Amyloid angiopathy in a Volga German family with Alzheimer's disease and a presenilin-2 mutation (N141I).

We report the neuropathological features in 6 members of a Volga German family with autosomal dominant Alzheimer's disease linked to chromosome 1 who had a presenilin-2 mutation (N141I). The most significant feature in this family was the presence of severe or moderately severe amyloid angiopathy in five family members with clinical dementia. The index case with the presenilin-2 mutation had late-onset dementia at age 73 years, died of an acute intracerebral hemorrhage, and pathologically showed severe amyloid angiopathy but only rare neuritic senile plaques and neurofibrillary tangles. That she was apolipoprotein E epsilon2/3 heterozygous suggests that the epsilon2 allele may have exerted a selective protective effect resulting in late onset relatively mild Alzheimer's disease despite severe amyloid angiopathy. This family emphasizes the need for more investigation into the role of presenilin mutations in amyloid deposition, especially in the cerebral vasculature, and the role of these changes in clinical dementia.

The mean A beta load in the hippocampus correlates with duration and severity of dementia in subgroups of Alzheimer disease.

Using image analysis techniques to quantify the percentage area covered by the immunopositive marker for amyloid beta-peptide (A beta), we examined subjects with combinations of either early-onset or late-onset Alzheimer disease (AD) and either familial Alzheimer disease (FAD) or sporadic Alzheimer disease (SAD). We measured the mean and maximum A beta loads, in the hippocampus of each subject. There were no statistically significant differences in the mean A beta load between familial and sporadic AD subjects. Although sample sizes were too small for statistical testing, subjects with the epsilon 4/epsilon 4 allele of the apolipoprotein E (ApoE) gene had higher mean A beta loads than those with the epsilon 3/epsilon 3 or epsilon 3/epsilon 4 alleles. Members of the Volga German families (recently linked to chromosome 1) all had high mean A beta loads, and one of the chromosome 14-linked subjects had the highest mean A beta load while the other had a relatively small load, but the sample was too small for statistical comparisons. The duration of dementia and neuropsychological test scores showed a statistically significant correlation with the mean A beta load in the hippocampus, but not with the maximum A beta load. This difference indicates that the mean A beta load may be a more useful feature than the maximum A beta load as an objective neuropathological measure for cognitive status. This finding may help to improve the established methods for quantitative assessment of the neuropathological changes in AD.

Chromosome 17 and hereditary dementia: linkage studies in three non-Alzheimer families and kindreds with late-onset FAD.

Several previous families with differing clinical and pathologic characteristics have demonstrated linkage to the 17q21-22 region. We have performed a linkage analysis with chromosome 17 markers on three families showing autosomal dominant inheritance of non-Alzheimer dementia and 60 kindreds with late-onset familial Alzheimer's disease (FAD). Family A shows unequivocal evidence of linkage with a maximum lod score of 5.0 for marker D17S934 (theta = 0.001). This family has an unusual syndrome of a schizophrenia-like psychosis beginning in the fifth or sixth decade followed by severe dementia with an average disease duration of 13.8 years. Neuropathology from five autopsies in this family has shown marked neurofibrillary tangle formation (NFT), degeneration of the amygdala, and no amyloid plaques. This confirms the presence of a gene associated with dementia on 17q and extends the related phenotype to include schizophrenia-like symptoms and classic NFT pathology. A second family with early aphasia progressing to dementia and cortical-basal ganglion-like degeneration also has suggestive evidence for linkage to 17q. A third family with very early-onset dementia (mean, 31 years) and nonspecific pathology can be excluded from the 17q region and emphasizes additional genetic heterogeneity in non-Alzheimer hereditary dementia. Finally, we also present evidence against linkage to D17S579 in the set of 60 families with late-onset FAD, providing further evidence that the chromosome 17 gene is unlikely to be involved in the pathogenesis of typical AD.

Clinical and pathological phenotype of the original family with Charcot-Marie-Tooth type 1B: a 20-year study.

Charcot-Marie-Tooth type 1B is an uncommon form of hereditary motor and sensory neuropathy caused by mutations in the P(0) myelin protein gene on chromosome 1. We report here a 20-year observation of 13 members of the first family with Charcot-Marie-Tooth disease to demonstrate linkage to chromosome 1 and now known to have a C270A mutation in the P(0) gene altering the extracellular domain of the protein. Affected individuals generally show an early age at onset, often indicated by delayed ability to walk. Proximal muscle weakness of the lower extremities is common and often marked, but the individuals remain ambulatory and there is no decrease in life span. Motor nerve conduction velocities of the fastest fibers are severely slowed (mean, 9-11 m/sec), even when compared with 3 families having Charcot-Marie Tooth type 1A (mean, 19-21 m/sec). Variability of disability between family members suggests that genetic and environmental factors in addition to the P(0) mutation play a role in the final phenotype. Nerve biopsy specimens demonstrate hypertrophy, onion bulb formation, loss of myelinated fibers, and occasional myelin thickening similar to that described in P(0) myelin knockout mice. Autopsy of the 92-year-old great-grandmother in this family demonstrated diffuse involvement of sensory and motor nerves, with loss of myelin in the posterior columns of the spinal cord and loss of anterior horn neurons but without other involvement of the central nervous system. This family demonstrates the long-term phenotypic consequences on the peripheral nervous system of a specific point mutation in the P(0) myelin gene.

Clinical-neuropathologic findings in multi-infarct dementia: a report of six autopsied cases.

To clarify the neuropathologic criteria for the diagnosis of vascular dementia principally caused by large-vessel cerebral infarction, we solicited autopsy cases of vascular dementia from 10 university neuropathology laboratories. We included only those cases with progressive dementia clinically diagnosed as Alzheimer's disease (AD) or multi-infarct dementia, in whom autopsy revealed only cerebral infarction, without significant neuropathologic features of AD or other neurodegenerative disorders. Only six cases, all men, met these criteria. Each of them had, for a year or longer, gradually increasing cognitive impairment sufficient to interfere with daily activities, without clear evidence of "stepwise" progression. The age of onset of dementia was 66 years or less in five of the six patients. The duration of dementia ranged from 2 to 14 years. Five of the six cases had a history of either cerebral ischemia or acute stroke with residual focal neurologic deficits. Only two were known to have hypertension. At autopsy severe atherosclerosis of the cerebral arteries was present in three cases; two of these had a thrombotic occlusion of one internal carotid artery and one had partial obstruction of other cerebral arteries. In five of six brains, gross infarctions were present involving the thalamus, caudate, putamen, or large portions of the frontal, parietal, and temporal lobes of one or both hemispheres. Vascular amyloid was absent in all but one of these five brains. In four cases, the dementia was clinically indistinguishable from AD except for a history of focal neurologic deficits. The difficulty encountered in finding large numbers of cases of VaD without coexisting neuropathologic evidence of AD suggests that "pure" vascular dementia is very uncommon.

Amyloid (Abeta) deposition in chromosome 1-linked Alzheimer's disease: the Volga German families.

Amyloid beta protein (Abeta) deposition was investigated in the frontal cortex of 6 cases of (genetically confirmed) chromosome 1-linked Alzheimer's disease (AD) (PS-2 gene mutation) among the Volga German families using the end-specific monoclonal antibodies BA27 and BC05 to detect the presence of Abeta40 and Abeta42(43), respectively. In all patients, Abeta42(43) was the predominant peptide species present, although the total amount of Abeta40 and Abeta42(43) deposited in plaques did not differ from that seen in sporadic AD and was significantly lower than that occurring in AD due to PS-1 gene mutations. Therefore, mutations in the PS-2 gene, like those in the presenilin-1 (PS-1) and amyloid precursor protein (APP) genes, are associated with an initial and preferential deposition of Abeta42(43) within the brain. Although the mechanism(s) whereby the PS-1 and PS-2 gene mutations operate remains unclear, it seems from the present study that the effect of the PS-2 gene mutation on the brain is much less severe, at least as far as Abeta deposition is concerned, than that of the PS-1 mutation, which seems to confer a much earlier and a much more aggressive development of AD.

The clinical phenotype of two missense mutations in the presenilin I gene in Japanese patients.

We report the clinical and neuropathologic phenotypes associated with two different missense mutations in the presenilin 1 (PS-1) gene in Japanese patients with early-onset familial Alzheimer's disease (FAD). In the AM/JPN1 pedigree a missense mutation (C-->T) was found at nucleotide 1102, which is predicted to cause an alanine-to-valine missense substitution at codon 260. In this family, the disease had a mean age of onset of 40.3 years and an indolent course (range, 8-19 years). Neuropathologic studies in 3 members of this pedigree showed widespread senile plaques, neurofibrillary tangles, and neuronal loss, as well as abundant perivascular subpial amyloid deposits in the Virchow-Robin spaces and the presence of Pick-like intraneuronal inclusions in the dentate gyrus. In the second pedigree, transmitting a C-->T nucleotide substitution at position 1027, leading to the missense mutation of alanine to valine at codon 285, the disease had a later onset (mean, 51 years) but a more rapid course. Comparison of the disease phenotypes associated with other missense mutations in exon 9 of PS-1 reveals no clinical or pathological phenotype, which uniquely distinguishes Alzheimer's disease associated with PS-1 mutations from other forms of early-onset FAD, implying that direct mutation screening is required to identify these cases.

Neuropathologic diagnostic outcomes from a cohort of outpatients with suspected dementia.

BACKGROUND: Researchers, clinicians, patients, and families need to know the accuracy of clinical dementia diagnoses. METHODS: A prospective cohort of outpatients presenting with complaints of cognitive impairment to a geriatric clinic was established from 1978 to 1982. All patients initially received a standardized clinical evaluation and then were followed longitudinally. RESULTS: Of 304 patients originally enrolled, 72 have come to autopsy and neuropathologic evaluation. Of those patients, 56 had been clinically diagnosed with Alzheimer's disease (AD) and 16 had been diagnosed with other conditions. The sensitivity, specificity, and diagnostic accuracy of the clinical diagnosis of AD compared with neuropathologic diagnosis was 95%, 81%, and 92%, respectively. CONCLUSION: Our findings support the conclusion that the practicing clinician using standardized clinical criteria can accurately diagnose AD approximately 90% of the time. These data may also be useful in the planning of future care of the AD patient.

Amyloid beta protein (Abeta) deposition in chromosome 14-linked Alzheimer's disease: predominance of Abeta42(43).

Amyloid beta protein (Abeta) deposition was investigated in the frontal cortex of 8 cases of (genetically confirmed) chromosome 14-linked Alzheimer's disease (AD) using the end-specific monoclonal antibodies BA27 and BC05 to detect the presence of Abeta40 and Abeta42(43), respectively. In all patients, Abeta42(43) was the predominant peptide species present. The total amount of Abeta40 and Abeta42(43) deposited was more than twice the amount deposited in cases of sporadic AD of similar disease duration, although the ratio between the extent of Abeta40 and Abeta42(43) deposition was unaltered, compared with sporadic AD. Therefore, (one of) the effects of the mutations in the presenilin 1:PS-1 (S182) gene may be to cause or at least promote an early and excessive deposition of Abeta42(43) within the brain, a property shared with other inherited forms of AD, such as those due to amyloid precursor protein mutations, and Down's syndrome (trisomy 21).

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part X. Neuropathology confirmation of the clinical diagnosis of Alzheimer's disease.

This report summarizes the neuropathologic findings in the first 106 autopsies of CERAD (Consortium to Establish a Registry for Alzheimer's Disease) dementia patients diagnosed clinically as having Alzheimer's disease (AD). In 92 (87%) of the 106 cases, neuropathologists confirmed Alzheimer's disease (AD) as the primary dementing illness. Coexistent Parkinson's disease (PD) changes were present in 19 (21%) and vascular lesions of varying nature and size in 26 (28%) of these 92 AD cases. The 14 cases in which AD was not interpreted as the primary dementing illness can be divided into four major subgroups based on their neuropathology findings: PD and related pathology (n = 5), hippocampal sclerosis (n = 3), miscellaneous neurodegenerative and other disorders (n = 3), and no significant changes (n = 3). Despite the relatively high level of clinical diagnostic accuracy, further refinement of assessment batteries may facilitate distinction of non-AD dementias from AD.

Phenotype of chromosome 14-linked familial Alzheimer's disease in a large kindred.

We report the clinical and neuropathological features of chromosome 14-linked familial Alzheimer's disease (14qFAD) in affected members of the L family. Some clinical information on all 16 known affected individuals and detailed neuropathological findings in 6 family members were available for review. Common features of the phenotype of 14qFAD in the L family included onset of dementia before the age of 50, early progressive aphasia, early-appearing myoclonus and generalized seizures, paratonia, cortical atrophy, numerous and extensive senile plaques and neurofibrillary tangles, and prominent amyloid angiopathy. Descriptions of phenotypic features were available for six additional recently defined 14q-linked FAD kindreds: the findings in four of them (FAD4, FAD2, A, B) indicated a relatively consistently shared 14qFAD phenotype, conforming closely with the specific clinical and neuropathological characteristics noted in the L family. Comparisons also suggested several ostensible phenotypic variants in 14qFAD: (1) In two 14q-linked kindreds (SNW/FAD3, FAD1), affected individuals in some instances were noted to survive to age 70 or beyond and the mean age at onset (> 49 years) in these two kindreds was somewhat higher than in their five 14qFAD counterparts (< 48 years in each); (2) in the SNW/FAD3 kindred, seizures and myoclonus were absent in all 10 subjects examined; and (3) cerebellar amyloid plaques were variably present within and among several 14qFAD kindreds. Comparisons with phenotypic features recently detailed in three kindreds (TOR3, F19, ROM) with codon 717 amyloid precursor protein gene mutations (i.e., APP717 FAD) suggested several distinctions: Prominent progressive aphasia, myoclonus, seizures, and paratonia were all apparently less prevalent in APP717 FAD, with language function predominantly spared over the initial disease course. The extent of homogeneity and heterogeneity in the clinical and neuropathological phenotype of 14q-linked FAD and its possible meaningful distinctions from the phenotypes of APP717 FAD await further determination.

Transgenic animal models for Alzheimer's disease.

The neuropathology of Alzheimer's disease is characterized by the deposition of abnormal protein aggregates. The main constituent of the deposition is beta-amyloid protein. A seminal role of this protein is supported by the discovery of point mutations in the gene of its precursor protein in certain forms of familial Alzheimer's disease. In vitro (cultured neuronal cells), overexpression of the precursor protein or a part of the precursor leads to degeneration of neurons, suggesting neurotoxicity of its derivatives. At this time, all of the reported transgenic mice bearing DNA construct for the precursor or a part of the precursor, however, have not developed convincing pathological changes similar to what is observed in patients with Alzheimer's disease. This interesting discrepancy between in vitro and in vivo suggests suppressors in vivo which ameliorate beta-amyloid precursor protein derivative-mediated neurotoxicity.

Phenotypic heterogeneity in families with the myoclonic epilepsy and ragged-red fiber disease point mutation in mitochondrial DNA.

Two families with a point mutation in mtDNA associated with myoclonic epilepsy and ragged-red fiber disease showed pronounced clinical heterogeneity. The mothers of the two families had adult-onset myopathy with ragged-red fibers, partial deficiency of cytochrome c oxidase, and sensory neuropathy. Members of the first family had variable clinical features of progressive ataxic-myoclonic encephalomyopathy and of the other family, primarily adult-onset myopathy. There was a point mutation from A to G at nucleotide pair 8344 located in the tRNALys gene of the mtDNA of all patients tested, three in Family 1, and the mother of Family 2. This clinical heterogeneity may reflect the effects of varying proportions of mutant and wild-type mtDNA in the different organ systems in each individual.

Trichinosis with ventilatory failure and persistent myocarditis.

Life-threatening infections with Trichinella spiralis are rare in countries that have adopted laws requiring cooking of raw garbage fed to pigs. Thus such infections may pose a diagnostic dilemma for clinicians unfamiliar with their presentation. We report a case of imported trichinosis in a Mexican national who developed respiratory failure, myocarditis, and sinus arrest. The patient recovered uneventfully after the administration of benzimidazole and corticosteroid drugs, although a pacemaker was required to maintain normal cardiac rhythm. Symptomatic myocarditis is a rare complication of trichinosis that is often associated with increased morbidity and mortality. This report illustrates and reviews important features of the epidemiology, clinical presentation, and management of trichinosis.

A simple method of rapid freezing adequately preserves brain tissue for immunocytochemistry, light and electron microscopic examination.

A simple and reproducible method for cryopreservation of brain tissue from patients with Alzheimer's disease is described. Fresh brain slices (1 cm thick) obtained less than 6 h postmortem are placed in sealed plastic bags, sandwiched between 0.3-cm-thick aluminium sheets, and frozen by placing the entire "sandwich" between layers of dry ice pellets. The frozen brain slices are stored at -85 degrees C. Specific anatomic areas can be retrieved at any time for light and electron microscopic, immunocytochemical, autoradiographic and neurochemical studies.

Comparison of the severity of neuropathologic changes in familial and sporadic Alzheimer's disease.

We compared the density of neurofibrillary tangles (NT) and neuritic (senile) plaques (NP) in 10 cortical areas, the amygdala, the hippocampus, the parahippocampal gyrus, and the cerebellum in patients with familial (FAD) and sporadic (SAD) Alzheimer's disease with early (< 55 years), intermediate (55-70 years) and late (> 70 years) ages of onset of dementia and age-matched controls. From a total of 199 cases of pathologically confirmed AD in our laboratory, 60 cases with appropriate brain sections and information as to family history, age of onset, duration of dementia, and brain weight were available for semiquantitative analysis of the frequency of NT and NP utilizing the Consortium to Establish a Registry for Alzheimer's Disease protocol. There were 28 SAD and 32 FAD (including seven Volga Germans) cases and 16 age-matched controls. In all brain regions, cases had more severe changes than controls (p < 0.001). Brain weight correlated inversely with duration of disease (p < 0.001). No significant differences were found in the severity scores of NT and NP between FAD and SAD. There was an inverse correlation between age of onset of dementia and the density of NT and NP in all regions in FAD and SAD combined. P values for NT were in the frontal (superior-middle and orbital, p < 0.0005; gyrus rectus, p = 0.0029), parietal (p = 0.0007), and medial occipital cortex (areas 17 and 18, p < 0.01), and for NP were in the superior temporal gyrus (p = 0.0085) and area 17 (p = 0.0003), and age of onset of dementia. In summary, using these criteria we found no compelling evidence that the neuropathologic characteristics of FAD are different from those of SAD.

Survival curves, reproductive life span and age-related pathology of Mus caroli.

Although Mus caroli is being used in a number of laboratories as an experimental animal, basic information concerning its life span, reproductive ability, and age-related pathologies has been unavailable. Here we present this basic information, and discuss the similarities to and differences from the laboratory mouse, Mus musculus domesticus [strains A/StTrWo and (A/StTrWo x C57BL/6NNia)F1] and, from published data, wild-type Mus musculus.

Familial presenile dementia with psychosis associated with cortical neurofibrillary tangles and degeneration of the amygdala.

We report a family in which 13 members in three generations had the presenile (age 42 to 66 years) onset of dementia with an autosomal dominant pattern of inheritance. An early symptom in eight individuals was prominent antisocial psychotic or belligerent behavior, often leading to the initial clinical diagnosis of paranoid schizophrenia. Duration of illness was longer than is usual in Alzheimer's disease (AD), ranging from 14 to 26 years in six members. Three affected siblings and a cousin have come to autopsy, and all had neurofibrillary tangles without senile plaques in several regions of the neocortex, amygdala, and parahippocampal gyrus. The hippocampus was free of both neurofibrillary tangles and senile plaques in all four, but in three there was neuronal loss with gliosis in the CA1 region of Ammon's horn bilaterally. There also was neuronal loss and neurofibrillary tangles in the nucleus basalis. The neurofibrillary tangles were tau-2 and Alz-50 positive and were composed of paired helical filaments ultrastructurally. The disease in this kindred appears to be a unique hereditary disorder that is distinct from familial AD.

Predicting outcome in hypoxic-ischemic coma. A prospective clinical and electrophysiologic study.

A prospective analysis of 40 patients with hypoxic-ischemic coma lasting at least 6 h following sudden cardiac arrest was undertaken. The patients, all of whom had preserved brain-stem function, were studied electrophysiologically with electroencephalography (EEG), and median nerve somatosensory evoked potentials (SEPs) within 48 h to establish prognostic indices. Our results indicate that preserved brain-stem function does not necessarily predict favorable outcome following cardiac arrest as 26 of 40 (65%) patients died without awakening. The bilateral absence of cortical evoked potentials predicted death without awakening in 19 of 26 patients (73%) while malignant EEG change was similarly predictive in 11 patients (42%). Bilateral absence of cortical evoked potentials and/or malignant EEG change reliably predicted unfavorable outcome in 21/26 patients (81%). Patients with normal or delayed central conduction time (CCT) as well as 'benign' or 'uncertain' EEG findings had an uncertain prognosis as some entered a persistent vegetative state (PVS) or died without awakening. Fourteen patients (35%) awakened of whom 5 (13%) recovered completely while another 9 (23%) had varying degrees of motor or cognitive impairment. SEP and EEG findings did not distinguish between these outcomes.

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease.

The Neuropathology Task Force of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) has developed a practical and standardized neuropathology protocol for the postmortem assessment of dementia and control subjects. The protocol provides neuropathologic definitions of such terms as "definite Alzheimer's disease" (AD), "probable AD," "possible AD," and "normal brain" to indicate levels of diagnostic certainty, reduce subjective interpretation, and assure common language. To pretest the protocol, neuropathologists from 15 participating centers entered information on autopsy brains from 142 demented patients clinically diagnosed as probable AD and on eight nondemented patients. Eighty-four percent of the dementia cases fulfilled CERAD neuropathologic criteria for definite AD. As increasingly large numbers of prospectively studied dementia and control subjects are autopsied, the CERAD neuropathology protocol will help to refine diagnostic criteria, assess overlapping pathology, and lead to a better understanding of early subclinical changes of AD and normal aging.