Novel findings in two cases of biopsy-proven small artery disease:
Spontaneous cerebral hemorrhage in CADASIL and severe white matter edema in amyloid angiopathy
MacLean A, Salloway S, Woods R, Stopa E, Cortez S, Douglas F, Wilterdink J, Rogg J
Departments of Clinical Neurosciences and Psychiatry and Human Behavior, Department of Pathology, Department of Diagnostic Imaging, Brown Medical School, Rhode Island Hospital, and Butler Hospital, Providence, RI, United States.
Presented at: The 8th International Conference on Alzheimer s Disease and Related Disorders. Stockholm. Sweden, 2002 . Neurobiology of Aging, abstract #644.
Background: There is a growing interest in the pathogenesis and clinical manifestations of small artery disease of the brain. We report two cases with novel findings in biopsy-proven cerebral small artery disease. In the first case a 56-year-old man with a 6-year history of multiple sclerosis (MS) diagnosis was admitted with an acute change in mental status. MRI revealed a moderate size hematoma in the right frontal lobe and severe subcortical white matter disease. Biopsy of the right frontal lobe revealed thickened arterioles with degeneration of the smooth muscle layer throughout the brain and meninges. Gene testing was positive for a Notch3 mutation known to play a role in CADASIL (Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). In the second case a 67 year-old non-hypertensive woman without dementia developed a stuttering neurological course accompanied by lobar and microhemorrhages and severe fluctuating levels of white matter edema on MRI. Biopsy of the right frontal lobe revealed severe amyloid angiopathy (AA) without evidence of amyloid plaques. Segmental edema improved after treatment with corticosteroids. MRI examples and biopsy slides from both cases are presented.
Discussion: These are two dramatic examples of subcortical vascular disease associated with lobar hemorrhages and microbleeds. Although cerebral microbleeds have been reported in CADASIL, this is only the third case report of spontaneous cerebral hemorrhage in CADASIL. Severe fluctuating white matter edema has rarely been reported in AA and has been reported in one case of biopsy-proven CADASIL. In both cases there is severe arteriopathy and disruption of vascular integrity, although the pathogenesis differs.
Conclusions: The possibility of hemorrhage needs to be considered when evaluating new events and deciding on therapy for stroke prevention in CADASIL patients. Amyloid angiopathy and CADASIL should be considered in cases of fluctuating signal hyperintensities on MRI.
EFFECT OF APOE GENOTYPE ON MICROVASCULAR BASEMENT MEMBRANE IN ALZHEIMER S DISEASE
S Salloway1, T. Gur1, T. Berzin1, B. Zipser1, S Correia1, V. Hovanesian1, J. Fallon1, V. Kuo-Leblanc1, D. Glass2, C. Hulette3, C. Rosenberg3, M. Vitek3, and E. Stopa1
1Brown Medical School, Providence, RI,
2Regeneron Pharmaceuticals, Inc., Tarrytown, NY
3 Bryant Alzheimer Ctr, Duke University School of Medicine, Durham, NC
Under review: Journal of Neurological Science.
APOE4 homozygosity has been associated with an increased risk of sporadic Alzheimer s disease through a mechanism, which has yet to be defined. Recent evidence has suggested that microvascular basement membrane injury may be a critical factor in the pathogenesis of AD-related dementia. In previous studies we have shown that the synaptic organizing protein agrmn can be found in neurons, and is a major component of the brain microvascular basement membrane. Here we compare the basement membrane surface area of cortical microvasculature in AD brains by staining with an anti-agrin antibody. Quantitative morphometric analysis was used to determine the mean basement area ( 2) of prefrontal cortical microvessels. An average of 10 capillaries were measured in each of 35 cases of AD genotyped for APOE status. APOE4,4 homozygotes had smaller capillary basement membrane areas (17.4 2 6.2) than APOE3,3 homozygotes (26.9 2 6.5), p<0.001. The capillary basement membrane areas (CBMA) of heterozygotes APOE3,4 did not differ significantly from APOE3,3 or APOE4,4. Braak stage did not contribute significantly to CBMA. However, a preliminary analysis suggests an interaction between APOE4,4 and Braak V-VI producing smaller CBMA, a finding which needs to be confirmed with a larger sample. These data support the hypothesis that APOE4,4 is associated with thinning of the microvascular basement membrane in Alzheimer s Disease.
IMPAIRED AWARENESS, BEHAVIOR DISTURBANCE, AND CAREGIVER BURDEN IN ALZHEIMER S DISEASE:
Susan Rymer,1 Stephen Salloway, MD, MS,1,3,4 Lauren Norton, PhD2,4 Paul Malloy, PhD,2,4 Stephen Correia, PhD,1,2 Diane Monast RN1
Departments of Neurology1 and Psychology2, Butler Hospital, Providence, Rhode Island, Department of Clinical Neurosciences3 and Psychiatry and Human Behavior4, Brown University School of Medicine, Providence, RI
Accepted August 2002: American Journal of Geriatric Psychiatry
Purpose. Caregiver burden, the stress experienced due to caregiving, is determined by many factors. This study examined the contributions of the patient s awareness of memory deficit and behavioral disturbance to caregiver burden in Alzheimer s disease.
Design and Methods. Participants were forty-one Alzheimer s patients and their caregivers. Dementia severity, functional impairment, awareness of memory deficit, and behavioral disturbance were measured and examined in relation to caregiver burden.
Results. Positive correlations were found between caregiver burden and both impaired awareness of memory deficit and behavioral disturbance. Regression analyses demonstrated that both impaired patient awareness of memory deficit and behavioral disturbance contributed to caregiver burden over and above dementia severity and functional impairment. However, when both were entered together into regression equations, only behavioral disturbance contributed to caregiver burden. Of the problem behaviors, measures of disinhibition contributed most to caregiver burden.
Implications. These data further our understanding of the multiple contributors to caregiver burden. We conclude that both patient awareness of memory deficit and behavioral disturbance impact caregiver burden, with behavioral disturbance making the greater contribution.
KEY WORDS: Alzheimer s disease, awareness of deficit, behavioral disturbance, anosognosia, disinhibition, insight, dementia.
CADASIL syndrome: A genetic form of vascular dementia
Stephen Salloway & Joseph Hong
Journal of Geriatric Psychiatry and Neurology, vol. 11: 71-77, 1998
Mental disorders due to cerebral microvascular disease have been known for over 100 years. Recently, an autosomal dominant form of cerebral arteriopathy (CADASIL) has been described in association with a Notch3 family gene on the short arm of chromosome 19. CADASIL causes subcortical lacunar infarction and dementia in over 80% of cases and depression in a large proportion of patients. Clinically, CADASIL may appear to be very similar to hypertensive microvascular disease (Binswanger s disease), a condition that is seen in the elderly. This article reviews the clinical, pathologic, and genetic features of CADASIL. CADASIL is of interest to neurologists and psychiatrists because it is the first syndrome of vascular dementia and depression with an identified gene. How the gene causes the widespread arteriopathy is not yet known. Insights gained from the study of CADASIL should help us better understand its etiology, as well as the options for treatment of the more common forms of microvascular disease seen in the elderly.
WHEN FAMILIAL FTLD IS SUSPECTED: CLINICAL AND ETHICAL ISSUES IN FAMILIAL RESEARCH AND DIAGNOSIS
Frontotemporal dementia (FTD) refers to a group of dementing disorders involving cortical degeneration of the frontal and temporal lobes of the brain. FTD is the third most common type of dementia.(l) The disorder affects both males and females equally with symptom onset typically occurring between the ages of 35-75 years.(2) The disease onset, however, is usually insidious with a slow progressive course, making it difficult to accurately determine age of onset or duration of illness in a particular patient.(3) Disease duration generally ranges from 3 to 17 years.(3) Recent studies report that between 20-40% of affected patients have clear family histories of FTD, suggesting that there may be a heritable component to the disease.(2) In the past, FTD was often mistaken for Alzheimer s Disease and Lewy Body Disease. However, increased research and discussion of the distinctive clinical features and underlying neuropathology of FED have generated more precise clinical diagnostic criteria.
The purpose of this paper is to examine FED and explore the ethical issues involved in conducting familial research and providing diagnoses to patients with FED and their caregivers. The first section of this paper will briefly review the clinical and neuropathological features of FTD, its history as a diagnostic entity distinct from other dementing disorders, and current hypotheses about its genetic basis. The second section will discuss clinical and neuroimaging findings in a family in which two to three of six siblings appear to have FED. In the final section, I discuss the ethical issues identified while researching this family and interviewing caregivers about their experiences with the disorder. This section focuses specifically on the ethical and psychosocial issues that doctors and other healthcare providers should consider before providing patients with a diagnosis of FED and discussing the illness with caregivers and potentially afflicted family members.
Sophie C. Debiens
Summer UTRA Proposal, 2002
Description of project
Ischaemic vascular diseases are very common among the elderly. In developed countries, stroke is the third leading cause of death and vascular dementia is the second cause of dementia after Alzheimer s disease. In 1977, Sourander and Walinder described a syndrome of hereditary multi-infarct dementia now known as CADASIL, for cerebral autosomal dominant arteriopathy with subcortical infarction and lekoencephalopathy. This disease is characterized by frequent subcortical ischaemic events, vascular dementia accompanied by frontal-like symptoms and a higher proportion of depression. Diffuse white-matter abnormalities can be seen on MRI and alteration of the vascular smooth muscle cells is observed in biopsies. Using linkage analysis studies, this disease has been mapped to the Notch-3 gene on the short arm of chromosome 19.
The Notch 3 gene has been sequenced in fourteen unrelated patients showing the CADASIL phenotype. The results of this report and others have determined that 85% of the mutations occur in exons 3, 4, 11 and 18. The point mutations lead to addition or deletion of a cysteine moiety. The frequency of notch3 mutations in the large population of older people with subcortical cerebrovascular disease is not known, and the relationship between specific mutations and the phenotypic expression of CADASIL, such as the pattern of subcortical hyperintensities on MRI, has not been studied.
The first part of the proposed project is to develop a method for detecting notch3 mutations, based on new molecular techniques that could be performed at the hospital in a time-efficient manner and that would allow for verification of all exons if necessary. We believe that an assay based on the DNA melting point technique will be sensitive enough to detect known and possibly unknown single point mutations in any exon of the Notch-3 gene. In order to achieve the high level of accuracy required for diagnosis, we will modify the general procedure to accomodate the individual physical and chemical properties of each exon such as the length, the GC content, etc.
The second part of the project focuses on making vectors for a transgenic animal model of CADASIL. In order to better understand the mechanisms of this disorder, a Notch-3 knock-out will be made. Our first goal will be to construct the targeting vector with the appropriate sequence to inactivate the Notch-3 gene. Then, embryonic stem cells will be injected and implanted into a pseudo-pregnant mother. This step will be performed with collaborators at Duke University.
This project fits well with my undergraduate work in neuroscience and my planned graduate training in bioengineering. It will build on my prior experience in molecular biology and help me develop and apply new skills to study a genetic model of vascular dementia. This is a unique opportunity to work under the supervision of faculty from the Departments of Neurology, Pathology and Neuroscience. My work on developing a notch3 assay and vectors for a notch3 knock-out will hopefully make a valuable contribution to the Brain Science Program at Brown.