Absence of linkage of chromosome 21q21 markers to familial Alzheimer's disease.

Alzheimer's disease is the most common form of dementia among the elderly population. Although the etiology is unknown, inheritance plays a role in the pathogenesis of the disease. Recent work indicates that an autosomal dominant gene for Alzheimer's disease is located on chromosome 21 at band q21. In the present study of a group of autopsy-documented kindreds, no evidence for linkage was found between familial Alzheimer's disease (FAD) and chromosome 21q21 markers (D21S1/D21S72 and the amyloid beta gene). Linkage to the D21S1/D21S72 locus was excluded at recombination fractions (theta) up to 0.17. Linkage to the amyloid gene was excluded at theta = 0.10. Apparent recombinants were noted in two families for the amyloid gene and in five families for the D21S1/D21S72 locus. These data indicate that FAD is genetically heterogeneous.

Diagnostic tests in the evaluation of dementia. A prospective study of 200 elderly outpatients.

We studied the components of the diagnostic evaluation in 200 patients older than 60 years of age with suspected dementia who received standardized diagnostic evaluation and follow-up. The most common dementia diagnoses were Alzheimer's-type dementia (74.5%) and dementia due to toxic effects of drugs (9.5%). Eleven patients with hypothyroidism, metabolic encephalopathies due to hyponatremia, hyperparathyroidism, and hypoglycemia required laboratory tests for diagnosis, whereas the other dementia diagnoses were made primarily on the basis of data available on the history and physical and neurologic examinations. The complete blood cell count, blood chemistry battery (especially sodium, calcium, and glucose concentrations), and thyroid function tests were of definite value for the diagnosis of unsuspected disease and were useful as routine tests in evaluating patients for dementia. A careful history and physical examination accompanied by complete blood cell count, chemistry battery, and a thyroid function test would have been effective in diagnosing treatable illnesses causing cognitive impairment. Other diagnostic tests could have been used selectively based on results of the examination and screening tests. Estimated diagnostic charges from a selective approach would be 25% to 34% of those for the "routine" evaluation.

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.

Neuropathological findings in patients with clinical diagnoses of probable Alzheimer's disease.

To assess prospectively the accuracy of standard antemortem clinical diagnostic criteria for Alzheimer's disease, post-mortem examinations were performed on 25 patients who had met DSM-III criteria for primary degenerative dementia and National Institute of Neurological and Communicative Disorders and Stroke criteria for probable Alzheimer's disease. Seventeen patients (68%) met neuropathological criteria for Alzheimer's disease. Two presenile-onset patients had diffuse neocortical senile plaques of insufficient number for definite Alzheimer's disease. Six patients had non-Alzheimer's disease diagnoses. Five of these six had presenile-onset dementia. These results suggest caution in the antemortem diagnosis of Alzheimer's disease in presenile-onset dementia.

Skin punch biopsy in the diagnosis of juvenile neuronal ceroid-lipofuscinosis. A comparison with leukocyte peroxidase assay.

Electron microscopical examination of skin punch biopsy specimens was compared with the leukocyte peroxidase assay in establishing the diagnosis of juvenile neuronal ceroid-lipofuscinosis in three families with at least one affected child. Although the leukocyte peroxidase assay failed to distinguish between the patients, heterozygotes, and normal subjects, skin biopsy specimens containing characteristic cytosomes were found only in the children with this disease. In fact, in two families, the three affected members were identified by this method after the biopsy specimens had been randomized. Although only one to four cells containing such cytosomes were identified in each patient, not only cytosomes with curvilinear bodies but also those with rectilinear as well as "fingerprint" profiles were found. Thus, the skin punch biopsy appears to be a useful diagnostic aid the juvenile as well as the late infantile forms of neuronal ceroid-lipofuscinosis.

Parkinson's disease in patients with Alzheimer's disease.

Because patients with Alzheimer's disease often develop clinical manifestations of Parkinson's disease, we examined the substantia nigra in 40 cases of pathologically confirmed Alzheimer's disease for the changes of Parkinson's disease (neuronal loss, Lewy bodies, or neurofibrillary tangles). Eighteen patients had one or more of these changes in the substantia nigra. Subsequently, we reviewed their clinical records and found that rigidity, with or without tremor, had been noted in 13 patients, and nine patients had a second diagnosis of possible or definite Parkinson's disease. Eleven (85%) of these patients had the pathologic changes of Parkinson's disease. These findings suggest that the majority of patients with Alzheimer's disease with extrapyramidal signs have the pathologic changes of Parkinson's disease in the substantia nigra.

Nonviral intranuclear filamentous inclusions.

Intranuclear filamentous structures have been found in cells of both central and peripheral nervous tissues in eight patients with a variety of neurologic diseases. The structures were curly, fibrillary strands, resembling paramyxoviral filaments morphologically, but larger in diameter (25 to 40nm). Their appearance was granular with indistinct, hazy outlines, and on cross section they were solid rather than tubular. These structures are probably not viral but chromatin fibers. The illustration of sequential development of the fibrillary structures from usual chromatin clumps supports this view. Thus, the finding of intranuclear fibrillary material in the cells of a number of patients with neurologic diseases must be interpreted with caution.

Lymphoma and leukemia manifested by steroid-responsive polyneuropathy.

Subacute polyneuropathy that responded to prednisone was the initial symptom in two patients, one of whom was later found to have histiocytic lymphoma and the other, chronic lymphocytic leukemia. Sural nerve biopsy specimens in both showed extensive segmental demyelination. In the first patient, there was invasion of the myelinated axons by macrophage processes, and the later course of the neuropathy appeared to parallel that of the lymphoma. In the second patient, there was diffuse lymphocytic infiltration of the perineurium and endoneurium, lymphocytes were found beneath the basal lamina, and the demyelination was characterized by extensive vesicular degeneration of the myelin sheath. The demyelination appeared to be cell mediated in the first patient. This was probably the mechanism in the second patient as well, but simple mechanical compression by infiltrating leukemic cells was another possible explanation.

Cerebral embolism, marantic endocarditis, and cancer.

Two subjects with cerebral embolism were found at autopsy to have marantic (nonbacterial thrombotic) endocarditis (NBTE) and an unsuspected carcinoma. A additional 16 subjects with marantic endocarditis and cancer were found on reviewing the autopsy records of 22 subjects with NBTE. Of these 18 subjects with NBTE and cancer, eight developed a stroke during their illness, in five as the initial manifestation of cancer. Although the association of cancer and marantic endocarditis is generally well recognized, cerebral embolism from this source should be more seriously considered as one of the "remote effects" of cancer on the nervous system.

Family with dominantly inherited ataxia, amyotrophy, and peripheral sensory loss. Spinopontine atrophy or Machado-Joseph Azorean disease in another non-Portuguese family?

A family of German extraction with progressive ataxia, eye movement abnormalities, peripheral sensory loss, and spinal muscular atrophy of adult onset is described. Three members came to autopsy, and neuropathologically, the major changes included varying degrees of atrophy of the basis pontis and degeneration of the spinocerebellar tracts, Clarke's columns, anterior horn neurons, and fasciculus gracilis. The dentate nucleus was spared, and there was slight neuron loss from the substantia nigra in one patient. Clinically and neuropathologically, our family resembles that reported by Boller and Segarra as having spinopontine atrophy. However, several kindreds with similar findings have recently been described as having Azorean or Machado-Joseph disease in non-Portuguese families. Comparison of clinical and neuropathological features in spinopontine atrophy and Machado-Joseph disease, both in Portuguese and non-Portuguese families, reveals clinical and pathological similarities and differences between the two. The major differences in our patients include only minor extraocular movement abnormality and absence of protuberant eyes, and muscular rigidity clinically, and the sparing of the substantia nigra and the dentate nucleus neuropathologically. These differences suggest that spinopontine atrophy, as manifested in our family, is distinct from Machado-Joseph disease. Our family showed no linkage to the HLA locus on chromosome 6.

Comparison of postmortem magnetic resonance imaging and neuropathologic findings in the cerebral white matter.

Two types of high-signal intensity abnormalities are frequently found bilaterally in the cerebral white matter of brains of elderly patients on T2-weighted magnetic resonance imaging (MRI) scans. One is located in the immediate periventricular region; the other, in the deep subcortical white matter (centrum semiovale). The diagnostic implications of this second type continue to be uncertain. To determine the neuropathologic correlates of these lesions, the brains from seven elderly patients were fixed in buffered formaldehyde solution, subjected to MRI scanning, and examined neuropathologically. Variable degrees of bilateral periventricular (subependymal) sharply defined areas of high-signal intensity were found in all the brains, and the larger of these showed corresponding areas of myelin pallor with gliosis and dilated perivascular spaces. Discrete bilateral patches of high-signal intensity were found in the centrum semiovale in five patients. Myelin and axon stains showed varying degrees of diffuse white matter pallor in many areas examined, both with and without these areas of high-signal intensity on MRI scans. Neither the myelin nor the axon stains showed discrete white matter abnormalities that corresponded to the MRI findings. We believe that these changes, so commonly found on MRI scans in the elderly, reflect actual changes in the white matter but that their nature and clinical significance need to be elucidated.

Subcortical degeneration in Alzheimer's disease.

Although Alzheimer's disease is generally considered a degenerative disease that primarily affects the cerebral cortex, subcortical structures such as the substantia innominata and certain brainstem nuclei may be involved. In 28 patients with progressive dementia and pathologically confirmed Alzheimer's disease, we found senile (neuritic) plaques and neurofibrillary tangles in the thalamus in 25 patients, in the hypothalamus in 22, and in the mamillary body in 17. The severity of these lesions seemed to be greater in those with presenile onset of dementia, but was not related to the duration of dementia. Alzheimer's disease is a much more diffuse disorder than is usually appreciated.

Acute and chronic progressive encephalopathy due to gasoline sniffing.

Acute encephalopathy caused by gasoline sniffing is well recognized, but has been thought to be completely reversible. We report a patient who developed a progressive encephalopathy characterized by ataxia, tremor and dementia following repeated, deliberate gasoline inhalation. Blood and urine lead levels were consistently elevated and at autopsy, the formalin-fixed brain lead content was between 5200 and 6500 micrograms/100 gm of tissue. This case shows that repeated gasoline sniffing can result in irreversible encephalopathy and that both the acute and chronic encephalopathy probably result from organic lead intoxication and not from the gasoline itself.

Cerebrospinal fluid and serum creatine kinase BB activity after out-of-hospital cardiac arrest.

In patients resuscitated from out-of-hospital cardiac arrest, neurologic outcome was compared with creatine kinase isoenzyme BB activity (CKBB) in cerebrospinal fluid (CSF) in 20 patients and in serum in 52 patients. CSF CKBB was 2 units per liter or less in patients with complete neurologic recovery but was significantly elevated in patients without neurologic recovery (mean, 55 units per liter) or with incomplete neurologic recovery (mean, 7 units per liter). Serum CKBB was detected more than 6 hours after cardiac arrest in only 4% of patients with complete neurologic but in all patients without neurologic recovery. These results demonstrate a relationship between CSF and serum CKBB and neurologic outcome after cardiac arrest.

Presenile Alzheimer disease: amyloid plaques in the cerebellum.

Seven of 24 patients with pathologically proved Alzheimer disease had amyloid plaques resembling kuru plaques in the cerebellum. In all seven patients, the dementia was presenile in onset, there was a positive family history of the disease in five patients, and other neurologic symptoms were present in five. Similar plaques have been described in one of two patients with familial Alzheimer disease from whom spongiform encephalopathy was induced in subhuman primates after intracerebral inoculation of brain tissue. These observations suggest that some cases of familial Alzheimer disease may be clinically distinct from senile dementia and may not be genetic in origin.

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.

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.

Cerebrospinal fluid creatine kinase activity and neurologic recovery after cardiac arrest.

We evaluated prospectively the relation between cerebrospinal fluid creatine kinase activity (CSF CK) and neurologic recovery after out-of-hospital cardiac arrest. Without knowledge of the enzyme results, we determined whether patients awoke, followed commands, or had comprehensible speech. CSF CK was significantly higher in never-awakening than in awakening patients. After cardiac arrest, elevation of CSF CK predicts poor neurologic recovery.

A new method of measuring brain atrophy: the effect of aging in its application for diagnosing dementia.

A new method of measuring cerebral atrophy using a ratio of brain parenchyma to ventricular and subarachnoid space is described. It uses digitized brain CT. This ratio was measured prospectively on 117 consecutive elderly patients referred for evaluation of cognitive dysfunction. Diagnosis was determined by preestablished criteria and confirmed by follow-up. Despite the improved accuracy and reproducibility of this method, its ability to differentiate persons with senile dementia of the Alzheimer's type (SDAT) from those suffering from pseudodementia was confounded by age, and was hence of limited utility. We conclude that even with sophisticated measures of cerebral atrophy, CT is unable to discriminate among common causes of cognitive dysfunction in the elderly.

A case of persistent cortical deafness: clinical, neurophysiologic, and neuropathologic observations.

A 61-year-old man became deaf after the second of two cerebral infarctions which successively involved the temporal and adjacent cortices. He remained completely deaf until death 27 months later. Click stimulation demonstrated normal short-latency potentials, middle-latency responses better developed to stimulation of the right than of the left ear, and absent long-latency potentials. Neuropathologic examination showed cystic infarctions involving both transverse temporal gyri and adjacent cortical areas with preservation of the brainstem auditory nuclei. Persistent deafness can result from bilateral lesions involving the auditory and adjoining cortices.