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Symptoms of mania have been given inadequate attention as a source of agitated behavior in the dementia patient. Characterized by elevation in mood or grandiosity, pressured speech, and impulsivity, mania is common among the elderly population, with a prevalence approaching 20% in some studies. Because it is so highly associated with behavioral agitation, mania has a significant impact on patient management, and can often lead to the institutionalization of difficult patients. Here we present a case series of three elderly individuals who had signs of mania in conjunction with dementia. Refractory to psychotropic medications, all were given an acute plus maintenance courses of right-unilateral electroconvulsive therapy (ECT). The patients achieved significant improvement in signs of mania and agitation, as well as in mental status scores. We conclude that a short course of ECT, followed by maintenance treatments every 2 weeks, can contribute significantly to the management of dementia patients whose behavioral agitation is associated with signs of mania.

To assess the long-term outcome following unilateral pallidotomy for advanced Parkinson's disease, we performed nonblinded Core Assessment Program for Intracerebral Transplantations protocol assessments in 10 of the original 15 patients in our pilot study for 4 years following surgery. Although Unified Parkinson's Disease Rating Scale motor examination scores returned to baseline levels at 3 and 4 years, most patients continued to show sustained improvements in contralateral tremor, akinesia, and drug-induced dyskinesias. Contralateral tremor was absent at 4 years in all seven patients with preoperative tremor. Contralateral "off" arm movement times (averaged for three tasks) decreased by 37% at 1 year and by 30% at 4 years. Contralateral dyskinesia scores improved by 82% at 1 year and by 64% at 4 years. In contrast, after reaching speeds equal to the contralateral side at 1 year, ipsilateral "off" movement times increased by 13% over baseline levels at 4 years. Although most gait and postural stability measures showed modest initial improvement followed by a return to baseline values, "on" stand-walk-sit task performance declined significantly at 4 years. Despite the restriction of our surgeries to one side and the expected natural progression of Parkinson's disease, the results of patient self-assessments suggest that 4 years after unilateral pallidotomy, most patients continue to experience a quality of life above preoperative levels.

Few prospective studies have focused on elderly patients with mania, despite the rapidly aging population and the difficulties encountered in treating older patients with manic symptoms. Retrospective studies generally have found that the number of new cases of mania and the prevalence of mania in the population decrease with age, although there is evidence to contradict this widely held belief. The diagnosis of mania in the elderly is confounded by the overlap of manic symptoms with other syndromes that occur with aging, including dementia, delirium, and medical illnesses. The treatment of mania is more difficult in the elderly, and new treatments such as the atypical antipsychotics and the anticonvulsants take on a more important role in treatment regimens for older patients.

It is a challenging task to review transcranial magnetic stimulation (TMS) studies in neuropsychiatric disorders alongside assessments of longstanding clinical applications of ECT as an empirical treatment. The task is challenging because TMS was developed as a probe of neural mechanisms, whereas, in marked contrast, ECT has been a clinical technique from its inception. Since the onset of modern psychopharmacology, the understanding of the potential applications of ECT to neuropsychiatric disorders is generally restricted to case reports of patients with intractable disease that have had at least a partial response to ECT. Studies of the possible efficacy of TMS in neuropsychiatric conditions have a significant advantage over ECT as the treatments are associated with less morbidity. The only serious known complication in TMS is a risk of seizures that may increase in patients with neuropsychiatric conditions such as course brain disease. Only cortical structures are themselves accessible to TMS using current technology. Present TMS techniques, however, seem capable of affecting activity in deeper brain structures that are functionally linked to cortical brain regions. TMS permits novel explorations of relationships between regional brain activity and symptoms of a number of neuropsychiatric disorders, as well as in research relating activity in functionally related brain regions to modulation of cognition and affective states in healthy individuals. This is particularly true at present because TMS and powerful neuroimaging and neuropsychological tools are all making rapid advances simultaneously.

Background: To examine the magnetic resonance (MR) images of bipolar patients across a wide age range for the presence of hyperintense lesions compared to age- and gender-matched control subjects., Methods: Consecutive admissions to a mood disorders unit over a 2-year period were evaluated retrospectively for the presence of bipolar disorder by DSM-III-R criteria and whether they received an MR scan. Bipolar patients (n = 70, mean age = 49.9 +/- 19.7 years) were age- and gender-matched to control subjects (n = 70, mean age = 53.2 +/- 18.1 years) and the MR scans were rated to assess for the presence of hyperintensites., Results: Compared to control subjects, the bipolar patients demonstrated hyperintense lesions in the subependymal region, subcortical gray nuclei, and the deep white matter., Conclusions: Hyperintense lesions in bipolar patients are found in both the subcortical white matter and gray nuclei and may play an important role in the etiology of bipolar illness.

Rapid-rate transcranial magnetic stimulation (rTMS) allows for the noninvasive examination of the cerebral cortex. Recent studies have begun to investigate whether rTMS may be therapeutic for the treatment of depression. In the present study, the authors report on the safety and efficacy of rTMS in treating 50 patients with refractory depression. Overall, there were 21 responders (42%). Interestingly, 56% of the young patients responded, but only 23% of the elderly patients responded to rTMS. Overall, rTMS was well tolerated in all patients. Specifically, no patient developed a new onset of seizures during rTMS. The authors discuss the extant literature on rTMS for the treatment of depression along with future areas of research.

Background: Depressive symptoms are frequent complications of Alzheimer's disease (AD). We hypothesized that AD patients with depression would be more likely than nondepressed AD patients to show deep white-matter, subcortical gray-matter, and periventricular hyperintensities on magnetic resonance imaging (MRI)., Methods: In a retrospective study of 31 AD patients, depression was characterized by clinical diagnosis (DSM-III-R major depression, depressive symptoms, or no depression), a clinician-rated depression scale, and informant ratings of premorbid (before memory disorder) as well as current depression using the NEO Personality Inventory (NEO-PI), and related to qualitative and quantitative ratings of MRI hyperintensities., Results: In contrast to reports in nondemented elderly patients, there was no relationship between clinical diagnosis of major depressive episode and hyperintensities; however, clinician-rated depressive symptoms were higher in subjects with large anterior hyperintensities. In the early-onset AD group only, MRI abnormalities were related to greater premorbid depression, and less increase in depression after the onset of dementia, as rated by informants on the NEO-PI., Conclusions: Results highlight the need to consider early- and late-onset AD separately when assessing relationships between personality and MRI abnormalities, and to consider premorbid personality style when drawing conclusions about the etiology of depressive features seen in AD.

To study patterns of iron deposition in the putamen in aging, we reviewed brain magnetic resonance imaging (MRI) scans of 56 normal subjects. We developed the Signal Hypointensity in the Putamen (SHIP) Scale, a semiquantitative measure, to evaluate putamen nuclei for extent of iron deposition relative to the globus pallidus. The SHIP score was highly reliable (kappa = 0.76) and significantly correlated with age (P < 0.0001). We found that age-related iron deposition in putamen nuclei follows a characteristic pattern along a posterolateral-to-anteromedial gradient. This gradient may be related to the microvasculature of the putamen. Other studies are needed to replicate our findings in patients with affective and other neuropsychiatric disorders and to clarify the pathophysiological mechanisms that govern these changes.

The effects of posterior internal pallidal ablation (GPi pallidotomy) on parkinsonian signs and symptoms were studied in 15 patients with medically intractable Parkinson's disease (PD). The sensorimotor territory of the internal portion of the globus pallidus and the adjacent optic tract and internal capsule were identified with microelectrode recording and stimulation. Radiofrequency lesions were then created in the identified sensorimotor territory. Pallidotomy significantly improved all cardinal parkinsonian motor signs (tremor, rigidity, akinesia/bradykinesia, and gait dysfunction) and reduced drug-induced motor fluctuations and dyskinesias. The improvements occurred predominately contralateral to the lesion, but were also present ipsilaterally. Early postoperative (3-month), mean total United Parkinson's Disease Rating Scale scores improved by 30.1% from preoperative values. Mean combined "on/off" Schwab and England Scale scores, a measure of functional independence, increased from 48.8% to 73.0% postoperatively. The mean total United Parkinson's Disease Rating Scale and Schwab and England scores did not show a statistically significant decline over the 1-year postoperative period. Surgery resulted in little morbidity, including a lack of significant deficits on neuropsychological and psychiatric testing. Physical and social functioning and vitality measures on the Medical Outcome Scale also showed significant improvement over the postoperative period. The findings of this pilot study demonstrate that ablation of the sensorimotor portion of the internal pallidum is a highly effective treatment for advanced PD, with benefits sustained at 1 year.

Mania in late life is often complicated by comorbid medical conditions, medication intolerance, and inadequate medication response. Lithium remains the primary medication in the acute and prophylactic treatment of mania in the elderly. However, certain anticonvulsants (valproic acid and carbamazepine) have a number of advantages, including a more tolerable side effect profile and increased efficacy in subgroups of patients, such as patients with secondary mania due to neurological and other medical disorders. Future research is needed to focus on the double-blind trials of somatic treatments, including ECT, in the elderly.

Objectives: To detect cases of Alzheimer's disease (AD) in a large population of twins living throughout the United States and to examine concordance for AD in twins as a function of age and genotype for apolipoprotein E (APOE)., Setting: Nationwide survey., Design: Multistage screening and field evaluation beginning with two telephone interviews and culminating with laboratory tests, longitudinal neuropsychological measures, physician examination, and diagnostic consensus among experts., Participants: Membership in 1990-1991 of intact pairs in the National Academy of Sciences--National Research Council Registry of veteran twins, then aged 62 to 73 years., Main Outcome Measures: Completeness of case detection was examined in collateral studies. Zygosity and APOE genotypes were determined by restriction mapping. Concordance was calculated by the proband method., Results: Ninety subjects who screened positively for AD were studied in person, and 60 whose differential diagnoses included AD were followed up, as were their co-twins. Sensitivity of screening was estimated at greater than 99%, but 24% of subjects refused participation after initial screening. Seven of 38 diagnoses of AD have been confirmed at autopsy, and 31 other subjects eventually met criteria for probable or possible AD (prevalence estimate, 0.42%, 95% confidence interval, 0.29% to 0.56%), with good interrater reliability (intraclass r = .86). Excluding one discordant pair with unknown zygosity, concordance rates were 21.1% (4/19) for monozygotic and 11.1% (2/18) for dizygotic probands. Concordance was 50% for twins sharing the epsilon 4/epsilon 4 genotype at APOE, but there were no affected co-twins of 15 probands with onset before age 70 years, no epsilon 4 allele, and no family history of AD. The mean (SD) period of discordance in the latter pairs was 11.3 (3.3) years., Conclusions: The multistage case-detection approach achieved reliable and valid diagnoses of AD with high apparent sensitivity but substantial attrition after initial screening. Genetic influences in AD at this age are limited, except among homozygotes for allele epsilon 4 at APOE. Subjects with early-onset AD who lack the epsilon 4 allele are not rare, and their condition appears to have little genetic influence. They should be ideal for studies on environmental cause of AD.

Depression is a psychiatric syndrome seen in about 1-2% of elderly patients. When depression is seen for the first time late in life, genetic and psychosocial factors appear to be less important. Structural changes in the brain appear to be more important. In this paper the author presents the concept of arteriosclerotic depression and relates the occurrence of structural changes in the brain to atherosclerosis and the structural changes to the occurrence of depression. Evidence in support of this concept is presented.

Magnetic resonance scans of five geriatric patients presenting with formed visual hallucinations in the absence of other psychopathology were compared with those of 12 healthy elderly subjects for the presence and extent of subcortical and periventricular signal hyperintensity. While the number of discrete brain lesions did not differ between groups, scans from the patient group contained a higher incidence (100% vs. 50%) and greater mean size (11.1 vs. 2.9 mm) of periventricular signal hyperintensity in the posterior region. Peripheral visual acuity was impaired in all of the patients, but cerebrovascular risk factors were not elevated in this group. The authors suggest that structural abnormalities in the area of the primary visual pathway may predispose some older individuals, particularly those with poor peripheral visual acuity, to develop the symptom of visual hallucination.

1. The present study was done to assess the brain metabolites measured by proton magnetic resonance spectroscopy (MRS) in normal individuals. 2. Proton spectroscopy STEAM voxel technique with chemical shift imaging was used to provide localized metabolic information from the brains of 34 normal volunteers (15 males) between the ages of 21 and 75 years. 3. Choline, Creatine and N-acetyl aspartate (NAA) was lower in white matter than gray matter. Choline/NAA and choline/creatine ratios were also lower in white matter. The choline, creatine and NAA were lower in older subjects in the voxel representing cortical and subcortical gray matter. There were no differences between males and females. 4. This preliminary study suggests that age matching is essential for comparative studies of disease states using proton MRS.

We conducted a co-twin control study among 50 elderly twin pairs with onsets of Alzheimer's disease (AD) separated by 3 or more years. Twenty-three male pairs (46%) were screened from the (U.S.) National Academy of Sciences-National Research Council Registry (NAS-NRC Registry) of World War II veteran twins; others (mostly women) had responded to advertisements or were referred from AD clinics. Twenty-six pairs (52%) were monozygous. The onset of AD was inversely associated with prior use of corticosteroids or ACTH (odds ratio [OR], 0.25; 95% confidence interval [CI], 0.06 to 0.95; p = 0.04). Similar but weaker trends were present among pairs discordant for history of arthritis or for prior daily use of nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin. The association was strongest when we combined use of steroids/ACTH or NSAIDs post hoc into a single variable of anti-inflammatory drugs (AIs) (OR, 0.24; CI, 0.07 to 0.74; p = 0.01). The inverse relation was strong in female (volunteer) twin pairs but was not present in the younger men from the NAS-NRC Registry. AIs had typically been taken for arthritis or related conditions, but a similar result was apparent after controlling statistically for the arthritis variable (OR, 0.08; CI, 0.01 to 0.69; p = 0.02). AIs have been proposed as a means of retarding the progression of AD symptoms, and these data suggest that AIs may also prevent or delay the initial onset of AD symptoms. Because of limitations in the case-control method, our results require corroboration with hypothesis-driven research designed to control bias and confounding.

The bicaudate and bifrontal indices have been used in prior computed tomographic studies to investigate atrophy of the caudate nuclei in patients with Huntington's chorea and cerebral atrophy. However, the relationship between these indices and caudate volume has not been documented previously. In this study, we used high-field magnetic resonance imaging (MRI) to determine the effects of normal aging on the bicaudate and bifrontal indices and to study the relationship between these indices and caudate volume. The subjects were 49 normal volunteers, aged 22 to 82 years, who were without any significant neurologic or psychiatric disorders. Age was positively correlated with bicaudate index (r = .59; P < .0001) and bifrontal index (r = .40; P < .0047). Age was negatively correlated with caudate nuclei volume (r = -.47; P < .0005). Caudate volume was negatively correlated with bicaudate (r = -.27; P < .06) and bifrontal (r = -.31; P < .03) indices. These findings are consistent with prior reports of caudate nuclei degeneration with increasing age. Linear and volumetric caudate measurements with MRI may prove useful in the investigation of caudate nuclei function in the neuromotor decline with normal aging and in disorders such as Huntington's chorea.

Purpose: To evaluate further the clinical utility of the interuncal distance (IUD) measured from axial MR scans as a reflection of hippocampal atrophy., Methods: The IUD measured from the axial MR scans of 17 healthy control subjects was correlated with the volume of the amygdala hippocampal complex obtained from coronal MR images. The IUD was also measured on axial MR scans in 12 patients with possible or probable Alzheimer disease., Results: The correlation between the total amygdala hippocampal volume and the IUD was insignificant for control subjects (r = -0.38, P = .13). When analysis of covariance was performed with the IUD as the dependent variable and age and diagnosis as the independent variables, overall R2 was 0.25. Age (F = 5.02, df = 1, P = .034), but not diagnosis (F = 0.02, df = 2, P = .88), had a significant effect., Conclusions: The IUD has no significant correlation with the amygdala hippocampal volume. The IUD appears to be a better measure of overall brain volume, which changes with age. In our patient population diagnosed with mild to moderate Alzheimer disease, the IUD measurement was not found to be useful in distinguishing their scans from those of the volunteers.

Hypercortisolemia is a frequently observed abnormality in patients with major depression. It has been hypothesized that the hippocampus, as a major feedback site for glucocorticoids, is involved in the pathophysiology of hypercortisolemia. Some have in fact posited that the hippocampus is marked by diminished size in depressed patients with hypercortisolemia. We tested this hypothesis by examining the relationship between hippocampal volume, assessed with magnetic resonance imaging, and hypercortisolemia using the dexamethasone suppression test (DST) in a group of 19 depressed patients. No differences in hippocampal volume were observed between patients and control subjects (n = 30). Within the patient group, DST suppressors did not differ from DST nonsuppressors in hippocampal volume. However, a relationship between hippocampal volume and 11 p.m. cortisol concentration was observed after covariance adjustment for age and sex. Furthermore, significant negative correlations were observed between hippocampal volume and both age of depressive onset and number of hospitalizations. The results of this study therefore provide limited support for the hypothesis regarding an essential role of the hippocampus in the neuroendocrine elevation of glucocorticoids in depression.

Parkinson's disease (PD) is associated with changes in the substantia nigra, which communicates with subcortical nuclei. This study investigates subcortical nuclei volume in PD in vivo by magnetic resonance (MR) imaging. Caudate, putaminal, and thalamic nuclei were measured on axial MR images using a point counting method and systematic sampling. PD patients (n = 21) had significantly smaller subcortical nuclei than age- and sex-matched controls (p < 0.001) and depressed patients (p < 0.01). The decline in PD was not correlated with age, sex, or cortical volume. Depressed patients had significantly smaller caudate and putaminal nuclei than controls (p < 0.05 and 0.01, respectively) but thalamic nuclei were not significantly different. Caudate, putaminal, and thalamic nuclei volumes of controls were significantly negatively correlated with age (r = -0.58, p < 0.01; r = -0.77, p < 0.001; r = -0.57, p < 0.01, respectively). Depressed subjects demonstrated a negative trend. Volumetric measurements by MR imaging may be a useful in investigating the role of the basal ganglia in neurological disorders.

Purpose: To assess the effects of age and gender on the interuncal distance measured from MR images., Methods: High-field strength MR images (axial) of 75 volunteers, 21-82 years old and free of neurologic disorders, were used to measure the interuncal distance., Results: The interuncal distance increased with age (r = 0.66, P < .0001). The mean (SD) interuncal distance for all subjects was 21.4 (4) mm with a range of 12 to 29 mm., Conclusions: The interuncal distance in healthy subjects is unlikely to exceed 30 mm. Our data may be of clinical significance in view of a previous report stating that the interuncal distance may be enlarged in pathologic hippocampal degeneration, such as in patients with Alzheimer disease.

The etiology of depression in the elderly is poorly understood. In this study, magnetic resonance imaging was used to evaluate the role of subcortical structures in the pathophysiology of depression in the elderly. Elderly depressed patients were found to have smaller caudate nuclei, smaller putaminal complexes and in increased frequency of subcortical hyperintensities compared with normal, healthy controls. These findings were more pronounced in patients with late-onset depression. Based on these findings, the authors discuss the role of the basal ganglia in the pathophysiology of depression in the elderly.

The relationship between dexamethasone suppression test (DST) results and in vivo pituitary volume was studied in 24 psychiatric inpatients. The principles of systematic stereology were used to measure pituitary volume from 3-mm contiguous sagittal spin-echo magnetic resonance (MR) images of the brain. There was no correlation between pituitary volume and 3 p.m. or 10 p.m. postdexamethasone (post-DEX) plasma cortisol concentrations. However, when multiple regression analysis was performed to relate pituitary volume to gender, age, and post-DEX plasma cortisol concentrations, there was a significant relationship between pituitary volume and age, gender, and 10 p.m. post-DEX cortisol plasma concentration. This is the first study to demonstrate a method that directly measures, rather than estimates, in vivo pituitary volume. Furthermore, it suggests that activation of the hypothalamic-pituitary-adrenal axis in psychiatric patients, as manifested by elevated post-DEX cortisol concentrations, may influence pituitary volume.

Purpose and Methods: High-field MR images at 1.5 T were used to characterize the effects of age and gender on pituitary size and shape in a sample of 71 adult volunteers (40 females), aged 21 to 82 years., Findings: For all subjects, age was inversely correlated with pituitary height (r = -.43, P less than .0002) and cross-sectional area (r = -.35, P less than .0028). Age-specific gender differences were also present in pituitary height and area. A convex upper pituitary margin was more common in females (P = .002) and younger subjects (P = .009)., Conclusions: This study confirms that aging is accompanied by gender-specific changes in pituitary size and shape, and provides normative data that may facilitate evaluation of the pituitary gland in neuroendocrine disorders.

A role of the caudate nucleus in depression has been suggested from relevant clinical conditions, such as patients with Huntington's disease or caudate infarcts, as well as animal studies. Correlations of caudate nucleus disease with depressive symptoms have been limited to autopsy studies and cases of gross pathological disorder, such as large infarcts. We used serial axial high-field magnetic resonance images and an unbiased stereological technique to estimate the volumes of the caudate nuclei in 50 patients who met DSM-III criteria for major depression (23 men, 48.3 +/- 17 years old) in comparison with 50 age- and gender-matched normal controls free of major neurological and psychiatric disorders. Depressed patients had smaller caudate nucleus volumes (5.2 +/- 1.6 cm3) compared with controls (6.2 +/- 1.7 cm3). Right and left caudate nucleus volumes were smaller in depressed patients compared with controls. Age was negatively correlated with caudate nucleus volumes in depressed patients as well as in controls. Caudate nucleus volumes in depressed patients were inversely correlated with the bicaudate and bifrontal indices. These results may be the first demonstration of diminished caudate nucleus volumes in depression and suggest a role for the caudate nucleus in the pathogenesis of major depression.

High-field magnetic resonance (MR) images were used to study posterior fossa morphology in 27 patients with major depression and 36 normal control subjects. Depressed patients demonstrated smaller brain stem and cerebellar vermis than controls. These differences were highly significant for the anterior cerebellar vermis and medulla. There was also a striking age-related decline in midbrain size in depressed patients as well as in controls. Our results are consistent with several lines of evidence implicating a role for the cerebellar vermis in affective disorders and, in addition, provide the first MR documentation of the differential effects of aging on posterior fossa morphology in normal subjects compared with patients with major depression.

Objective: Clinical reports over the last 60 years suggest that the amobarbital interview is effective in relieving catatonic symptoms. This has never been substantiated with methodologically sound trials. The authors postulated that a randomized blind comparison of intravenous amobarbital and saline would demonstrate the superiority of amobarbital in relieving catatonic mutism., Method: The subjects were 20 inpatients with catatonic mutism. They were randomly assigned to either saline (N = 10) or a 5% amobarbital solution (N = 10), and the infusions were administered intravenously at a rate of 1 cc/min or less over 10 minutes by a blinded physician. A second blinded physician administered a semistructured interview during the infusion to control for the effect of suggestion. A third blinded physician rated patient responsiveness, reactivity, and arousal. Any patient who was unresponsive to the initial infusion was crossed over to the other infusion. Interviews were videotaped for determination of interrater reliability., Results: In the initial infusions, six of 10 patients responded to amobarbital and zero of 10 responded to saline. Four of the saline nonresponders responded when given amobarbital. Response was evident by the 4th minute of the amobarbital infusion. Interrater reliability was high. The responders and nonresponders differed significantly in the variance of the weight-adjusted amobarbital dose, and the responders tended to be older and female., Conclusions: Intravenous amobarbital is superior to saline in relieving catatonic mutism, although only 50% of these patients responded. The nonresponders were distinguished from the responders by a greater variance in the weight-adjusted dose of amobarbital.

Purpose: To determine the effects of age on estimated midbrain volume., Patients and Methods: T2-weighted MR imaging and an unbiased stereologic method were used in 75 volunteers; the subjects ranged in age from 21 to 82 years and were without any significant neurologic or psychiatric disorders., Results: Age was negatively correlated with estimated midbrain volume (R = -.39, P less than .0005), with the anteroposterior diameter through the substantia nigra (R = -.33, P less than .004) and with the interpeduncular distance (R = -.24, P less than .04). The linear measurements for the right and left side were almost identical. These findings are consistent with prior reports of nigrostriatal degeneration with increasing age. Furthermore, they suggest a close symmetry of age-related changes between the right and left side in normal subjects., Conclusions: Volumetric and linear measurements of midbrain morphology with MR may prove useful in the investigation of neurologic disorders such as Parkinson disease.

Magnetic resonance imaging is presently being utilized to understand the neuropathology of affective disorders. Present research has demonstrated brain changes in affective disorders that correlate with neuroendocrine findings and are similar to changes noted in normal aging.

In a retrospective study, brain magnetic resonance images of 12 patients with the onset of manic symptoms after the age of 50 years were compared to age- and sex-matched control subjects for the incidence, size, and location of subcortical hyperintensities. Compared with controls, the patients demonstrated a significantly greater number of large subcortical hyperintensities, particularly in the middle third of the brain parenchyma. The lesions occurred with equal frequency in the right and left hemisphere. There were no differences between the two groups in the size of the ventricles or the presence of periventricular hyperintensities.

The basal ganglia are recognized as putative mediators of certain cognitive and behavioral symptoms of major depression. Moreover, patients with basal ganglia lesions have repeatedly exhibited significant affective symptomatology, including apathy, depressive mood, and psychosis. Using high resolution, axial T2 intermediate magnetic resonance images, and a systematic sampling stereologic method, we assessed putamen nuclei volumes in 41 patients with major depression (DSM-III) and 44 healthy volunteer controls of similar age. Depressed patients had significantly smaller putamen nuclei compared with controls. Age was negatively correlated with putamen size in both groups. These results are the first demonstration of diminished putamen volumes in depression and further support a role for basal ganglia structures in the etiopathogenesis of depression.

Intermediate T2-weighted MR images and a systematic sampling stereological method were used in 37 normal volunteers, 24 to 79 years old, to assess the effects of age and sex on cerebellar volume. Female subjects (n = 21) had significantly smaller cerebellar volumes compared with males (n = 16) of similar age (t = -3.9, p less than .0008, two-tail t test). Using straight-line, univariate regression, we determined that age was not a significant predictor of cerebellar volume (R2 = 0.07, t = -1.66, p = 0.11), whereas gender did appear to account for a significant amount of variability in cerebellar volume (R2 = 0.33, t = -4.13, p = .0002). The mean absolute cerebellar volume in this study was 112 ml (SD +/- 16) for all subjects, 104 ml (SD +/- 10) for females, and 122 ml (SD +/- 16) for males. This study demonstrates the feasibility of using MR images along with a systematic stereological method to assess in vivo human cerebellar volume, thereby providing a research tool to correlate cerebellar morphology with cognitive and neuromotor function.

A quantitative magnetic resonance imaging study of regional brain T1 spin-lattice relaxation times in 29 normal volunteers and in 20 patients with major depression revealed significantly shortened T1 relaxation times for the hippocampus in depressed patients. These differences were particularly prominent in elderly depressed patients. T1 relaxation times are reflective of the content and macromolecular environment of tissue water protons; shorter hippocampal T1 values may reflect differences in the content or organizational properties of hippocampal water protons. These findings are consistent with several lines of evidence that have implicated a role for the hippocampus in the regulation of mood and in the pathophysiology of the stress response, and they suggest that major depression may be associated with biophysical tissue changes in the aging hippocampus.

A brain magnetic resonance imaging (MRI) study of the corpus callosum in 36 normal volunteers, ages 26-79 years, revealed that age was positively correlated with the T1 spin-lattice relaxation time of the corpus callosum and was negatively correlated with the corpus callosum cross-sectional area. T1 relaxation times are sensitive to the content and macromolecular environment of tissue water, and variations in callosal T1 may reflect differences in the content or relaxation properties of callosal water. Such changes also potentially could occur secondary to alterations in the composition of callosal myelin. This study confirms and extends prior morphological studies that have reported age-related dimensional changes in the corpus callosum and, in addition, provides evidence of age-related biophysical tissue differences in the human corpus callosum.

Midsagittal magnetic resonance (MR) images of 36 normal volunteers, ranging in age from 26 to 79 years, were used to evaluate the effects of age on the size of posterior fossa structures (cerebellar vermis, midbrain, pons, medulla and fourth ventricle). Our results demonstrate a highly statistically significant age-related decline in the cross-sectional area of the midbrain (r = -.44, p less than 0.007), a less prominent decline in the area of the anterior cerebellar vermis (r = -.33, p less than 0.05) and striking intercorrelations between the dimensions of the pons, medulla and cerebellar vermis. To the best of our knowledge, this is the first MRI demonstration of midbrain atrophy during aging in normal adults.

The neurotransmitter and neuropeptide changes in Alzheimer's disease are outlined in Table 1. Many of the changes, such as decreases in CSF ACh and SRIF, are well documented and correlate with the severity of the dementia; however, they are relatively nonspecific. The changes in neurotransmitter availability have offered new insight into both the pathophysiology and possible treatment strategies in Alzheimer's disease. It is evident that the disease is characterized by pathologic involvement of multiple neurotransmitter systems, including those that utilize ACh, SRIF, CRF, and, most probably, monoamines and excitatory amino acids. The role each system has in the signs and symptoms of Alzheimer's disease remains obscure.

The magnetic resonance scans of 22 patients with early-onset Alzheimer's disease (AD) were compared to 16 age-matched neurologically normal controls for the presence of white matter subcortical hyperintensities (SCH) and periventricular hyperintensities (PVH). Patients with AD were significantly more likely to have evidence of PVH (p less than 0.01) than age-matched controls. There was no significant difference between the two groups in either the frequency of SCH or the size of the largest lesion. Within the AD group, there was no difference demonstrated in the location of the SCH, either in the anterior-posterior plane or between the two hemispheres. Patients with AD more frequently demonstrated ventriculomegaly (p less than 0.001) and sulcal widening (p less than 0.05) compared with controls. This study suggests that the SCH seen in early-onset AD patients on MRI are related more to the aging process than to the AD process and that the increased frequency of PVH may have a relationship to the disease process.

We examined the relationship between platelet [3H]-imipramine binding and leukoencephalopathy as assessed by 1.5 Tesla Magnetic Resonance Imaging (MRI) in 21 elderly depressed patients who satisfied DSM-III criteria for major depression. Both drug-free platelet [3H]-imipramine binding and brain MRI studies were obtained during the same episode of depression. Our findings show a significant inverse relationship between frequency of subcortical hyperintensity (SCH) and the number (Bmax) of platelet [3H]-imipramine binding sites. Patients with Bmax less than 850 fmol/mg protein had significantly larger SCH compared with patients with a higher Bmax. These data provide further support to the potential use of platelet [3H]-imipramine binding studies and brain MR imaging as diagnostic adjuncts in geriatric depression and suggest, moreover, that these two biological markers may be linked in geriatric patients with depression.

1. The frequent occurrence of hypothalamo-pituitary dysfunction in patients with eating disorders as well as prior reports that nutritional and endocrine status influence pituitary morphology, led us to hypothesize that pituitary size and shape may be altered in patients with eating disorders. 2. Magnetic resonance imaging (MRI) does not use ionizing radiation and is currently one of the most feasible modalities available to study the pituitary gland in vivo. Using MRI, we have previously reported in a preliminary study that female patients with eating disorders had significantly smaller pituitary glands than controls. In addition MRI excluded any pituitary mass lesions. 3. In this report, we confirm our previous MRI findings and provide further evidence of pituitary abnormalities in an expanded sample of eating disorder patients. Preliminary data on pituitary volume estimates from MRI scans are provided for a subset of patients and controls.

Putamen nuclei were assessed in 36 normal volunteers using magnetic resonance imaging and a systematic sampling method. There was a significant decrease in the volume of the putamen nuclei with advancing age (r = -0.74, p less than 0.0001), and an associated decline in the volume of the caudate nuclei (r = 0.60, p less than 0.0001). The implications of these findings in age-associated motor abnormalities are discussed.

Many patients with dementia have symptoms of depression and agitation in addition to the underlying cognitive impairment. These symptoms can be management problems for both the physician and the caregiver. In many cases, however, pharmacologic intervention is helpful. Even in dementia, depressive symptoms usually respond to antidepressant therapy. Neuroleptic medications are the drugs most commonly used to manage behavioral symptoms, such as agitation, suspiciousness, emotional lability, hostility and sleeplessness. A few studies have shown that ergoloid mesylates (Hydergine) can modestly improve cognitive function. Some experimental drugs also show promise in partially reversing the symptoms of intellectual decline.

Using intermediate weighted magnetic resonance imaging (MRI) and a systematic sampling stereological method in 39 normal volunteers aged 24-79 years old, we demonstrated a marked age-associated decline in caudate nuclei volume (r = -0.69, p less than 0.0001). The mean absolute volume of the caudate nuclei in this study (9.4 cm3) was almost identical to that reported in a previous autopsy study and further confirms the validity of this stereological technique for use with MR images. This technique will provide a method for measuring the caudate and other nuclei in vivo, from brain images and, as such, a research tool to correlate age-associated changes in cognitive, sensory and motor function with caudate nucleus volume and other brain regions.

Dopamine (DA) and the dopaminergic agonists n-propylnorapomorphine (NPA), 2-amino-6,7-dihydroxytetrahydronaphthalene (ADTN) and apomorphine (APO) inhibit forskolin-stimulated adenylate cyclase activity in a dose-dependent fashion by more than 40% in membrane preparations of the porcine anterior pituitary gland. These agonists exhibit apparent dissociation constants that follow an expected dopaminergic order of potency (NPA greater than ADTN greater than or equal to APO greater than DA). The inhibition is dependent on guanine nucleotides and is reversible by dopaminergic antagonists (spiroperidol greater than (+)-butaclamol much greater than (-)-butaclamol). The potencies of these agonists in inhibiting forskolin-stimulated adenylate cyclase activity correlate with the agonist dissociation constants (KH) for binding to the high affinity receptor state (RH) in porcine anterior pituitary membranes (De Lean et al., Mol. Pharmacol. 1982, 22, 290-297) and the EC50 for inhibition of prolactin release from rat anterior pituitary cells in culture (Caron et al., J. Biol. Chem. 1978, 253, 2244-2253). Furthermore, the intrinsic activities of dopamine and the other agonists for inhibition of forskolin-stimulated adenylate cyclase are similar and correlate well with the ability of these agents to induce a comparable proportion (50%) of the receptor in a high affinity state. Together these data provide additional support for the physiological relevance of the high affinity agonist binding state of the D2 receptor in mediating the decrease in prolactin secretion via attenuation of adenylate cyclase.