K. Ranga

Accuracy and reproducibility of brain and tissue volumes using a magnetic resonance segmentation method.

Magnetic resonance (MR) imaging now allows the qualitative and quantitative assessment of the human brain in vivo. As MR imaging resolution has improved, precise measurement of small brain structures has become possible. Methods of measuring brain regions from MR images include both manual and semiautomated methods. Despite the development of numerous volumetric methods, there have been only limited attempts so far to evaluate the accuracy and reproducibility of these methods. In this study we used phantoms to assess the accuracy of the segmentation process. Our results with simple and complex phantoms indicate an error of 3-5% using either manual or semiautomated techniques. We subsequently used manual and semiautomated volumetric methodologies to study human brain structures in vivo in five normal subjects. Supervised segmentation is a semiautomated method that accomplishes the division of MR images into several tissue types based on differences in signal intensity. This technique requires the operator to manually identify points on the MR images that characterize each tissue type, a process known as seeding. However, the use of supervised segmentation to assess the volumes of gray and white matter is subject to pitfalls. Inhomogeneities of the radiofrequency or magnetic fields can result in misclassification of tissue points during the tissue seeding process, limiting the accuracy and reliability of the segmentation process. We used a structured seeding protocol that allowed for field inhomogeneity that produced reduced variation in measured tissue volumes. We used repeated segmentations to assess intra- and inter-rater reliability, and were able to measure small and large regions of interest with a small degree of variation. In addition, we demonstrated that measurements are reproducible with repeat MR acquisitions, with minimal interscan variability. Segmentation methods can accurately and reliably measure subtle morphometric changes, and will prove a boon to the study of neuropsychiatric disorders.

Subcortical Structural Changes in ECT-Induced Delirium

A prolonged (interictal) delirium was induced by electroconvulsive therapy (ECT) in 6/36 (17%) elderly depressed patients. Brain magnetic resonance imaging or brain computerized axial tomography revealed structural changes in the basal ganglia and white matter in all six patients who developed delirium. These findings are consistent with our previous work and with several lines of data that have implicated the basal ganglia and subcortical white matter in the development of delirium from other causes. These results suggest that lesions in these areas may predispose one to developing an interictal delirium during a course of ECT. (J Geriatr Psychiatry Neurol 1990;3:172-176).

Plasma dexamethasone concentrations and the Dexamethasone Suppression Test.

Altered bioavailability or altered pharmacokinetics of dexamethasone (dex) may contribute to a positive Dexamethasone Suppression Test (DST) in psychiatric patients. We measured plasma dex and plasma cortisol concentrations in 32 patients with primary major depressive disorder (MDD), 14 patients with other psychiatric disorders, and 16 normal controls. Cortisol was measured by the competitive protein binding (CPB) assay and dex by RIA (IgG Corp.). Additionally, cortisol was measured by a fluorescent polarization immunoassay (FPIA) available on the Abbott TDx analyzer in an attempt to validate this method for use in the DST. The agreement between FPIA and CPB cortisol results was excellent. Depressed nonsuppressors, by definition, had significantly higher mean plasma cortisol concentrations than depressed suppressors, psychiatric controls, and normal volunteers at 8:00 AM, 3:00 PM, and 10:00 PM postdex. When DST nonsuppressors and suppressors were compared regardless of diagnostic group, plasma dex concentrations were significantly lower (p less than 0.01) in the DST nonsuppressors. There was a significant negative correlation between plasma cortisol levels and plasma dex levels across all subjects at 8:00 AM (r = -0.365, n = 44, p less than 0.05). When the subjects were sorted by diagnostic category, there was a strong, but not statistically significant, trend toward lower plasma dex concentrations in the melancholic nonsuppressors versus the melancholic suppressors and between the psychiatric control non-suppressors and the corresponding suppressor group. These relationships disappeared when we restricted our analyses to an empirically derived middle range of plasma dex concentrations within which the DST results were considered to be valid. We conclude that bioavailability or pharmacokinetics of dex may significantly contribute to DST results. Further investigation is needed to determine whether or not the quantification of dex and its metabolites and their determination at which specific timepoints during the DST will enhance the predictive or interpretive value of the DST in psychiatric patients.

Magnetic resonance findings in patients with early-onset Alzheimer's disease

The magnetic resonance scans of 22 patients with early-onset Alzheimers 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.

Platelet (3H)-Imipramine Binding and Leukoencephalopathy in Geriatric Depression

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.

5 Neuropeptides and neurotransmitters in Alzheimer's disease: focus on corticotrophin releasing factor

Alzheimers disease (AD) is a progressive degenerative disease of the nervous system characterized neuropathologically by the presence of senile plaques and neurofibrillary tangles in amygdala, hippocampus and neocortex (Katzman, 1986). AD is now known to be the most common cause of dementia in the elderly and accounts for approximately 50-60% of all cases of dementia. It is believed to affect about 10% of the population over the age of 65 years, although a recent epidemiological study conducted in an East Boston community (Evans et al, 1989) suggests that the prevalence of AD in those 85 years or older may be as high as 47%. These data, as well as the continuing growth of the older population groups in developed countries, emphasizes the need to define potentially modifiable causal factors for AD (Evans et al, 1989). The constellation of clinical and pathological markers in AD is also associated with selective abnormalities of specific neurotransmitter and neuropeptide systems. Identification of these abnormalities has opened new avenues for assessing the preand postsynaptic integrity of these neuronal systems in AD, and offered hope for potential drug therapy. This chapter reviews neuropeptide and neurotransmitter chemistry in AD, focusing in particular on the role of corticotrophin releasing factor (CRF) in the pathophysiology of AD.

Alterations in Platelet [3H]-Imipramine Binding, 5HT Uptake and Plasma α1-acid Glycoprotein Concentrations in Patients with Major Depression

ABSTRACT Several aspects of platelet serotonergic function have been investigated in patients with major depression. The specificity of the decreased number of platelet binding sites for [3H]-imipramine were investigated. Blood samples for platelet receptor binding were obtained from normal controls (n-102), patients with panic disorder (n-18), atypical depression (n-7), mania (n-16), fibromyalgia (n-24), and Alzheimers disease (n-14) as well as patients with major depression (n-155). Only patients with major depression exhibited a significant decrease in the density of [3H]-imipramine binding sites on platelets. In addition, in vitro experiments revealed that imipramine was less effective in inhibiting radiolabeled serotonin (5HT) uptake into platelets in elderly depressed patients, when compared to either elderly normal controls or young-middle aged depressed patients. Lastly, an increase in the concentration of plasma α1-acid glycoprotein, a putative endogenous inhibitor of the [3H]-imipramine binding site, in drug-free depressed patients was observed.

The Biology of Late-Life Depression

Current evidence suggests that depression is clearly not a single entity but a syndrome characterized by a broad spectrum of symptom type and severity, and chronicity of illness. Depression is one of the most frequent psychiatric disorders in the geriatric population, though figures of prevalence have ranged from 5 to 44% depending on the method of identification (Blazer & Williams, 1980). Interestingly, data from the ECA study revealed that the lifetime prevalence of depression was four times lower in persons aged 65 years or older than in individuals aged 25 to 44 at the time of the ECA (Myers, Weissman, Tischer, et al., 1984). However, Berkman et al. (1986) obtained data to support the view that the presence of significant depressive symptoms, but not major depression, are more frequent among the elderly. In that study only 1–2% of the subjects fulfilled DSM III criteria for major depression but more than 10% had depressive symptoms. It is unclear at the present time whether those depressive symptoms are largely due to psychosocial factors, biological factors, or a combination of the two. Several investigators have suggested that depression in late life is a distinct entity from depression in early life. Genetic predisposition seems to play only a modest role in the aethiopathogenesis of geriatric depression when compared with a younger age group (Hopkinson, 1964; Mendlewicz, 1976).