Biomedical subjects
Publications and source records attributed to J C Morris.
There is a growing need for methods for measuring and staging the natural history of dementia of the Alzheimer type. One instrument, designed with that purpose in mind, is the Washington University Clinical Dementia Rating. We tested its reliability using multiple clinicians in a videotape-design study, and it proved reliable under these study conditions.
An 82-year-old cognitively healthy man was assessed longitudinally until very mild senile dementia of the Alzheimer type was diagnosed by clinical research criteria and documented by psychometric testing at age 85 years. Four months after diagnosis, Alzheimer's disease was confirmed neuropathologically. The diagnostic difficulties involved in distinguishing early senile dementia of the Alzheimer type-Alzheimer's disease from normal aging are examined and clinical and pathologic features useful for their discrimination are discussed.
Six cases of adult dementia with mesolimbic pathology are reported. The core clinical syndrome consists of parkinsonism, progressive dementia, and behavioral disturbances (generally depression). The histopathologic findings uniformly include a loss of pigmented neurons in the ventral tegmental area plus neurofibrillary tangles and/or cell loss in the entorhinal cortex and pyramidal cell layer of the hippocampus (perforant pathway). Neuronal depletion in the ventral tegmental area frequently is associated with similar cell loss in the adjacent substantia nigra and in the locus ceruleus. The development of neurofibrillary tangles in the perforant pathway occurs in the absence of senile plaques and is possibly related to diminished dopaminergic input.
We assessed language function, using a brief clinical Aphasia Battery and psychometric measures, in 150 subjects with senile dementia of the Alzheimer type (SDAT) and 83 elderly controls. Aphasia occurred only in demented subjects, and its prevalence increased with severity of dementia. Aphasia in mildly demented subjects was associated with both an earlier age of onset and more rapid progression of SDAT than in similarly demented nonaphasics. Language dysfunction in SDAT subjects was characterized by early decline in measures of comprehension and written expression, whereas other components, including oral naming, were less profoundly affected. Performance on the verbal psychometric measures, the Sentence Repetition and the Token tests, correlated strongly with Aphasia Battery scores and declined only minimally in nonaphasics, despite increasing dementia. We conclude that aphasia is a common feature of SDAT subjects and identifies a subgroup with more rapid progression of dementia. Furthermore, it represents language-specific dysfunction beyond the global cognitive impairment of SDAT.
Forty-three subjects with mild senile dementia of the Alzheimer type (SDAT, so-called probable Alzheimer's disease) were studied longitudinally by serial administration of several tests to rate dementia. Comparison was made with 58 healthy elderly controls. The clinical diagnosis was confirmed in all 16 autopsies. At 5 years after entry into the study, the cumulative rate of nursing home placement was 73%, and of death, 30%, rising at 7 years to 84% and 44%, respectively. Four of six clinical measures of dementia were found to correlate with the natural history of SDAT. Several measures are better than a single one in carrying out longitudinal studies of the disorder.
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.
Thyrotropin (thyroid-stimulating hormone or TSH)-receptor antibodies, important in the pathogenesis of Graves' disease, can be assayed by one of two methods: (1) bioassays that measure stimulation of thyroid cellular activity by patient immunoglobulins or (2) radioreceptor assays that measure inhibition of binding of labeled TSH to TSH receptors by the same substances. In this study, we report our experience with bioassay of thyroid-stimulating immunoglobulins (TSI) based on measurement of generation of cyclic adenosine monophosphate in a clone of the Fisher rat thyroid cell line (FRTL-5) in 279 patients, and we compare, in 163 consecutive samples, the results obtained by a radioreceptor assay for thyrotropin-binding inhibiting immunoglobulins (TBII). Among the untreated, hyperthyroid patients with Graves' disease, TSI were present in 95% (38 of 40), and TBII were present in 85% (17 of 20). In patients with euthyroid Graves' disease, TSI were found in 57% (16 of 28), and TBII were present in 41% (7 of 17). Of 49 nongoitrous and euthyroid controls, only 4% had TSI and 3% had TBII. Extremely high TSI indices were found in all patients who had pretibial dermopathy (N = 10) or severe Graves' ophthalmopathy (N = 19) requiring orbital decompression. We conclude that both assays are highly sensitive and specific in diagnosing Graves' disease. The TSI bioassay was more sensitive (P less than 0.001) than the TBII radioreceptor assay in detection of Graves' disease. In our experience, both assays have proved useful in the diagnosis of euthyroid Graves' disease with ophthalmopathy and atypical manifestations of hyperthyroid Graves' disease.
The frequency of symptoms of depression (Feighner criteria) was evaluated in subjects with dementia of the Alzheimer type (DAT) and matched controls enrolled in a longitudinal natural history study of DAT. Despite enrollment criteria which excluded subjects with affective disorders, the collateral sources of subjects with DAT described these subjects as having significantly more "depressive" symptoms than controls without dementia at entry, and at 15- and 34-month follow-up. The collateral sources of the subjects with DAT reported that these demented individuals experienced significantly greater loss of interest, decreased energy, difficulty in thinking and concentrating, and psychomotor agitation or retardation then did the control group. The subjects with DAT reported fewer symptoms than did their collateral sources, but like their collateral sources, they did not report a global elevation of all Feighner symptoms, but rather related significantly greater difficulty in thinking and concentrating than the controls and a tendency toward loss of interest and psychomotor changes. No subject became clinically depressed. The results suggest a significant overlap between the symptoms of dementia and depression. The frequency with which the above symptoms occur in DAT confounds the use of Feighner and, by extension, DSM-III criteria in diagnosing depression in cognitively impaired individuals with DAT.
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Synthetic peptides of the alpha-subunit of human glycoprotein hormones have been shown previously to inhibit binding of [125I]iodo-hCG to ovarian membranes, thus indicating the importance of the alpha-subunit in the structure-function relationships of the gonadotropic hormone. These same synthetic alpha-subunit peptides, the sequences of which are common to all human glycoprotein hormones, were found to inhibit the binding of [125I]iodo-TSH to human thyroid membrane preparations and FRTL-5 rat thyroid cells. The active portions of the subunit were represented in synthetic peptides alpha 21-35, alpha 31-45, alpha 26-46, and alpha 81-92, indicating that 2 separate sites within the alpha-subunit have binding activity for TSH. Peptides alpha 26-46 and alpha 31-45 were also found to potently inhibit the stimulation of adenylate cyclase activity by bovine TSH in TSH bioassay using FRTL-5 cells. Seven other synthetic peptides, including the remainder of the 92-amino acid sequence of the alpha-subunit, demonstrated little or no ability to inhibit binding of the tracer or inhibit the bioactivity of intact TSH. The findings were very similar to those of previous studies involving hCG binding, except that the two active sites appeared to be somewhat shifted towards the COOH-terminal end of the subunit. These studies support the concept of the importance of the alpha-subunit in receptor binding of all glycoprotein hormones and demonstrate the utility of the overlapping synthetic peptide strategy in investigations of protein structure-function relationships.
Transforming growth factor-beta (TGF beta) has been shown to influence the growth and differentiation of many widely varied cell types in vitro, including some that are endocrinologically active. We have investigated the previously unknown effects of this unique growth factor in the differentiated rat thyroid follicular cell line FRTL-5. The cells demonstrated specific, high affinity binding of TGF beta, and as with other epithelial cells, the growth of these thyroid follicular cells was potently inhibited by addition of TGF beta to the culture medium. TGF beta caused a significant reduction in TSH-sensitive adenylate cyclase activity in the cells. The addition of (Bu)2cAMP along with the growth factor to cultures partially reversed the characteristic morphological changes seen with TGF beta, but did not reverse the growth inhibition. To further investigate the possible mechanisms of the effects of TGF beta on the cells, we measured the influence of the growth factor on [125I]TSH binding. TGF beta did not compete for specific TSH-binding sites; however, exposure of the cells to TGF beta for 12 or more h resulted in a dose-dependent down-regulation of TSH receptors that was fully reversible. While cellular proliferation was potently inhibited by TGF beta, differentiated function, as manifest by iodine-trapping ability, was stimulated by the growth factor. This stimulation of iodine uptake was independent of, and additive to, the stimulatory effects of TSH. Finally, FRTL-5 cells in serum-free medium and in response to TSH were shown to secrete TGF beta-like activity that competed for [125I]TGF beta in a RRA. These studies suggest that TGF beta may represent an autocrine mechanism of controlling the growth response to TSH in thyroid follicular cells, while allowing the continuance of differentiated function.
Synthetic peptides, representing specific portions of the alpha-subunit of the human glycoprotein hormones, can inhibit both the binding of labeled TSH to thyroid membranes and adenylate cyclase stimulation by TSH in vitro. The same synthetic peptides (alpha 26-46 and alpha 31-45) significantly (P less than 0.05) inhibited the adenylate cyclase-stimulating activity of thyroid-stimulating immunoglobulins (TSI) from 10 patients with hyperthyroid Graves' disease. Peptide alpha 26-46 was the most potent, resulting in 79.1 +/- 8.8% (+/- SE) inhibition at 133 micrograms/mL, while peptide alpha 31-45 inhibited TSI activity by 36.3 +/- 5.2%. Peptides alpha 61-75 and alpha 81-92, that had only minimal ability to inhibit TSH-mediated cAMP generation, did not significantly inhibit TSI activity. The inhibitory action of alpha 26-46 was dose dependent, and a significant negative correlation was found between the maximum TSI activity of the serum sample and the inhibition achieved by the synthetic peptide, suggesting that differences in TSI affinity and/or titer may account for the variable inhibitory activity of the peptides. These results suggest that TSI interact with the TSH receptor at the site that recognizes the portion of the TSH alpha-subunit represented by the synthetic peptide alpha 26-46 and, thus, support the concept that the TSH-binding site of the TSH receptor is the site of antigen binding between TSI and the thyroid cell.
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Behavioral changes in 44 subjects with well-characterized mild senile dementia of the Alzheimer's type (SDAT) and 16 subjects with only questionable SDAT were compared to a control group of 58 subjects. Answers to both open-ended questions and personality items from the Blessed Dementia Scale were examined. Seventeen items were classified into seven categories by factor analysis and then further categorized into four clinically useful groups: passive, agitated, self-centered, and suspicious. Over 75% of subjects with mild SDAT had behavioral changes compared to 10% of controls. Passive symptoms were the most common, occurring in two-thirds of mild SDAT subjects. Agitated and self-centered symptoms were also common, occurring half as frequently as passive symptoms. Passive symptoms occurred alone in 25% of those with mild SDAT, whereas passive symptoms, together with agitated and/or self-centered symptoms, were present in 11-16% of subjects with mild SDAT. Agitated or self-centered symptoms rarely occurred alone. Characterizing the behavioral symptoms of SDAT is important for their clinical implications and for an approach to understanding brain-behavioral relationships.
In a longitudinal study of senile dementia and healthy aging, the occurrence of serious falls was examined in participants with senile dementia of the Alzheimer's type (SDAT) (n = 44) and in cognitively healthy elderly control participants (n = 56) over a 4-year period. Falls occurred in 36% of SDAT individuals versus 11% of controls. The higher frequency of falls in demented participants was not explained by greater neurologic deficit nor by increased drug use compared with controls. However, males with SDAT who reported falls, had higher mean blood pressures and were more likely to be medicated than males with SDAT who did not fall. These differences were not observed in women. Falls in SDAT participants were associated with an increased rate of institutionalization. SDAT is an important risk factor for serious falls, and falls are associated with loss of independence in demented patients.
Passive, agitated, and self-centered behavioral changes were noted on initial evaluation in two-thirds, one-third, and one-third, respectively, of subjects with mild senile dementia of the Alzheimer's type (SDAT). Over a 50-month follow-up period, the percentage of patients who exhibited agitated and self-centered behaviors doubled. The percentage of subjects who demonstrated all three behavioral changes increased from 11% at entry to the study (mild SDAT) to over 50% when the dementia had reached a severe stage. The presence of personality changes at a mild stage of dementia did not predispose subjects to more rapid progression to a more advanced stage of illness.
Comedication with phenytoin and carbamazepine is frequently used in patients with refractory seizures, although the benefit of this strategy has not been established. To assess whether the combination is a rational anticonvulsant treatment, we determined the therapeutic index (toxicity:efficacy ratio) for the drugs, alone and together, in mice, The individual agents were virtually identical in anticonvulsant and neurotoxic activity, and combined use had no additional therapeutic advantage. Analysis of drug concentrations in brain showed an additive pharmacodynamic interaction for phenytoin and carbamazepine, indicating that the combination is unlikely to be superior to either drug alone. Thus, we find no experimental justification for the simultaneous use of phenytoin and carbamazepine in the treatment of epilepsy.
The significance of periventricular lucencies in the white matter on CT in demented patients is not understood. We studied the relationship of these changes to mental status of subjects with senile dementia of the Alzheimer type. A semiquantitative method showed more numerous and extensive lucencies in demented than in healthy elderly. Neuropathologic examination of five subjects with these changes and confirmed Alzheimer's disease revealed diffuse white matter pallor without infarction. There were no hypertensive vascular changes, although limited hyaline thickening was present.