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Background To understand the earliest signs of cognitive decline caused by Alzheimer disease (AD) and other illnesses causing dementia, information is needed from well-characterized individuals without dementia studied longitudinally until autopsy. Objective To determine clinical and cognitive features associated with the development of AD or other dementias in older adults. Design Longitudinal study of memory and aging. Setting Alzheimer’s Disease Research Center, St Louis, Mo. Main Outcome Measures Clinical Dementia Rating, its sum of boxes, and neuropathologic diagnosis of dementia. Participants Eighty control participants who eventually came to autopsy. Results Individuals who did not develop dementia showed stable cognitive performance. Entry predictors of dementia were age, deficits in problem solving as well as memory, slowed psychomotor performance, and depressive features. Minimal cognitive decline occurred prior to dementia diagnosis, after which sharp decline was noted. Even individuals who were minimally cognitively impaired (Clinical Dementia Rating = 0.5) typically had neuropathologic AD at autopsy. Histopathologic AD also was present in 34% of individuals who did not have dementia at death; these individuals without dementia showed an absence of practice effects on cognitive testing. Conclusions Increased age, depressive features, and even minimal cognitive impairment, as determined clinically by Clinical Dementia Rating sum of boxes and by slowed psychomotor performance, identify older individuals without dementia who develop dementia. Older adults who do not develop dementia have stable cognitive performance. The absence of practice effects may denote the subset of older adults without dementia with histopathologic AD, which may reflect a preclinical stage of the illness.

Background Tau and β-amyloid (Aβ) are proposed diagnostic biomarkers for Alzheimer disease (AD). Previous studies report their relationship to clinical diagnoses of AD and other dementias. To understand their value as predictors of disease-specific patholody, levels determined during life must be correlated with definitive diagnoses in mixed dementia groups and cognitively normal subjects. Objectives To correlate antemortem cerebrospinal fluid (CSF) tau and Aβ levels with definitive dementia diagnosis in a diverse group of patients; to calculate statistics for CSF tau and Aβ. Design Prospective study. Setting Ten clinics experienced in the diagnosis of neurodegenerative dementias. Patients One hundred six patients with dementia and 4 cognitively normal subjects with a definitive diagnosis, and 69 clinically diagnosed cognitively normal subjects. Main Outcome Measures Correlation of CSF tau and Aβ with final diagnosis. Results Mean tau level was 612 pg/mL for the 74 patients with AD, 272 pg/mL for 10 patients with frontal dementia, 282 pg/mL for 3 patients with dementia with Lewy bodies, and 140 pg/mL for 73 cognitively normal control subjects. Tau was less than 334 pg/mL for 20 patients with AD. Aβ 42 was reduced in patients with AD (61 fmol/mL) compared with patients with frontal dementia (133 fmol/mL) and control subjects (109 fmol/mL), but not compared with patients with dementia with Lewy bodies (14 fmol/mL) or prion disease (60 fmol/mL). Conclusions Elevated CSF tau levels are associated with AD pathology and can help discriminate AD from other dementing disorders. However, some patients with AD have a level less than the mean ± 2 SDs of the cognitively normal cohort.

Background Psychosis is common in patients with Alzheimer disease. While the relationship between psychosis and clinical variables has been examined frequently, few studies have examined the relationship between psychosis and the 2 major neuropathological hallmarks of Alzheimer disease: neurofibrillary tangles and senile plaques. We characterized the occurrence of psychosis in relation to dementia severity and determined if subjects with Alzheimer disease and psychosis had a greater neurofibrillary tangle or senile plaque burden than subjects with Alzheimer disease and no psychosis. Methods One hundred nine subjects with Alzheimer disease were followed longitudinally with semistructured assessments in order to assign a Clinical Dementia Rating and determine whether psychosis was present. After the subjects died, their brains were obtained for histological examination. Analysis of variance was used to compare the densities of neurofibrillary tangles, total senile plaques, and cored senile plaques in subjects with psychosis vs subjects without psychosis, in several neocortical regions, the hippocampus, and the entorhinal cortex. Results Psychosis occured commonly in Alzheimer disease, affecting 63% of subjects. The frequency of psychosis increased with increasing dementia severity. More importantly, we found that subjects with psychosis had a 2.3-fold (95% confidence interval, 1.2-3.9) greater density of neocortical neurofibrillary tangles than did subjects without psychosis. The increase was independent of dementia severity. No similar relationship with psychosis was seen for total senile plaques or cored senile plaques. Conclusions The increase in psychosis frequency that occurs with the progression of dementia severity and the independent association between psychosis and neurofibrillary tangle density suggest the possibility that some common underlying process or processes specific to Alzheimer disease may regulate both phenomena.

Objective To study differences between subjects with Alzheimer disease (AD) and cognitively intact control subjects, with respect to brain histologic markers of AD, and the relationship of those markers in the AD group to severity of dementia, age at death, sex, and apolipoprotein E genotype. Setting Washington University Alzheimer's Disease Research Center, St Louis, Mo. Design and Subjects Consecutive neuropathologic series of 224 prospectively studied volunteer research subjects, 186 with dementia of the Alzheimer type (DAT) or "incipient" DAT and confirmed to have AD by postmortem examination and 13 cognitively intact subjects, confirmed to lack postmortem findings of AD. Main Outcome Measures Brain densities (number per square millimeter) of senile plaques and neurofibrillary tangles, extent of cerebral amyloid angiopathy, cortical Lewy bodies, and apolipoprotein E genotype. Results Neocortical neurofibrillary tangle densities were substantially correlated with dementia severity, and to a greater degree than was true for senile plaque densities. When infarcts, hemorrhages, and Parkinson disease changes coexisted with AD, neurofibrillary tangle and senile plaque densities were lower. Plaque-predominant AD was found in a greater proportion of subjects with milder than more severe dementia. Entorhinal cortical Lewy bodies were no more frequent in plaque-predominant AD than in the remaining AD cases. Increasing age at death was negatively correlated with dementia severity and densities of senile plaques and neurofibrillary tangles. The apolipoprotein E ϵ4 allele frequency was greater in AD than in control subjects but decreased with increasing age. After controlling for dementia severity, senile plaque densities were only weakly related to ϵ4 allele frequency, and only in hippocampus. However, the degree of cerebral amyloid angiopathy was clearly related to ϵ4 allele frequency. Among subjects diagnosed during life as having DAT or incipient DAT, only 7% were found to have a neuropathologic disorder other than AD causing their dementia. Conclusions (1) The order of the strength of relationships between densities of histologic markers and dementia severity in AD is neurofibrillary tangles greater than cored senile plaques greater than total senile plaques. (2) Advanced age at death is associated with somewhat less severe dementia and fewer senile plaques and neurofibrillary tangles. (3) Plaque-predominant AD may represent a developmental stage in AD. (4) Despite a substantial effect of apolipoprotein E ϵ4 as a risk factor for AD, on decreasing the age at AD onset, and increasing the amount of cerebral amyloid angiopathy, its effect on senile plaque densities is variable and complex, being confounded with age, dementia severity, and methodologic differences. (5) Stringent clinical diagnostic criteria for DAT, even in the very mild stage, and senile plaque–based neuropathologic criteria for AD are highly accurate.

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.

We studied 8 subjects longitudinally in whom isolated language dysfunction had developed gradually at a mean age of 62.8 years. The language deficits initially displayed by the subjects were characteristic of the syndrome of "progressive aphasia without dementia." By 5 years after onset of progressive aphasia, however, 7 of the 8 subjects additionally had developed mild dementia as diagnosed by clinical means, and the remaining subject demonstrated declining performance in both verbal and nonverbal psychometric measures. Thus, generalized cognitive impairment occurred in all. Neuropathologic evidence of a diffuse dementing disorder was present in the 2 subjects studied postmortem. One had Alzheimer's disease with disproportionate involvement of the left inferior parietal cortex, and the other displayed widespread neocortical neuronal loss and microvacuolation in the absence of specific histopathologic markers. In this series, progressive aphasia was a precursor of global dementia.

The management of severe flexor tendon injuries of the hand has been dramatically improved by tendon sheath reconstruction with an artificial tendon, followed by conventional tendon grafting. The purpose of this study was to investigate the nature of neosheath formation. In 25 chickens, the flexor tendons and sheaths in a toe were excised and replaced with a United States Army artificial tendon. An artificial tendon was also placed in the back, and four weeks later, tendons and surrounding tissue as well as normal tendon sheaths were excised and submitted for light, transmission electron microscopy and scanning electron microscopy. In all instances, neosheaths formed around the silastic coated artificial tendon. The neosheaths formed in the foot and back were similar to normal sheath, having the same cellular and fibrous composition. Reconstruction of the normal anatomy with an artificial tendon explains why this surgical technique gives superior results to other less physiologic procedures in patients with severe hand injuries.

Clinical investigations of Alzheimer's disease (AD) have been limited by diagnostic inaccuracy. We employed explicit clinical inclusion and exclusion criteria to identify subjects with senile dementia of the Alzheimer type (SDAT). In a consecutive series of 26 postmortem examinations from this sample, AD was histologically verified in all subjects and was the primary dementing illness. Seventeen of the 26 SDAT subjects had been diagnosed when only mildly demented. Two control subjects were examined neuropathologically; AD was absent in both. We conclude that research clinical diagnostic criteria for SDAT, even in its mild stage, are valid.

The tissue distribution and function of opioid peptides in humans is incompletely defined. We report here that, unlike that in other species, the human anterior pituitary gland contains high concentrations of methionine-enkephalin (met-enkephalin). The met-enkephalin immunoreactive material was isolated and identified as authentic met-enkephalin by fast atom bombardment-mass spectrometry and Edman degradation sequencing. The met-enkephalin was localized in a large subpopulation of TSH immunoreactive cells (thyrotrophs). No other proenkephalin-derived opioid peptides were found in the pituitary, and there was no overlap between proopiomelanocortin and met-enkephalin immunoreactive cells. These results suggest that the human anterior pituitary gland contains a novel met-enkephalin precursor and a possible role for met-enkephalin in regulating human thyroid function.

Vasospasm and intrarenal thrombosis are characteristics of acute renal allograft rejection. A possible mediator of these phenomena is thromboxane A2. Single kidneys were exchanged between nonimmunosuppressed mongrel dogs. At intervals after transplantation, rejecting and normal kidneys were removed and slices of cortex and medulla were prepared for incubation. The in vitro release of thromboxane B2 (TxB2), prostaglandin E2 (PGE2), and 6-keto-prostaglandin F1a (6-keto-PGF1 alpha) into the incubation media was measured by radioimmunoassay. Within 72 hr of transplantation the cortex of rejecting kidneys synthesized 10 to 30 times as much PGE2 and TxB2 as normal controls. A similar increase was not observed for 6-keto-PGF1 alpha synthesis. In the medulla there was a selective reduction in 6-keto-PGF1 alpha production within five days of transplantation. In both cortex and medulla there was a significant increase in the ratio of TxB2 to 6-keto-PGF1 alpha production. Reversal of the normal TxB2:6-keto-PGF1 alpha ratio could induce the widespread intrarenal thrombosis and vasospasm that characterizes acute renal allograft rejection.

Melatonin, a secretory product of the pineal gland, can suppress the neonatal rat pituitary LH and FSH responses to LHRH in both intact animals and pituitary cultures. The present study has examined the effect of melatonin on an enriched gonadotroph cell preparation to determine whether the indole interacts directly with the gonadotroph or requires other pituitary cells to mediate the inhibition of gonadotropin release. Monodispersed anterior pituitary cells were prepared from 15- day-old female rats by a modification of the procedure of Hopkins and Farquhar. This procedure, in contrast to certain other methods tested in our laboratory for monodispersion, produced cells maximally responsive to both LHRH and melatonin and comparable to those dissociated with collagenase in our earlier studies. The dispersed cells were fractionated by velocity sedimentation on a 1–3% bovine serum albumin gradient. LH, FSH, TSH, PRL, and GH concentrations in cell lysates of each fraction were measured by double antibody RIA....

The intestine is lined by a continuously regenerating epithelium that maintains gradients in 'liver' fatty acid binding protein (L-FABP) gene expression along its horizontal and vertical axes, i.e., from duodenum to colon and from crypt to villus tip. To identify cis-acting DNA sequences responsible for these regional differences, we linked portions of the L-FABP gene's 5' nontranscribed region to the human growth hormone (hGH) gene and examined hGH expression in transgenic mice. Nucleotides -596 to +21 of the rat L-FABP gene correctly directed hGH expression to enterocytes and hepatocytes. However, anomalous expression was observed in small intestinal crypts, colon, and renal proximal tubular epithelial cells. Addition of nucleotides -4000 to -597 of the L-FABP gene, in either orientation, suppressed renal hGH expression and restored a nearly normal horizontal, but not a vertical, hGH gradient in the intestine. Thus, horizontal gradients of gene expression within the intestine can be maintained by orientation-independent, cis-acting suppressor elements.

In twenty-nine consecutive autopsies after burns that involved an average of 61 per cent of the body surface, 62 per cent of the histological sections of the intrinsic muscles of both hands showed patchy or total destruction of the muscles in one or more intrinsic compartments. Considering all of the twenty-seven totally burned upper extremities, 70 per cent had severe necrosis of one or more intrinsic muscles. Of the eighteen totally burned upper extremities in which escharotomy had been performed 72 per cent had severe intrinsic-muscle necrosis, while in the nine without escharotomy 66 per cent showed severe necrosis.

The response of adenyl cyclase to glucagon, ACTH and epinephrine was determined during the various steps of a fractionation scheme yielding purified fat cell plasma membrane. The adenyl cyclase activity of the homogenate was stimulated about 5X by 10.0 HIM NaF, 7X by 5.0 μg of epinephrine/ml, 3.5X by 500 munits of ACTH/ml and 5.5X by 10.0 pig of glucagon/ml and a combination of the three hormones was non-additive, producing only a 7X response. During the fractionation process the hormonal responsiveness was lost in distinctive amounts and patterns so that the final plasma membrane adenyl cyclase had none of the original glucagon, 20% of the original ACTH and 30% of the original epinephrine responses. During the purification steps 70% of the homogenate adenyl cyclase activity was lost in a pattern distinct from the loss of hormone receptors and the loss could not be restored or prevented. The ACTH and epinephrine stimulation of the plasma membrane adenyl cyclase was blocked by EGTA and propranolol, respect...

The distribution of ATPase activity among the subcellular fractions of isolated fat cells has been described. The mitochondria contained half of the total activity of the intact cell and homogenate with the plasma and microsomal membranes contributing about 12% together. The ATPase specific activities of the mitochondria and plasma membranes were equal and about five times that of the microsomal fraction. The Na + -K + , ouabain-sensitive ATPase represented about 6–10% of the total ATPase specific activity of the plasma membrane. Only the intact cellular and mitochondrial ATPase were sensitive to 2,4-DNP (2,4-dinitrophenol). Oligomycin significantly inhibited intact cell ATPase activity as well as mitochondrial, plasma membrane, and microsomal fraction ATPase activity. Oligomycin seemed to inhibit a plasma membrane Mg 2+ -ATPase independent of Na + and K + and greater than could be accounted for by mitochondrial contamination of the plasma membrane fraction. A possible role for the extramitochondrial oligomycin-sensitive ATPase in protein synthesis is discussed.

Porcine growth hormone (pGH) and porcine prolactin (pPRL) were measured by radioimmunoassay in pituitary homogenates and subcellular fractions derived therefrom. A nonnormal population distribution was found for pPRL content and concentration; larger anterior pituitary glands exhibited a high pPRL content and concentration, and prolactin cell hyperplasia. Nearly 90% of both hormones present in the post-nuclear supernatant sedimented with the large secretory granule fraction, and the bulk of the protein found in this fraction was accounted for by these two hormones. Electrophoresis of secretory granule extracts on polyacrylamide gel, followed by radioimmunoassay of gel segment eluates, revealed a distribution of immunoreactive hormone which paralleled the migration of stainable protein bands, with the exception of very slowly migrating protein species which were not immunoreactive in either assay system. (Endocrinology 92: 477, 1973)

A rapid method of preparing plasma membranes from isolated fat cells is described. After homogenization of the cells, various fractions were isolated by differential centrifugation and linear gradients. Ficoll gradients were preferred because total preparation time was under 3 hr. The density of the plasma membranes was 1.14 in sucrose. The plasma membrane fraction was virtually uncontaminated by nuclei but contained 10% of the mitochondrial succinic dehydrogenase activity and 25–30% of the RNA and reduced nicotinamide adenine dinucleotide cytochrome c reductase activity of the microsomal fraction. Part of the RNA and NADH-cytochrome c reductase activity was believed to be native to the plasma membrane or to the attached endoplasmic reticulum membranes demonstrated by electron microscopy. The adenyl cyclase activity of the plasma membrane fraction was five times that of Rodbell's "ghost" preparation and retained sensitivity to epinephrine. The plasma membrane ATPase activity was five times that of the homogenate and microsomal fractions. Electron microscopic evidence suggested contamination of the plasma membrane fraction by other subcellular components to be less than the biochemical data indicated.

PRL-secreting epithelial cell lines (PECL) derived from Furth's MtT/W15 transplantable rat pituitary tumor have been studied as monolayer cultures for up to 18 months. Tumor epithelial cells were mechanically dispersed, plated at high density, and selectively enriched by picking and pooling colonies, thereby avoiding single cell-cloning conditions, in order to study the long term natural evolution of tumor cell populations in vitro. Fibroblast-like cells, prevalent in primary and early passages, underwent a series of morphological changes, which have been interpreted by others as in vitro aging or differentiation, and were eliminated from the cultures within 9 months. PECL phenotypes were heterogeneous and differed from sc MtT/W15 tumors with respect to morphological differentiation and modal chromosome number (48 for solid tumors: 48-92 for PECL; 42 for diploid). PECL were devoid of secretory granules by electron microscopy, but accumulated neutral lipid, complex lysosomes, and endocytotic vesicles. PECL differed from one another in plating efficiency (0.6-7.3%) and basal secretion rates for PRL and GH. Population doubling times decreased during the culture interval from 100 to 24-37 h in different PECL. RIA of medium from early cultures (less than 7 months) disclosed that PRL always exceeded GH levels, mimicking the serum hormone ratio of MtT/W15 tumor-bearing Wistar-Furth rats. Basal hormone release declined with time from a maximal initial rate of 93 micrograms/mg cell protein.24 h for PRL and 2.3 micrograms/mg cell protein.24 h for GH. GH production ceased by 7 months in all PECL, but PRL secretion persisted for 18 months. PRL production increased during exponential growth as a direct function of cell number and protein, and reached a maximum during confluency. Immunoperoxidase-conjugated antibody staining localized PRL in the Golgi region but not in secretory granules, consistent with a rapid release rate for the hormone. In preliminary experiments, rat hypothalamic extract (one hypothalamic extract RP-1 equivalent per dish) and 17 beta-estradiol (1 X 10(-8) M), but not TRH (5 X 10(-8) M), stimulated PRL secretion from PECL/F3, whereas only hypothalamic extract stimulated total cell protein after exposure to the agents for 3-6 days. Long term cultures of PECL exhibited reduced oncogenicity when transplanted in W/Fu rats. During serial passages, in vivo, PRL secretion decreased from 154 microgram/ml serum to the normal range within the same time framework that PRL secretion from cultured PECL/F3 was observed to decrease and stop in vitro. We believe that this phenomenon represents an expressed program within the cells rather than being merely a reflection of the in vitro environment.

We report an 18-yr-old youth with a metastatic foregut carcinoid tumor, Cushing's syndrome, and hypersomatotropic gigantism. Administration of cyproheptadine caused a dramatic fall in urinary cortisol excretion and plasma ACTH levels associated with clinical remission of the Cushing's syndrome. GH secretion was not affected by cyproheptadine administration. Ectopic ACTH secretion was confirmed by RIA of tumor extracts and immunohistochemical demonstration of ACTH-containing cells in hepatic metastases. There were two sources of GH production demonstrated in this patient. Ectopic secretion of GH by the carcinoid hepatic metastases was documented by both RIA and immunohistochemical techniques. A somatotrophic pituitary tumor was also present. The histological characteristics of this tumor suggest adenomatous hyperplasia rather than de novo neoplastic change as the likely mechanism of its pathogenesis. GH releasing factor-like activity was demonstrated in extracts of plasma and in extracts of the carcinoid tumor. We conclude that cyproheptadine exerted an effect on the ectopic ACTH-producing cells but not on the ectopic GH-producing cells or on adenohypophyseal GH secretion. Production of a GH releasing factor-like activity by the carcinoid tumor may have caused the pituitary somatotrophic tumor.

The effects of chronic hypersomatotropism on pancreatic islet function were studied in rats bearing the growth hormone secreting tumor MtTW15. These rats did not become hyperglycemic and minimally hyperinsulinemic in the fed state following prolonged massive elevations of serum growth hormone. Islets from tumor-bearing rats were grossly larger and beta cells more granulated than in control rats by light microscopy. Electron microscopy confirmed the increase in cell cytoplasm and increased number of beta granules per cell. Isolated islet preparations from tumor-bearing rats contained four times the insulin found in control rats. Fed control and tumor-bearing rats had comparable serum glucose and immunoreactive insulin concentrations after glucose intragastrically and tolbutamide intravenously. After a forty-eight-hour fast the tumor-bearing rats had higher serum immunoreactive insulin than controls and their insulin levels were higher after glucose and tolbutamide than controls. Some of the tumor-bearing rats became hypoglycemic during the forty-eight-hour fast. The increased stored insulin in the tumor-bearing rats was mobilized by a combination of the individually potent insulinogenie stimuli theophylline and glucagon.

Article abstract— Objective: To determine the feasibility of using high-dimensional brain mapping (HDBM) to assess the structure of the hippocampus in older human subjects, and to compare measurements of hippocampal volume and shape in subjects with early dementia of the Alzheimer type (DAT) and in healthy elderly and younger control subjects. Background: HDBM represents the typical structures of the brain via the construction of templates and addresses their variability by probabilistic transformations applied to the templates. Local application of the transformations throughout the brain (i.e., high dimensionality) makes HDBM especially valuable for defining subtle deformities in brain structures such as the hippocampus. Methods: MR scans were obtained in 18 subjects with very mild DAT, 18 healthy elderly subjects, and 15 healthy younger subjects. HDBM was used to obtain estimates of left and right hippocampal volume and eigenvectors that represented the principal dimensions of hippocampal shape differences among the subject groups. Results: Hippocampal volume loss and shape deformities observed in subjects with DAT distinguished them from both elderly and younger control subjects. The pattern of hippocampal deformities in subjects with DAT was largely symmetric and suggested damage to the CA1 hippocampal subfield. Hippocampal shape changes were also observed in healthy elderly subjects, which distinguished them from healthy younger subjects. These shape changes occurred in a pattern distinct from the pattern seen in DAT and were not associated with substantial volume loss. Conclusions: Assessments of hippocampal volume and shape derived from HDBM may be useful in distinguishing early DAT from healthy aging.

The pituitary tumor removed from a patient with the Forbes-Albright syndrome was studied by light microscopy, by electron microscopy, and by hormonal analysis. The patient did not have detectable levels of plasma growth hormone following arginine infusion and lacked clinical features of acromegaly. Galactorrhea, present for 3 yr, ceased after hypophysectomy. By light microscopy the tumor was a pituitary adenoma composed of cords of densely granulated eosinophiles with a few chromophobes and basophiles. The eosinophilic granules in the tumor cells differed from growth hormone granules in size, shape and staining characteristics. The tumor granules were more irregular and averaged 500–600 mμ in diameter, in contrast to growth hormone granules which average 350–400 mμ in diameter. The strong erythrosin staining of the tumor granules was not abolished by orange G as it was in growth hormone granules from control cadaver pituitaries. Positive erythrosin staining is a characteristic property shared by ...