The FDA-approved compound, pramipexole and the clinical-stage investigational drug, dexpramipexole, reverse chronic allodynia from sciatic nerve damage in mice, and alter IL-1ß and IL-10 expression from immune cell culture.

During the onset of neuropathic pain from a variety of etiologies, nociceptors become hypersensitized, releasing neurotransmitters and other factors from centrally-projecting nerve terminals within the dorsal spinal cord. Consequently, glial cells (astrocytes and microglia) in the spinal cord are activated and mediate the release of proinflammatory cytokines that act to enhance pain transmission and sensitize mechanical non-nociceptive fibers which ultimately results in light touch hypersensitivity, clinically observed as allodynia. Pramipexole, a D2/D3 preferring agonist, is FDA-approved for the treatment of Parkinson's disease and demonstrates efficacy in animal models of inflammatory pain. The clinical-stage investigational drug, R(+) enantiomer of pramipexole, dexpramipexole, is virtually devoid of D2/D3 agonist actions and is efficacious in animal models of inflammatory and neuropathic pain. The current experiments focus on the application of a mouse model of sciatic nerve neuropathy, chronic constriction injury (CCI), that leads to allodynia and is previously characterized to generate spinal glial activation with consequent release IL-1ß. We hypothesized that both pramipexole and dexpramipexole reverse CCI-induced chronic neuropathy in mice, and in human monocyte cell culture studies (THP-1 cells), pramipexole prevents IL-1ß production. Additionally, we hypothesized that in rat primary splenocyte culture, dexpramixole increases mRNA for the anti-inflammatory and pleiotropic cytokine, interleukin-10 (IL-10). Results show that following intravenous pramipexole or dexpramipexole, a profound decrease in allodynia was observed by 1 hr, with allodynia returning 24 hr post-injection. Pramipexole significantly blunted IL-1ß protein production from stimulated human monocytes and dexpramipexole induced elevated IL-10 mRNA expression from rat splenocytes. The data support that clinically-approved compounds like pramipexole and dexpramipexole support their application as anti-inflammatory agents to mitigate chronic neuropathy, and provide a blueprint for future, multifaceted approaches for opioid-independent neuropathic pain treatment.

Interuncal distance measurements in healthy volunteers and in patients with Alzheimer disease.

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.

MR assessment of pituitary gland morphology in healthy volunteers: age- and gender-related differences.

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.

Magnetic resonance imaging of the caudate nuclei in depression. Preliminary observations.

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.

Posterior fossa abnormalities in major depression: a controlled magnetic resonance imaging study.

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.

A magnetic resonance imaging study of putamen nuclei in major depression.

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.

In vivo stereological assessment of human cerebellar volume: effects of gender and age.

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.

Pituitary abnormalities in eating disorders: further evidence from MRI studies.

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.