William M. McDonald

Inverse association of anti‐inflammatory treatments and Alzheimer's disease Initial results of a co‐twin control study

We conducted a co-twin control study among 50 elderly twin pairs with onsets of Alzheimers 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.

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.

Neuroanatomical substrates of depression in the elderly

SummaryThe 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 lateonset depression. Based on these findings, the authors discuss the role of the basal ganglia in the pathophysiology of depression in the elderly.

In vivo assessment of pituitary volume with magnetic resonance imaging and systematic stereology: Relationship to dexamethasone suppression test results in patients

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.

Occurrence of subcortical hyperintensities in elderly subjects with mania.

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.

Proton spectroscopy of human brain: Effects of age and sex

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.

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.

In vivo stereological assessment of caudate volume in man: Effect of normal aging

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.

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.

A magnetic resonance image study of age-related changes in human putamen nuclei.

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.