Progression of clinical deterioration and pathological changes in patients with Alzheimer disease evaluated at biopsy and autopsy.

OBJECTIVES: To quantify the progression of senile plaques, neurofibrillary tangles, cerebral amyloid angiopathy, and microglial activation in the cortex and white matter of patients with Alzheimer disease evaluated at both biopsy and subsequent autopsy and correlate these changes with the progression of neurologic impairment. SETTING: Academic referral center for patient with Alzheimer disease. PATIENTS: Four patients meeting the clinical criteria for Alzheimer disease, enrolled in a pilot study for the evaluation of response to intracerebroventricular administration of bethanechol chloride. The patients were followed up until death occurred and autopsy was performed. RESULTS: All 4 patients had progressive deterioration from the time of biopsy to autopsy (9-11 years). Pathological investigations showed a striking increase in the density of senile plaques and neurofibrillary tangles in 2 of 4 patients from biopsy to autopsy, and a significant increase in microglial activation in 1 of 4 cases. Severity of cerebral amyloid angiopathy varied significantly among patients, 1 of whom displayed striking amyloid deposition with associated subcortical white matter atrophy. CONCLUSIONS: These unique data demonstrate that the progressive neurologic impairment in Alzheimer disease is accompanied by a significant increase in senile plaque and neurofibrillary tangle counts in the frontal cortex and, possibly in some patients, by increased microglial cell activation. Cerebral amyloid angiopathy was associated with significant white matter disease.

Genetic locus heterogeneity in Lafora's progressive myoclonus epilepsy.

In 1995, we mapped a gene for Lafora's progressive myoclonus epilepsy in chromosome 6q23-25. In 1997 and 1998, we reduced the size of the locus to 300 kb, and an international collaboration identified mutations in the protein tyrosine phosphatase gene. Here, we examine for heterogeneity through the admixture test in 22 families and estimate the proportion of linked families to be 75 to 85%. Extremely low posterior probabilities of linkage (Wi), exclusionary LOD scores, and haplotypes identify 4 families unlikely to be linked to chromosome 6q24.

Subdural neomembranes and sudden infant death syndrome.

Cranial dura maters of 36 consecutive infants with sudden infant death syndrome (SIDS) and 16 control infants coming to the Department of Coroner were examined microscopically to determine if subdural neomembranes are associated with cases submitted as SIDS. Thirty-one percent (31%) of the infants with SIDS and 13% of control infants had organizing subdural neomembranes (p > 0.05). Overall prevalence of organizing subdural neomembranes was 25% in the group examined. In all but two cases, birth trauma could be excluded as a cause of head trauma by aging neomembranes histologically. No association was found between type of delivery (vaginal or Cesarean) and presence of a subdural neomembrane. Subdural neomembranes are common in infants autopsied in a forensic setting, but they may be missed without a microscopic examination. Subdural neomembranes have no demonstrated association with SIDS.

Multiple radiation-induced intracranial lesions after treatment for pituitary adenoma. Case report.

This 53-year-old man presented with a syncopal episode 31 years after undergoing craniotomy and external-beam radiation for a pituitary macroadenoma. A gadolinium-enhanced magnetic resonance (MR) image of the brain demonstrated a 2.5-cm enhancing mass in the right caudate region that had not been seen on previous studies. A stereotactically guided biopsy procedure was performed to obtain specimens from the mass, which were consistent with ependymoma. The MR image also revealed two additional lesions that appeared to be within the radiation fields: a right temporal meningioma and a left frontal cavernous malformation. A review of the literature found three previous reports in which ependymomas presented after radiation therapy.

Dementia with Lewy bodies: reliability and validity of clinical and pathologic criteria.

Clinical criteria for dementia with Lewy bodies (DLB) have been proposed, but their formulation, reliability, and validity require further study. Pathologic criteria for DLB are also undergoing evolution. Two studies were conducted with the goal of identifying the components of these evolving criteria that may benefit from further refinement; one study evaluated the components of the clinical criteria and another study operationalized the pathologic criteria for DLB. Twenty-four patients with a premorbid diagnosis of probable or possible Alzheimer's disease (AD) (n = 18), Parkinson's disease (PD) (n = 5), or progressive supranuclear palsy (PSP) (n = 1) were studied. Inter-rater reliability and validity of the clinical criteria were determined by a retrospective chart review, done by five neurologists, and a blinded pathologic evaluation. The Consortium on dementia with Lewy bodies (CDLB) pathologic criteria were operationalized to compare past criteria and test the validity of the evolving clinical criteria on the dementia patients. Three or more cortical fields (at 250 x magnification) with many (four or more) Lewy bodies (LBs) on ubiquitin immunoreactive sections were required to meet the CDLB neocortical score of > 6. Fifteen of the AD patients had at least one LB in a cortical section, four had many LBs, while three had no LBs; all patients with movement disorder had at least one LB in a cortical section. The sensitivity/specificity ratio of the CDLB probable DLB clinical criteria based upon many LBs being present was 75%/79%. Reformulated clinical criteria that require the presence of extrapyramidal signs significantly predicted those patients with many LBs versus those with few or no LBs (chi 2 = 5.48, p = 0.02) and increased clinical specificity to 100%. This preliminary study identifies components of the evolving clinical and pathologic criteria for DLB that require further refinement.

AIDS presenting as progressive multifocal leukoencephalopathy with clinical response to zidovudine.

Progressive multifocal leukoencephalopathy (PML) due to JC virus can be the initial manifestation of AIDS. A 40-year-old man seropositive for HIV-1 presented with aphasia, hemiparesis, and hemianopsia, and with magnetic resonance imaging of the brain typical of PML. He quickly became bed bound, incontinent, and mute. The diagnosis of PML was established by histopathology in a brain biopsy with positive immunocytochemistry for polyomavirus capsid proteins, and detection of JCV DNA by polymerase chain reaction using JCV-specific primers. High dose zidovudine therapy was initiated (1200 mg/day). Within two weeks the patient began to respond, and after three months he was able to walk and care for himself and was discharged. He lived for two years from the onset of PML. While cytarabine has been the drug most widely used for PML treatment, this is the second confirmed case with apparent response to zidovudine. High dose zidovudine may benefit some previously untreated AIDS patients with onset as PML.

Microvasculature in brain biopsy specimens from patients with Alzheimer's disease: an immunohistochemical and ultrastructural study.

Brain biopsy specimens from five patients with Alzheimer's disease obtained in the course of a trial of intracerebroventricular bethanechol were studied by immunohistochemical (antibody to A4 peptide) and ultrastructural techniques, with particular emphasis on the microvessels. In some cases, numbers of A4-immunoreactive lesions (senile plaques) correlated well with numbers of plaques demonstrable by silver stains. Prominent A4-immunoreactive amyloid angiopathy was seen in one patient. The patient with severe cerebral amyloid angiopathy (CAA) showed extensive arteriolar deposition of amyloid filaments with apparent destruction of the media but remarkably intact endothelium. A cell of origin for amyloid filaments was not apparent, although close proximity to smooth muscle cell remnants in the arteriolar media suggested this as one possible cell of origin. Frequent vessels showed medial or adventitial collagen deposition, even when the amount of amyloid was minimal or negligible. Thus relatively severe CAA can exist in the absence of overt endothelial injury, although related studies on this tissue indicate definite abnormalities of the blood-brain barrier. Conversely, destruction of smooth muscle cells and collagen deposition in vessel walls may be the cellular correlates of arteriolar weakening that can lead to CAA-related brain hemorrhage.

Progressive multifocal leukoencephalopathy in AIDS: a clinicopathologic study and review of the literature.

We reviewed the clinical, radiographic, and pathologic features of 15 patients with the acquired immune deficiency syndrome (AIDS) and progressive multifocal leukoencephalopathy (PML). Brain tissue from 10 autopsy and 6 biopsy specimens was studied using: in situ hybridization (ISH) for JC virus (JCV), immunohistochemistry for human immunodeficiency virus (HIV) p24 antigen, and electron microscopy. Thirteen patients presented with focal neurologic deficits, while 2 presented with a rapid decline in mental status. PML was commonly the initial opportunistic infection of AIDS and produced hemiparesis, dementia, dysarthria, cerebellar abnormalities, and seizures. Magnetic resonance imaging was more sensitive than computed tomography in detecting lesions, and often showed multifocal areas of PML. CD4+ T-cell counts were uniformly low (mean 84/mm3), except in 1 patient who improved on 3'-azido-3'-deoxythymidine (AZT). PML involved the cerebral hemispheres, brain stem, cerebellum, and cervical spinal cord. The distribution of brain involvement was consistent with hematogenous dissemination of the virus. In 2 brain specimens, multiple HIV-type giant cells were present within the regions involved by PML. When co-infection by HIV and papovavirus was present, PML dominated the pathological picture. ISH for JCV showed virus in the nuclei of oligodendrocytes and astrocytes. Occasionally there was staining for JCV in the cytoplasm of glial cells and in the neuropil, the latter possibly a correlate of papovavirus spread between myelin sheaths, as seen by electron microscopy. ISH demonstrated more extensive foci of PML than did routine light microscopy.

Neuroimaging in temporal lobe epilepsy: test sensitivity and relationships to pathology and postoperative outcome.

We studied patients with documented temporal lobe seizures to evaluate the predictive value of computed tomography (CT), magnetic resonance imaging (MRI), and F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) for surgical therapy and the relationships between these tests and the pathologic diagnoses. CT detected abnormalities in 32.5%, with an accuracy of 19% when accuracy was defined as congruence with electrophysiologic studies. MRI detected abnormalities in 81%, with an accuracy of 67%. FDG-PET detected abnormalities in 85%, with an accuracy of 82%. Pathologic change was detected in 79% of the excised temporal neocortex, 65% of amygdalae, and 93% of hippocampi. After follow-up periods of 20-71 months (mean 41 months), 67% of patients were free of seizures and 94% had at least a 90% reduction in seizure frequency. There was no relationship between the type of abnormality on MRI or the type of pathology and postoperative outcome. Better outcomes were associated with focal or regional ictal onsets as recorded by surface EEG. Worse outcomes were associated with hypometabolism that extended outside the temporal lobe. Pathologic change in the temporal neocortex was associated with extension of hypometabolism outside the temporal lobe.

Hippocampal pyramidal cell loss in human status epilepticus.

A pilot case-control quantitative study of the hippocampus in patients with severe status epilepticus was performed to identify specific patterns of pyramidal cell loss. Pyramidal cell densities from five patients who died following status epilepticus were compared with five normal controls and five controls matched for age, hypoxia/ischemia, previous epilepsy, and alcohol abuse. Neuronal densities were greatest in the normal control group and least in patients with status epilepticus. Significant reductions were identified in Sommer's sector (prosubiculum and CA1) as well as in CA3 when compared to normal controls.

Intracerebroventricular bethanechol for Alzheimer's disease. Variable dose-related responses.

Five male patients participated in a pilot open-label study of dose-related aspects of response to intracerebroventricular bethanechol in Alzheimer's disease. No patient had remission of symptoms, but three patients improved symptomatically and on tests of memory. Improvement was evident over a restricted range of doses for each subject, and symptoms were worse at doses below and above the optimal range. There was little overlap in the range of doses producing improvement among these three. Two patients had no consistent improvement in memory, and agitation, depression, paranoia, and seizures developed during treatment. Qualitative differences and variability in dosages producing responses complicate the identification of true drug response in the treatment of Alzheimer's disease.

A quantitative study of dendrite complexity in selected areas of the human cerebral cortex.

This study seeks relationships between the degree of dendrite complexity of four areas of the human cerebral cortex and the type of function subserved by those areas. Quantitative studies of basilar dendrite patterns in the trunk and hand-finger receptive zones of areas 3 and 1, superior gyrus of the prefrontal cortex (area 9), and supramarginal gyrus (area 39) of the parietal lobe, in the left hemisphere of 10 subjects are reported. Measurements of dendrite complexity were based on the Sholl method of counting dendrite intersections with a series of superimposed concentric rings centered on the middle of the neuron soma. The data were analyzed graphically to show (1) characteristic dendrite profiles generated by cells in each of these areas, (2) comparisons between dendrite systems of two paired areas, i.e., trunk vs. hand-finger, and hand-finger vs. supramarginal, and (3) cumulative dendrite-ring intersection patterns for all areas studied. The data provided only partial support for our working hypothesis suggesting a relationship between complexity of the dendrite arbor and the nature of the computational tasks performed by the area. However, complexity of dendrite systems in the trunk area was found to be generally less than that of any other. In addition, there were suggestive associations between the complexity of dendrite systems of the hand-finger zone of the primary sensory receptive area and the nature of the work with which the individual had been associated during his/her working life. It proved more difficult to discern relationships between structure and function in the cortical associative areas. The study underlines the large degree of interindividual variation in dendrite structure and the need for much more extensive information about the life history of individuals who serve as subjects for this type of study.

Lymphomatoid granulomatosis and malignant lymphoma of the central nervous system in the acquired immunodeficiency syndrome.

While primary and secondary malignant lymphomas have been well-documented in the CNS of patients with the acquired immunodeficiency syndrome (AIDS), only one case of lymphomatoid granulomatosis (LG) involving the CNS has been reported. We present three AIDS patients with multiple grossly evident foci of necrosis in the cerebral hemispheres which, on histologic evaluation, were seen to contain angiocentric mixed chronic inflammatory infiltrates with atypical mononuclear cells, luminal thrombosis, and infarction, which is typical of LG. LG was also identified in sections of the lung in one case. Lymphoma was found in other regions of the brain in two cases, suggesting the evolution of LG into cerebral lymphoma. In addition, widespread perivascular multinucleate syncytial giant cells, associated with human immunodeficiency virus (HIV) infection of the CNS, were identified in all patients. The features of LG, its relationship to lymphoma, and the possible etiologic role of an immunodeficiency state or the HIV virus in the pathogenesis of LG are discussed.

Cytomegalovirus in the nervous system of patients with the acquired immune deficiency syndrome.

Clinicopathological features of infection of the nervous system by cytomegalovirus (CMV) in 31 patients with the acquired immune deficiency syndrome (AIDS) are reviewed. Neuropathology was variable, ranging from rare isolated CMV inclusions in brain without associated inflammation or necrosis, to severe necrotizing ependymitis and meningoencephalitis. In 1 patient, CMV had produced a necrotizing meningoradiculitis which presented clinically as ascending paralysis. In the brains and spinal cords of 6 patients, evidence of human immunodeficiency virus (HIV) infection of neural parenchyma was seen in close proximity to CMV infection. Both viruses individually or together were associated with low grade (microglial nodule) encephalitis. In retrospect, the diagnosis of CMV had been a difficult one to make clinically in neurologically impaired patients with AIDS. The results suggest that CMV may also localize in the nervous system without significant clinical sequelae. Imaging studies and analysis of cerebrospinal fluid revealed abnormalities in many patients, but none of them (short of culture of CMV itself in two cases) appeared to be specific to this neurological complication of the immunodeficiency.

Altered behavior associated with damage to the ventromedial hypothalamus: a distinctive syndrome.

An adult manifested a tetrad of neurobehavioral findings consisting of episodic rage, emotional lability, hyperphagia with obesity, and memory impairment with intellectual decline following surgical removal of a craniopharyngioma. Post-mortem investigation of the topography of the lesion as well as review of previously reported cases suggest that this tetrad represents a specific neurobehavioral syndrome referable to damage to the ventromedial hypothalamus.

Denervation microangiopathy in senile dementia, Alzheimer type.

Structural analysis of the capillary plexus in the brains of 5 patients with clinical and neuropathological diagnosis of Senile Dementia, Alzheimer Type, revealed a group of striking physical alterations compared with tissue specimens from 5 age-matched controls. Capillary walls were thickened with irregular lumpy, nodulated contours which appeared due, in part, to infiltration of the vascular wall with rounded cell-like bodies. In some cases, these resembled the perikarya of pericytes or monocytes, or their protoplasmic extensions, which were often filled with lipids. In each case, there was no trace of the perivascular neural plexus which regularly invests the microvasculature of the brain parenchyma. The loss of this neural plexus, believed to originate largely from locus ceruleus and the basal forebrain, may be related to the changes in capillary wall structure, and these, in turn, may lead to profound alterations in blood-brain barrier function. We suggest that this subcortically induced denervation microangiopathy may serve as a pathogenic factor in the development of SDAT.

The neuropathology of AIDS. UCLA experience and review.

The central nervous system (CNS) has been examined at autopsy in 89 patients who died of the acquired immune deficiency syndrome (AIDS), including 14 patients who died primarily of neurologic complications of the disease. A total of 66 brains (74%) showed significant pathologic abnormalities, with opportunistic infections including cytomegalovirus (14) and cryptococcal (11) infections, progressive multifocal leukoencephalopathy (6), toxoplasmosis (6), and histoplasma microabscesses (1). Incidental Mycobacterium avium-intracellulare infection was found in 4 cases. Simultaneous CNS infection by more than one microorganism was encountered in 5 patients. Subacute (microglial nodule) encephalitis-related to cytomegalovirus infection or possibly brain infection by the causative agent of AIDS was present in 56 cases. Primary CNS lymphoma was noted in 3 patients. Secondary CNS deposits of lymphoma were found in 1 patient, and another patient had lymphomatoid granulomatosis. Vascular complications were not infrequently seen, and included infarcts secondary to vessel occlusion and disseminated intravascular coagulation in 4 patients and intracranial hemorrhage of variable severity in 13. White matter changes included vacuolar myelopathy (3 cases), central pontine myelinolysis (1 case), and foci of calcified, necrotizing leukoencephalopathy in pontocerebellar fibers of the basis pontis (2 cases). These findings highlight the variety of CNS complications in AIDS, some of which are not associated with clinical manifestations. Nevertheless, characterization of all lesions may be important in understanding the neurologic sequelae of AIDS.

Immunocytologic localization of herpes simplex type 1 viral antigens in herpetic retinitis and encephalitis in an adult.

An immunoperoxidase technique was utilized to identify herpes simplex type I viral antigens in the retina, optic nerve and brain of an adult with herpetic retinitis and encephalitis. Viral antigens were demonstrated in all layers of retina, retinal pigment epithelium and to a lesser extent, in choroid. Oligodendroglia in the right optic nerve and neuronal and glial cells in the grey and white matter of the left frontal, inferior parietal and temporal lobes of the brain also expressed herpes simplex antigens. The sensitive immunoperoxidase method allowed detection of viral antigens in many cells without intranuclear inclusions or surrounding inflammation, and thereby added valuable information regarding the anatomic and cellular localization of herpetic infection. The clinicopathologic features that characterize herpes simplex retinitis in the adult are compared to cytomegalovirus retinopathy.