The genetics of Alzheimer's disease: associations with hematologic malignancy and Down's syndrome.

Relatives of probands with histologically confirmed Alzheimer's disease had excessive morbidity from Alzheimer's disease, Down's syndrome, and hematologic malignancies. These associations coupled with two previously reported ones, the indistinguishable histopathological changes in brain in Alzheimer's disease and Down's syndrome, and the 20-fold increased incidence of leukemia among persons with Down's syndrome, are evidence that some instances of those disorders are associated with a unitary genetic etiology. The genetic defect may be expressed through disorganization of microtubules. Other evidence suggests that the same process may be involved in aging and in other chromosomal aberrations.

Pick's disease. Clinical genetics and natural history.

The relatives of 18 probands with neuropathologic evidence of Pick's disease were assessed with the main aim of estimating their risk for dementing illness. Fifteen secondary cases of dementia were discovered among relatives. The risks were significantly greater for probands' first-degree relatives than for second-degree relatives, which suggests an etiologic contribution from genes. Although numbers are small, the distribution of cases and their ages at onset are consistent in suggesting a sex effect, with male subjects more at risk than female subjects.

Dementia of the Alzheimer type. Clinical genetics, natural history, and associated conditions.

Relatives of 125 probands, who had dementia of the Alzheimer type as proved by autopsy, were subjects of a genetic investigation. The relatives exhibited an excess of dementing illness consistent with genetic transmission. Risk to relatives decreased sharply as severity of the proband's illness decreased. Also, when compared with a control group and the general population, the relatives had excesses of Down's syndrome, lymphoma, and immune diatheses. These associated conditions also were more likely to be present when the proband had severe illness. Mortality at all ages was increased among the relatives.

A trial of vidarabine for cytomegalovirus infection in renal transplant patients.

Vidarabine was evaluated in renal transplant patients as a potential therapeutic agent in cytomegalovirus (CMV) infection. Four patients received vidarabine on an open protocol, then ten additional patients were enrolled in a double-blind protocol. Among the nine patients who received vidarabine, no notable clinical improvement occurred in either the vidarabine- or placebo-treated groups. Thus, vidarabine showed no therapeutic effect in the treatment of CMV infections at the dosages used. Four patients showed dramatic CNS deterioration within several days of the onset of vidarabine therapy. Tremors and myoclonus were common, and one patient had unusual brain pathologic changes with widespread neuronal chromatolysis. The pathologic findings in the brain in the other three patients were complex and included intracerebral hemorrhage, Fabry's disease, coccidioidomycosis meningitis, and cerebral vascular occlusion. Thus, there was no conclusive proof that vidarabine contributed to the sudden neurologic deterioration of these patients.

Aberrant peripheral nerves and microneuromas in otherwise normal medullas.

The occurrence of aberrant peripheral nerve (PN) fibers in otherwise normal medullas was studied in 1,016 consecutively autopsied patients. Fine, myelinated PN fibers occurred as small parallel bundles or microneuromas about arteries and arterioles exclusively in the dorsal half of the medulla. They were more common in male than female patients, but were not related to any specific systemic disease process. The PN lesions were not found in patients under 20 years of age, but were observed in 1.5, 9.6, and 16.4% of those patients 20-49, 50-69, and 70-89 years of age, respectively. We regard these lesions as aberrant nerve fibers regenerated from cranial nerve roots rather than normally developed vascular nerves. We postulate that cranial nerve roots are subject to shearing or compression by strenuous motion of the neck in the course of ordinary activities and that the nerve fibers thus severed regenerate and grow into the pia-arachnoid and perivascular spaces to form the PN lesions. These PN lesions may become exaggerated under various abnormal circumstances such as overt traumatic injury and long-standing diseases affecting the medulla or cranial nerve roots.

Spinal autonomic neurons in Werdnig-Hoffmann disease, mannosidosis, and Hurler's syndrome: distribution of autonomic neurons in the sacral spinal cord.

In Werdnig-Hoffman disease, mannosidosis, and Hurler's syndrome, two groups of neurons (the Onuf's and intermediomedial nuclei) in the ventral horn of the mid-sacral region are found to share common selective sparing or vulnerability with the intermediolateral nuclei of the thoracolumbar and sacral regions of the spinal cord. This finding confirms the previous observations on the characteristic involvement or sparing in Fabry's disease (14), Shy-Drager syndrome (17), amyotrophic lateral sclerosis, anterior poliomyelitis, and neuronal intranuclear hyaline inclusion disease (15), and supports the assumption that the Onuf's and intermediomedial nuclei in the ventral horn represent autonomic neurons much as the thoracolumbar and sacral intermediolateral nuclei.

Pathology of Shy-Drager syndrome.

In four patients with the Shy-Drager syndrome, detailed pathological findings in the central nervous system are described. All four patients had striatonigral degeneration, olivopontocerebellar atrophy, pyramidal tract degeneration and ventral horn cell loss. Along with the multisystem degeneration, there was widespread loss of thoracolumbar autonomic neurons, which was demonstrated by comparative cell counts of the intermediolateral horns in two of the four patients. In all four patients, autonomic nuclei of the sacral cord, particularly the Onuf's and intermediolateral nuclei, were severely affected and diffuse cell loss in the nuclei seems to account for disordered bladder, rectal and sexual functions in Shy-Drager syndrome.

"Paramyxovirus-like" intranuclear inclusions occurring in the nervous system in diverse unrelated conditions.

Filamentous intranuclear inclusions similar to the "paramyxovirus-like" intranuclear inclusions described in active multiple sclerosis (MS) were observed incidentally in four patients who had diverse disorders such as rabies, mannosidosis, metachromatic leukodystrophy, cerebral aneurysm and ischemic infarcts. The observation is in support of the mounting evidence that the "virus-like" intranuclear inclusions are not specific for MS and may occur frequently in a variety of diverse conditions. Moreover, neither virological nor immunological evidence as to the viral nature of the intranuclear inclusions has been presented to date, and the intranuclear inclusions have been observed mostly in degenerating or autolyzed cells in biopsied or autopsied tissue samples. In view of all the circumstantial evidence, it is suggested that the intranuclear "paramyxovirus-like" inclusions may represent an alternation of nuclear chromatin common to antemortem degeneration and postmortem autolysis in a variety of cells, the nature of which remains to be elucidated.

A case of human rabies and ultrastructure of the Negri body.

A 60-year old man, eight weeks after being bitten on his finger by a stray cat, developed symptoms and signs of rabies which progressed rapidly over the next two weeks and he died of respiratory failure. Pathological examination revealed characteristic cytoplasmic inclusions in neurons of various parts of the central nervous system and the dorsal spinal and sympathetic ganglia. The diagnosis of rabies was confirmed by direct fluorescent antibody staining of the brain tissue obtained at autopsy. On histological examination, most, if not all, of the neuronal cytoplasmic inclusions were eosinophilic and homogeneous and lacked the basophilic inner granules or bodies characteristic of Negri bodies. Nevertheless, they were ultrastructurally identical with Negri bodies by virtue of being made up of finely fibrillar matrix and virus and/or related particles in varying numbers. This indicates that ultrastructurally typica Negri bodies may or may not have the histologically visible basophilic inner bodies depending upon the degree of virus replication. In light of the ultrastructural evidence, lyssa bodies described in rabies in the past may represent Negri bodies without histologically recognizable inner bodies or cytoplasmic inclusions unrelated to rabies, occurring ordinarily in normal or degenerating neurons. It is, therefore, suggested that the term, lyssa body, is obsolete and should no longer be used.

Striated muscle in the pineal gland of swine.

Striated muscle fibers (or cells) were observed in three of the six swine pineal glands. The muscle fibers occurred in clusters of several fibers about the parenchymal blood vessels. They were in general poorly developed, lacked regular cross striations and were not readily recognized histologically. The muscle fibers were, however, easily identified on electron microscopy because of the myofilaments they contain. In most of the muscle fibers, the myofilaments were arranged in ill-defined, disorderly bundles and rarely formed well-defined myofibrils and sarcomeres. The sarcotubular system was also poorly developed and triads were sparse and randomly scattered. Leptomeres were observed in several muscle fibers. The source of the muscle fibers in the pineal glands is not well understood and, whatever the source may be, the muscle fibers seem to remain poorly developed in the pineal glands.

Aberrant peripheral nerves and neuromas in normal and injured spinal cords.

Spinal cords from 20 patients (13-78 years of age) were studied for the occurrence of peripheral nerve fibers within the cord. Peripheral nerve fibers were observed in all but two younger patients, 13 and 24 years old, respectively, but all the spinal cords were otherwise normal. The nerve fibers were thin and predominantly myelinated. They were seen in two forms, small parallel bundles resembling normal nerve fascicles and larger interlacing bundles or whorled masses indistinguishable from traumatic neuromas. They almost always occurred in the perivascular spaces of the major parenchymal branches of the anterior sulcal artery and/or in the anterior median sulcus. The neuromas in the otherwise normal cords were identical with those occurring in the cord with old traumatic injury in three patients studied, but they were few in the former, while numerous and widespread in the injured segments of the latter. Accumulating evidence suggests 1. that most, if not all, of the parallel nerve bundles about the anterior sulcal artery in otherwise normal spinal cords represent aberrant, regenerated nerve fibers originating from ventral spinal nerve roots which are severed by clinically occult injuries in adult life, and 2. that the regenerated nerve fibers continue to grow into the anterior median sulcus and perivascular spaces and may become entangled or return upon themselves, forming neuromas as their way is blocked by the pia-glial barrier.

Axonal dystrophy in the gracile nucleus in children and young adults. Reappraisal of the incidence and associated diseases.

In 656 patients aged from one to 39 years, the incidence of axonal dystrophy in the gracile nucleus (ADG) is correlated with underlying diseases. The age-related incidence of ADG (minimal to severe) in these patients, 13, 53, 76 and 97% in the first, second, third, and fourth decades, respectively, is comparable to that observed by other investigators. The incidence drops to 8, 16, 31, and 60% when more than five spheroids in each gracile nucleus are taken into account. Diseases with which ADG is frequently associated vary according to the patient's age. Congenital biliary atresia and cystic fibrosis account for 71% of cases of ADG (mild to severe) in the first decade, while cystic fibrosis and malignancies account for 38 and 35% in the second decade, respectively. In the third decade, malignancies, renal diseases, cystic fibrosis, and heart diseases account for 30, 14, 12, and 12% of ADG cases, respectively, while malignancies, renal diseases, heart diseases, and diseases of digestive organs account for 30, 24, 15, and 11% in the fourth decade, respectively. The incidence of ADG also increases progressively with age, duration of the clinical course in the individual disease, or both, regardless of types of the diseases. This fact, when viewed together with the precocious development of severe ADG in patients with the malabsorption syndromes and in those with grave illnesses with protracted course leading to cachexia, seems to indicate that malnutrition represents a common factor correlated with severe ADG in the young patients. It seems to be premature at this time to disregard the hypothetical question that ADG in man is in some way related to deficiency or altered metabolism of vitamin E.

An unusual degenerative disorder of neurons associated with a novel intranuclear hyaline inclusion (neuronal intranuclear hyaline inclusion disease). A clinicopathological study of a case.

A 21-year-old woman with an unusual, progressive, degenerative neurological disorder is described. The disorder is characterized clinically by behavioral abnormality, peculiar involuntary movements, and ataxia starting in early childhood and subsequent development of dementia, choreoathetosis, rectal and bladder incontinence, bulbar and spinal muscular weakness, pes cavus, kyphoscoliosis, and generalized seizures. The clinical manifestations are correlated, with widespread pathological changes affecting almost all neuronal systems. The pathological changes are discussed in relation to the wide spectrum of "multisystem atrophies." Particular attention is directed to the ubiquitous occurrence of a novel intranuclear, eosinophilic, hyaline inclusion in almost all types of central, peripheral, and autonomic neurons. The ubiquitous neuronal involvement seems to explain the diffuse multiple system degeneration. The pathogenesis of the neuronal inclusions is unknown, but it is speculated that the disorder may represent a metabolic abnormality affecting the nuclear protein of neurons, rather than a viral infection. The pathological features, consisting of the neuronal intranuclear hyaline inclusions associated with multiple system atrophy, have not hitherto been described, and "neuronal intranuclear hyaline inclusion disease" is proposed as a name for the disorder. Rectal biopsy demonstrating the intranuclear hyaline inclusions in ganglion cells of the hyenteric plexuses may serve as a diagnostic procedure for the disorder.

Axonal dystrophy in the gracile nucleus in congenital biliary atresia and cystic fibrosis (mucoviscidosis): beneficial effect of vitamin E therapy.

In 63 patients with malabsorption syndromes, 16 with congenital biliary atresia (BA) and 47 with cystic fibrosis (CF), axonal dystrophy in the gracile nucleus (ADG) was studied. Of the 16 patients with BA, ADG of considerable severity was observed in all 10 over one year of age. Of the 47 patients with CF, it was observed in 32, 61 and 80% of the cases in the first, second, and third decades, respectively. Evidence is presented that there has been a substantial decrease in the incidence of ADG in CF patients in recent years and that the decreased incidence is attributable to vitamin E (Aquasol E) therapy. The beneficial effect of vitamin E supplementation in CF patients is proffered as strong evidence that ADG in BA and CF is related to vitamin E deficiency. The present study indicates that BA and CF patients require vitamin E supplementation to maintain a normal integrity of axons related to the gracile and perhaps other sensory nuclei. Critical neurological evaluation for possible dysfunction of the sensory nuclei in these patients with malabsorption syndromes is advised.

Aluminum levels in brain in Alzheimer's disease.

In both human Alzheimer's disease and aluminum encephalopathy of animals, changes are observed in neurofibrillary structures. We have found that brains from Alzheimer patients contain approximately 1.4 times the aluminum level found in a control series. Some possible methodological problems are discussed. We have proposed a plausible chemical mechanism for the changes of aluminum encephalopathy.

Pick's disease versus Alzheimer's disease: a comparison of clinical characteristics.

The clinical recognition of Pick's disease depends on its differentiation from Alzheimer's disease (AD). To identify distinguishing clinical features, we reviewed the clinical records of 21 patients with pathologically confirmed Pick's disease and matched them by sex, age of onset, and duration of dementia with 42 patients having pathologically confirmed AD. In the absence of temporal or frontal lobar atrophy on CTs, all the Pick patients and none of the AD patients had three of five clinical features: presenile onset (before age 65), an initial personality change, hyperorality, disinhibition, and roaming behavior. In addition, the Pick patients had a tendency toward reiterative and other speech disturbances. These findings suggest that Pick patients are potentially distinguishable from AD patients on the basis of clinical manifestations.

Dementia without Alzheimer pathology.

We studied five demented patients who, on neuropathologic examination, had cell loss and Lewy bodies in substantia nigra and locus ceruleus and few Alzheimer-type changes. The nucleus basalis had minimal cell loss in three patients and was not available in two. The lesions in the substantia nigra and locus ceruleus were unlikely to account for the dementia, and other structural or biochemical derangements, probably cortical but possibly subcortical, must also have been present but not visible at the light microscopic level.

Dementia lacking distinctive histologic features: a common non-Alzheimer degenerative dementia.

From a series of 460 dementia patients referred to a regional brain bank, 14 (3%) patients had a pathologic diagnosis of primary degeneration of the brain involving multiple sites (frontoparietal cortex, striatum, medial thalamus, substantia nigra, and hypoglossal nucleus), with cell loss and astrocytosis. There were no neuronal inclusions and essentially no senile plaques. This entity, which we have termed "dementia lacking distinctive histology" (DLDH), presented with memory loss and personality changes, and led to death, usually within 2 to 7 years. Dysarthria and dysphagia were prominent in the later phases of the illness in most patients. The psychometric findings of some of the patients were consistent with a "frontal" lobe dementia. A few patients had prominent caudate atrophy on CT as well as neuropathologically. Eight of our patients had positive family histories for neurologic disease, mainly dementia. DLDH, in addition to Pick's disease, is a major member of the frontal-lobe dementia group. In patients under age 70 years, the frontal lobe dementias represent an important diagnostic consideration.

Risk factors in Alzheimer's disease: a clinicopathologic study.

We investigated potential risk factors for Alzheimer's disease (AD) in a clinicopathologic study of 407 patients with definite AD, 100 non-Alzheimer dementia patients, and 50 normal subjects. The AD patients had more first-degree relatives with dementia than the non-AD dementia group (odds ratio of 1.85, 95% confidence interval of 1.07-3.20) or the normal elderly (odds ratio of 3.60, 95% confidence interval of 1.50-8.64) but did not have significantly more head injuries, medical and psychiatric illnesses, or relatives with Down's syndrome. The AD patients with a family history of dementia had their dementia at a later age than those without an affected relative. These findings indicate a familial risk for AD that is greater than for other dementing illnesses and has age-related penetrance. This study does not support other putative risk factors for AD such as head trauma and familial Down's syndrome.

Cocaine induced intracerebral hemorrhage: analysis of predisposing factors and mechanisms causing hemorrhagic strokes.

We analyzed 26 autopsy cases of cocaine induced intracerebral hemorrhage and compared those findings with those of 26 autopsy cases of cocaine induced cerebral aneurysm rupture. The incidence of hypertensive cardiovascular disease (HCVD) was significantly higher in persons with intracerebral hemorrhage than in those with aneurysm rupture. Our findings suggest that HCVD predisposes to cocaine induced intracerebral hemorrhage. We propose that the foregoing relationship results from a cocaine induced alteration of cerebral autoregulation in the context of increased cerebral blood flow.