Review: Vascular dementia: clinicopathologic and genetic considerations.

The incidence and severity of cerebrovascular disease (CVD) increase with advancing age, as does the risk of developing Alzheimer's disease (AD). Not surprisingly, heterogeneous forms of CVD may coexist with AD changes in the 'ageing brain'. These include angiopathies (affecting both large and small arteries) that result from 'classical' risk factors (hypertension, smoking and diabetes) and others (cerebral amyloid angiopathy) that are biochemically closely linked to AD. The morphologic consequences of these various vascular diseases are infarcts and/or haemorrhages of varying sizes within the brain, which lead to neurocognitive decline that may mimic AD - though the vascular abnormalities are usually detectable by neuroimaging. More subtle effects of CVD may include neuroinflammation and biochemical 'lesions' that have no reliable morphologic correlate and thus escape the attention of even an experienced Neuropathologist. The pathogenesis of hippocampal injury resembling ischaemic change - commonly seen in the brains of geriatric subjects - remains controversial. In recent years, genetically determined forms of microangiopathy (e.g. CADASIL, CARASIL, Trex1-related microangiopathies, CARASAL, familial forms of cerebral amyloid angiopathy or CAA) have provided interesting cellular and molecular clues to the pathogenesis of sporadic microvascular disease such as arteriolosclerosis and AD-related CAA.

Gemistocytic astrocytes in gliomas. An autoradiographic study.

Tritiated thymidine (3-H-T) was administered intravenously to seven patients with cerebral gliomas. Autoradiographs of biopsy specimens excised within the next four hours and of autopsy specimens from three of these patients obtained three weeks to six months after the single pulse of 3-H-T revealed the following: (a) no gemistocytic astrocytes and only a few giant astrocytes were labeled in biopsy specimens, despite a high overall labeling index of 5-10% (percentage of cells labeled in the total cell population); and (b) scattered foci of labeled genistocytes occurred in autopsy specimens, despite a sharp drop in overall labeling index. In histologic sections of these same specimens, genistocytes and giant cells occurred as the major cell types in an irradiated tumor, in large clusters near foci of degeneration, and as isolated cells in anaplastic foci. These findings suggest that: 1) gemistocytes and giant astrocytes are similar in origin and growth potential regardless of minor variations in morphology; 2) these cells multiply slowly, if at all, and are closely related to regressive changes within the tumor; 3) these cells may reflect profound proliferative activity in adjacent neoplastic cells; and 4) the labeling index and malignant potential of the tumor as a whole depend upon the more rapidly dividing tumor elements. Thus, if genistocytes and giant cells indicate malignancy, they do so secondarily, and the biologically harmless gemistocyte may be the loser in an intense competition for the substrates needed in cell proliferation.

Neuropathologic substrates of ischemic vascular dementia.

Ischemic vascular dementia (IVD) is a relatively uncommon entity, in the course of which multiple ischemic brain lesions result in progressive cognitive and memory impairment. Ischemic brain lesions may also aggravate the neuropsychologic deficit of Alzheimer disease (AD). In this review we summarize our experience based upon autopsy examination of the central nervous system in 20 patients (age range 68-92 years) enrolled in a longitudinal investigation of structural, neurochemical, functional neuroimaging, and neuropsychologic components of IVD, especially dementia associated with cerebral microvascular disease. While cystic infarcts were present in the CNS of 5 patients, the most commonly observed neuropathologic abnormalities were lacunar infarcts and microinfarcts--both types of lesion were encountered in over half of patients' brains. Evidence of (remote) hippocampal injury was found in 11/20 patients. Severe atherosclerosis and arterio/ arteriolosclerosis were both associated with the occurrence of multiple lacunar infarcts. Pronounced cerebral amyloid angiopathy (CAA) was noted in a single patient, who also showed other microscopic changes of severe AD. While fairly unusual as a nosologic entity, IVD appears to correlate with widespread small ischemic lesions distributed throughout the CNS. We furthermore propose an approach to quantifying the burden of ischemic vascular and parenchymal disease that may be associated with a dementia syndrome. A brief review of neuropathologic features of vascular dementia (both familial and sporadic) is presented.

The amygdala in Down's syndrome and familial Alzheimer's disease: four clinicopathological case reports.

Senile plaques and neurofibrillary tangles were quantified in 14 subnuclei of the amygdala in the brains of 3 patients with Down's syndrome (DS), aged 19, 56, and 64 years, and in 1 patient with familial Alzheimer's disease (AD), aged 54 years. The amygdala of the 19-year-old Down's case contained numerous senile plaques (SPs) but no neurofibrillary tangles (NFTs). The distribution of neuropathological change in the amygdala was similar among the Down's and the Alzheimer's cases. Medical and ventral regions contained more SPs and NFTs than did lateral regions, and the SPs in ventromedial subnuclei generally were the "mature" type with a prominent amyloid core. In general, the numbers of SPs and NFTs were parallel in a given subnucleus with the striking exceptions of the deep medial basal, deep cortical, and lateral central nuclei that contained far more SPs than NFTs, and the medial and lateral superficial cortical nuclei that contained numerous NFTs but few SPs. Several subnuclei strongly interconnected with hippocampus and entorhinal cortex were more heavily involved than subnuclei related to the nucleus basalis of Meynert. The patterns of SP and NFT deposition are consistent with amygdaloid abnormalities found by others in sporadic AD. These findings demonstrate the similarity in amygdaloid pathology among Down's syndrome, familial Alzheimer's disease, and sporadic AD. The presence of senile plaques in the amygdala of the 19-year-old patient with DS suggests that the amygdala is a focus of early pathological change in DS and possibly AD.

No neuropathologic evidence for an increased frequency of Alzheimer's disease among elderly schizophrenics.

BACKGROUND: There is currently controversy as to the frequency of Alzheimer's disease (AD) in elderly persons with schizophrenia. Several studies have reported an increased frequency of AD in elderly schizophrenics, whereas others have found no increase. This issue is important because it has been hypothesized that medications used to treat schizophrenia may exacerbate AD histopathology. METHODS: We examined autopsy cases from a state psychiatric hospital and a Veterans Affairs medical center. Charts were reviewed on 166 subjects to determine if the history warranted a DSM-IV diagnosis of schizophrenia. All subjects had complete gross and microscopic neuropathologic evaluations, which were reviewed for evidence of Alzheimer's disease. RESULTS: Retrospective chart review identified 51 subjects over the age of 55 who met DSM-IV criteria for schizophrenia (mean age = 71.7 years, SD = 8.6, range 56-95 years). Of these 51, only I met neuropathologic criteria for AD, a frequency of 2%. CONCLUSIONS: The frequency of subjects meeting neuropathologic criteria for Alzheimer's disease in our sample of schizophrenics was equal to or less than that found in the general population. Because institutionalized populations may contain an excess of elderly schizophrenic patients with severe behavioral pathologies, which may in turn reflect the presence of neurodegenerative processes such as Alzheimer's disease, our results may actually overestimate the frequency of Alzheimer's in the entire schizophrenic population. The frequency of Alzheimer's disease in the elderly with schizophrenia may be less than that in the general population.

The effects of age on rate of progression of Alzheimer disease and dementia with associated cerebrovascular disease.

BACKGROUND: Relatively little is known about how cerebrovascular disease affects progression of dementia. Previous studies have found no differences in progression of Alzheimer disease and vascular dementia, but these studies have not specifically examined age effects. OBJECTIVE: To test whether the rate of cognitive decline is different in Alzheimer disease compared with dementia with associated cerebrovascular disease in clinical and autopsy patient series. PATIENTS AND METHODS: We studied the longitudinal course of cognitive function as measured by the Mini-Mental State Examination (MMSE) in patients with clinically and neuropathologically diagnosed conditions evaluated through a university Alzheimer disease center. Clinical patients were grouped according to possible Alzheimer disease without stroke (n = 37), probable Alzheimer disease without stroke (n = 181), and dementia with stroke (n = 50). Autopsy cases were categorized into Alzheimer disease (n = 78) and dementia with vascular disease (n = 13). Data were analyzed using random-effects modeling of longitudinal change. RESULTS: There was a significant interaction between age and diagnosis in determining rate of change on the MMSE scores for both the clinical and autopsy samples. Rate of change decreased slightly with advancing age for Alzheimer disease groups, but increased with age for dementia with cerebrovascular disease groups. CONCLUSIONS: Dementia with cerebrovascular disease declined faster in patients 80 years and older compared with Alzheimer disease without associated cerebrovascular pathological conditions, but showed slower decline in patients younger than 80 years. This effect most likely reflects combined Alzheimer and vascular pathological conditions in older patients with cerebrovascular disease.

Pathogenesis of acute monocular blindness from leaking anterior communicating artery aneurysms: report of six cases.

This report describes six cases of leaking anterior communicating aneurysms, collected over 37 years, that caused acute monocular blindness. In two cases, surgical and pathologic evidence demonstrated the pathogenic mechanism: As the aneurysm enlarges, the down-pointing dome compresses the optic nerve from above and adheres to it. When the aneurysm ruptures through the adherent dome, it bleeds directly into the optic nerve, resulting in severe headache and monocular blindness. The other cases also suggest an alternative mechanism, namely, direct optic nerve compression by the aneurysm.

No association between the alpha 1-antichymotrypsin A allele and Alzheimer's disease.

The alpha 1-antichymotrypsin (ACT) A allele was recently associated with Alzheimer's disease (AD), and the ACT AA genotype was reported to be more frequent in AD subjects with the apolipoprotein E (APOE) epsilon4 allele. We examined ACT and APOE genotypes in a sample of 160 subjects with probable AD and in 102 elderly control subjects. ACT A allele frequencies were similar in AD subjects (0.503) and elderly controls (0.519). In addition, we found no evidence that in AD the AA genotype is more frequent in subjects with the APOE epsilon4 allele than in those without it. Our results do not support an association between the ACT A allele and AD.

Presynaptic congenital myasthenic syndrome due to quantal release deficiency.

OBJECTIVE: To provide clinical, electrophysiologic, and ultrastructural findings in three patients with a presynaptic congenital myasthenic syndrome (CMS). BACKGROUND: Familial infantile myasthenia and paucity of synaptic vesicles are the only two fully characterized CMS. We are describing here three patients with another form of presynaptic CMS characterized by deficiency of the action potential-dependent release without reduction of the spontaneous release of neurotransmitter from the nerve terminal. METHODS: The authors performed electromyography and anconeus muscle biopsies that included intracellular recordings and electron microscopy of the neuromuscular junction in three patients with presynaptic CMS. They also sequenced part of the P/Q-calcium alpha(1)-subunit gene (CACNA1A) and the acetylcholine receptor subunit (AChR) genes in these patients. RESULTS: In these patients there were additional neurologic findings including nystagmus and ataxia. In all three patients the end-plate potential quantal content (m) was markedly reduced but neither the amplitudes nor the frequencies of miniature end-plate potentials were diminished. Ultrastructurally, postsynaptic end-plate folds, nerve terminal size, and synaptic vesicle number were normal but double-membrane-bound sacs containing synaptic vesicles were present in the nerve terminal of all three patients. The screening of reported pathogenic mutations in the CACNA1A and a mutational analysis of AChR subunit genes were negative. CONCLUSION: This form of CMS appears to result only from a deficiency of the quantal release of neurotransmitter that may be due to an abnormal calcium mechanism or impaired endocytosis and recycling of synaptic vesicles.

Central nervous system coccidioidomycosis: a clinicopathologic study of treatment with and without amphotericin B.

The clinical and pathologic findings in 32 patients with central nervous system (CNS) coccidioidomycosis were studied. Seventeen patients had received more than 1.5 g of amphotericin B (AMB), chiefly intravenously, during treatment periods of up to eight years. Eight patients had received 246 mg to 1.3 g of AMB, and three patients had received only brief treatment (one to three days; total dose, no more than 100 mg). Fifteen patients had not received AMB. Significant clinical differences between the patients treated with and without AMB were longer survival time following diagnosis of illness (P less than 0.05) and more frequent cranial nerve signs in the treated patients (P = 0.089). The wide spectrum of macroscopic and microscopic lesions in the CNS included meningitis, ventriculitis, hydrocephalus, and cerebritis. Long-standing infections were associated with disseminated discrete foci of gliosis and infarcts in the brain, particularly in the basal ganglia and deep white matter, related to endarteritis obliterans in basilar meninges. In contrast to patients with CNS and systemic mycoses treated with amphotericin B methyl ester (J Infect Dis 146:125, 1982), no diffuse lesions of white matter were found in patients treated with or without AMB. Histopathologic patterns observed in this study included leptomeningitis alone, leptomeningitis with cerebritis, leptomeningitis with cerebritis and infarcts, and the unusual pattern of disseminated miliary granulomas. The frequency and extent of CNS lesions in the groups treated with and without AMB were not significantly different. It is concluded that AMB therapy, while prolonging survival, does not alter the spectrum of pathologic findings in CNS coccidioidomycosis infection.

Membrane fatty acid composition shows delta-6-desaturase abnormalities in Alzheimer's disease.

Brain membrane phospholipid fatty acid composition is investigated in Alzheimer's disease using fresh pathologically proven autopsy material. The most striking abnormalities in Alzheimer brains compared to age-matched controls are found in the n - 6 line of polyunsaturated fatty acids (PUFA) showing an elevation of 18:2 (n - 6) associated with a reduction of 20:4 (n - 6) and 22:4 (n - 6). The findings strongly indicate abnormalities in delta 6-desaturation. The decrease in 22:6 (n - 3) also supports delta 6-desaturase abnormalities. Alteration in PUFA desaturation/elongation processes and resultant membrane abnormalities may play a key role in the pathogenesis of Alzheimer's disease.

Inter-male aggressive signals in weakly electric fish are modulated by monoamines.

Apteronotus leptorhynchus is a gymnotid fish producing a constant high frequency electric organ discharge (EOD). Males of this species use transient increases in EOD frequency (chirps) as aggressive signals. They will also shift the frequency of their EOD away from the similar frequency of a nearby conspecific in order to protect their ability to electrolocate (jamming avoidance response, JAR). Monoamines have been implicated as modulatory agents for various sensorimotor and affective systems, including aggressive behaviour. Since these monoamines are present in the brain of this fish (unpublished observation), we have used these simple and quantifiable behaviours to study the role of monoamines, with special emphasis on possible specific effects on aggressive signalling (chirps). When serotonin (0.1 microgram) is injected directly into the ventricle of these fish it briefly inhibits chirping (aggression) without inhibiting the JAR; this is consistent with the hypothesis that, in mammals, serotonin inhibits aggressive behaviour. Noradrenaline (0.1 microgram) enhances both chirping and the JAR. Dopamine (0.1 microgram) enhances the JAR; it has powerful but inconsistent effects on chirping (inhibition or excitation).

Antigenic profile of plaques and neurofibrillary tangles in the amygdala in Down's syndrome: a comparison with Alzheimer's disease.

Most patients with Down's syndrome (DS) undergo a premature cognitive decline with aging, and eventually develop the neuropathologic changes of Alzheimer's disease (AD), including amyloid-containing neuritic plaques, and the formation of neurofibrillary tangles. The amygdala is a focus of marked neuropathologic change in older patients with DS and in AD. We examined the amygdala with immunocytochemical and histochemical methods in 6 cases with DS, ages 19, 20, 27, 29, 56 and 64 years and compared them to 4 cases with AD, ages 54, 76, 77 and 80 years. An antiserum to the A4 amyloid peptide demonstrated amyloid deposition in plaques in all 10 cases. Plaques were also revealed in all cases by the Alcian blue stain for glycosaminoglycans and by the Bielschowsky and Bodian silver stains. An antiserum to alpha-1-antichymotrypsin (ACT) showed plaques in the AD cases and in the 19, 56 and 64 year old DS cases. Neurofibrillary tangles were observed with silver stains only in the older DS and in the AD cases, and not in the 19, 20, 27 and 29 year old DS cases. Likewise, antisera to paired helical filament, to microtubule associated proteins tau and microtubule associated protein-2 (MAP-2), and to ubiquitin, all of which are components of neurofibrillary tangles, reacted with tangles and abnormal neurites only in the older DS and the AD cases. An antiserum to neurofilament epitopes labeled NFTs in the older DS cases and the AD cases, but not in the younger DS cases, except for two intraneuronal NFTs in the 27 year old case.(ABSTRACT TRUNCATED AT 250 WORDS)

Alzheimer's disease: beta-amyloid precursor protein expression in plaques varies among cytoarchitectonic areas of the medial temporal lobe.

The anatomic distributions of beta-amyloid peptide (beta AP) and beta-amyloid precursor protein (beta APP) in the medial temporal lobe were examined with immunocytochemistry in Alzheimer's disease. beta AP-containing plaques were found most frequently in the cortical and basal regions of the amygdala, and in the hippocampal CA1, subiculum, and dentate molecular layer. beta APP expression in plaques was found in a similar distribution, with some, but not all beta AP plaques also showing beta APP. In the cortical and basal amygdala, some cases showed beta APP in the centers of plaques, whereas in the hippocampus, all cases displayed beta APP mainly in plaque neurites. The lateral regions of the amygdala contained mainly diffuse beta AP plaques which had little beta APP. These findings suggest that although beta APP expression and beta AP deposition generally colocalize, processing of beta APP may vary among closely interconnected anatomic regions.

Beta-amyloid precursor detected in human cerebral cortex.

1. Amyloid deposition is one of the pathologic hallmarks of Alzheimer's disease. Since the isolation of the beta-amyloid gene, which revealed that the amyloid forming 4 kD protein is part of a larger precursor, interest has focused on the process by which amyloid is generated and deposited. 2. The authors have developed an immunologic means of detecting amyloid precursor proteins in human brain. 3. The method involves the expression of human beta-amyloid precursor cDNA in a recombinant vaccinia virus, so that antibodies are produced against the precursor proteins in their native forms. 4. By using this expression system, the amyloid precursor immunogens incorporate post-translational modifications that normally occur in vivo; this cannot be achieved with small synthetic peptides. 5. Using antibodies to the 695 residue amyloid precursor, we have detected using Western blot analysis a protein of approximately 120 kD in samples of cerebral cortex from three subjects with Alzheimer's disease and one control subject. 6. Additional antibodies to other amyloid-related proteins have been developed. These are being used to assess the differential expression of the various amyloid precursors and subdomains in additional cases.

Virus-simulating structures in the optic nerve head in Creutzfeldt-Jakob disease.

A 68-year-old man was treated for and died of Creutzfeldt-Jakob disease. At autopsy we found multiple virus-like particles in the optic nerve head, but saw no similar structures in the cornea. Although these particles were morphologically similar to those previously reported in brain, we believe that they are not virions but unrelated cellular structures. We speculate that the causative agents may be naked membrane bound nucleic acids rather than true viruses. We found no optic atrophy or other specific pathologic changes in the eyes; severe occipital cortical degeneration was responsible for the patient's visual loss.

Imaging findings of the developing temporal bone in fetal specimens.

PURPOSE: To trace the development of the normal fetal temporal bone by means of plain radiography, MR, and CT. METHODS: Eighteen formalin-fixed fetal specimens, 13.5 to 24.4 weeks' gestational age, were examined with a mammographic plain film technique, CT, and MR imaging at 1.5 T. Temporal bone development and ossification were assessed. RESULTS: The membranous labyrinth grows with amazing rapidity and attains adult size by the middle of the gestation period. The cochlea, vestibule, and semicircular canals are very prominent and easily recognized on MR images. The otic capsule develops from a cartilage model. Ossification of the otic capsule proceeds rapidly between 18 and 24 weeks from multiple ossification centers that replace the cartilaginous framework. The mastoid, internal auditory canal, vestibular aqueduct, and external auditory canal continue to grow after birth. CONCLUSION: The study of fetal developmental anatomy may lead to a better understanding of congenital disorders of the ear. Faster MR scanning techniques may provide a method for in utero evaluation of the fetal temporal bone.

A magnetic resonance template for normal cerebellar development in the human fetus.

OBJECTIVE: Although ultrasound is the primary imaging modality for prenatal anatomic evaluation, some central nervous system malformations may be better defined with high-resolution magnetic resonance imaging (MRI). MRI allows us to visualize the features of brain development that were previously only seen histologically by embryologists and anatomists. Although there are several reports of the postnatal development of the cerebellum as revealed on magnetic resonance (MR) images, systematic MR studies of cerebellar development during the fetal period are lacking. Our objective was to use high-resolution MRI to provide a template of cerebellar development during the late first and early second trimesters, a period when the diagnosis of congenital malformations is most medicoethically relevant. The MR findings were then correlated with histological data. METHODS: Twenty-six normal formalin-fixed fetal specimens with a gestational age of 9 to 24 weeks were examined with high-resolution MRI using a conventional clinical magnet and pulse sequences. The MR findings were correlated with the whole-mount histological specimens catalogued in a well-known fetal atlas. RESULTS: Resolution of the morphological features of cerebellar development in fetuses greater than 10 weeks gestational age was possible. Development of the rhombic lips, vermis, fourth ventricular roof, foramen of Magendie, and the cerebellar fissures was documented. Development of the cerebellum as revealed on MR images lagged behind the known stages of development by as much as 5 weeks. Features of cerebellar histogenesis were beyond the resolution of MRI. However, differences in signal intensity between gray and white matter of the developing cerebellum were detected and are postulated to represent differences in cellularity and water content of the constituent tissues. CONCLUSION: Direct correlation of MR images of fetuses during the late first and early second trimesters with anatomic atlases could result in a mistaken diagnosis of delayed or abnormal development of the posterior fossa contents because of a time lag in the detection of structures on MR images. An MR template of normal cerebellar development would be useful to avoid confusion of normal development with abnormal development and to identify the expected developmental features when provided the estimated gestational age of a fetus.

Subacute diencephalic necrosis and dural arteriovenous malformation.

We report a case of congestive venous necrosis involving the diencephalon symmetrically, presumably precipitated by a dural arteriovenous malformation (AVM). The patient presented with a 1-month history of intermittent confusion and gait ataxia. The initial radiological work-up revealed a dural AVM. The patient's subsequent deterioration was accompanied by computed tomographic findings of diencephalic congestion. Pathological examination showed subacute necrosis of the diencephalon. We discuss the pathogenesis of this case of subacute diencephalic necorsis and its possible relationship to the entity of subacute diencephalic angioencephalopathy.

A magnetic resonance template for normal neuronal migration in the fetus.

OBJECTIVE: Although the features of neuronal migration have been known since the turn of the century, the serial features of neuronal migration as seen with magnetic resonance imaging (MRI) have not been described. Our objective was to provide a template of the normal appearance and the temporal pattern of neuronal migration in the human fetal brain early in the second trimester as seen with MR imaging and to correlate our findings with histological sections and atlases. METHODS: Twenty-eight normal fetal specimens, which ranged from 9 to 24 weeks of gestational age, were imaged with a 1.5 T clinical MRI unit by use of conventional spin echo, fast spin echo, and three-dimensional Fourier transformation spoiled gradient refocussed pulse sequences. RESULTS: The three-dimensional Fourier transformation spoiled gradient refocussed pulse sequence provided the highest resolution images of neuronal migration. At 13 weeks of gestational age, the germinal matrix was identified. A five-layer pattern of the fetal forebrain, which included layers of neuroblast formation and migration, could be identified at 16 to 18 weeks by MRI. The germinal matrix and layers of migrating neurons diminished considerably in size by 21 weeks. Histological studies and correlation with anatomic atlases confirmed the MRI findings. CONCLUSION: Images obtained by use of MRI with standard clinical pulse sequences can document the appearance and the temporal patterns of neuronal migration in postmortem fetal specimens. With the evolution of high-resolution MRI and faster scanning techniques, these findings may serve as a template for the in utero MRI appearance of neuronal migration and thereby compliment the antenatal ultrasonic investigation of congenital anomalies.