concentration were determined in blood samples from 21 untreated patients with subcortical arteriosclerotic encephalopathy (SAE, Binswanger's disease). The results were compared with those obtained in blood samples from 40 untreated patients with lacunar infarcts and from 275 healthy control subjects without vascular risk factors. Pathological ("solid body") flow behaviour was detected in the blood of both groups of patients (SAE and lacunar infarcts). However, highly elevated plasma viscosity was a consistent feature only of SAE. The authors present the hypothesis that the high plasma viscosity in patients with SAE may account for the progressive degeneration of cerebral white matter. It is postulated that microcirculatory abnormalities due to microrheological changes may be one of the many missing links in the pathophysiology of SAE.