Age-related changes in frontal and temporal lobe volumes in men: a magnetic resonance imaging study.

BACKGROUND: Imaging and postmortem studies provide converging evidence that, beginning in adolescence, gray matter volume declines linearly until old age, while cerebrospinal fluid volumes are stable in adulthood (age 20-50 years). Given the fixed volume of the cranium in adulthood, it is surprising that most studies observe no white matter volume expansion after approximately age 20 years. We examined the effects of the aging process on the frontal and temporal lobes. METHODS: Seventy healthy adult men aged 19 to 76 years underwent magnetic resonance imaging. Coronal images focused on the frontal and temporal lobes were acquired using pulse sequences that maximized gray vs white matter contrast. The volumes of total frontal and temporal lobes as well as the gray and white matter subcomponents were evaluated. RESULTS: Age-related linear loss in gray matter volume in both frontal (r = -0.62, P<.001) and temporal (r = -0.48, P<.001) lobes was confirmed. However, the quadratic function best represented the relationship between age and white matter volume in the frontal (P<.001) and temporal (P<.001) lobes. Secondary analyses indicated that white matter volume increased until age 44 years for the frontal lobes and age 47 years for the temporal lobes and then declined. CONCLUSIONS: The changes in white matter suggest that the adult brain is in a constant state of change roughly defined as periods of maturation continuing into the fifth decade of life followed by degeneration. Pathological states that interfere with such maturational processes could result in neurodevelopmental arrests in adulthood.

Increased CSF volumes are associated with diminished subjective responses to cocaine infusion.

We evaluated the hypothesis that ventricular and cortical CSF volume increases are associated with reductions in the magnitude of euphoric effects produced by intravenous IV cocaine infusion in cocaine dependent (CD) individuals. Eleven CD patients participating in a cocaine-infusion study and eleven control subjects underwent magnetic resonance imaging (MRI). Two CSF regions of interest (lateral ventricles and frontal cortex CSF) and two comparison regions (third ventricle and posterior cortex CSF) were measured. Self-reported ratings of the intensity of euphoric response ("high") were obtained from the CD subjects at 3, 10, and 30 minutes after IV administration of cocaine. A significant negative correlation was observed between the volume of the lateral ventricles and subjective ratings of the "high" experienced at 3 minutes, but not at 10 and 30 minutes after cocaine infusion. In contrast, a significant negative correlation between frontal cortex CSF volume and the intensity of euphoric response was observed at 30 minutes after IV cocaine. No significant associations were observed between the volumes of the two comparison regions and any subjective ratings of "high." No significant volume differences were observed between the CD and control groups in any region. The results suggest larger lateral ventricular volumes are associated with a decrease in immediate euphoria while larger frontal cortex CSF volumes are associated with a decrease in the duration of the euphoria induced by cocaine infusion. The age-related brain volume reductions underlying the volume increase in these two CSF spaces may be the neurobiological basis of the age-related reduction in the rates of addiction.

The Frontal Lobe Score: part I: construction of a mental status of frontal systems.

OBJECTIVE: To develop a bedside mental status examination to assess the behavioural effects of damage to the frontal lobes. DESIGN: A prospective clinical comparison of patients with cerebral lesions of different locations. SUBJECTS: A total of 118 subjects were examined: 27 patients with cerebral lesions confined to the frontal lobes, 25 patients with cerebral lesions without involvement of the frontal lobes, 18 patients with mixed frontal/nonfrontal lesions, and 48 normal control subjects. MEASURES: Twenty-three mental status tests, clinical examinations and rating scales that had been reported as indicative of frontal lobe function were brought together. By statistical analysis, 12 tests and a neurobehavioural rating scale were selected. These constitute the Frontal Lobe Score (FLS). RESULTS: The FLS detected pure frontal lesions with a sensitivity of 77.7%. It discriminated patients with frontal lesions from normal control subjects with a specificity of 100%. Differentiation from patients with nonfrontal lesions was obtained with a specificity of 84%. CONCLUSION: The Frontal Lobe Score is a useful screening instrument for the clinical detection of effects of frontal lobe damage.

Age-related brain volume reductions in amphetamine and cocaine addicts and normal controls: implications for addiction research.

The study evaluated the relationship between age and frontal and temporal lobe volumes in young cohorts of cocaine-dependent (CD), amphetamine-dependent (Am), and normal control subjects. Ten CD, nine Am, and 16 age- and gender-matched control subjects underwent magnetic resonance imaging (MRI). The volume of the frontal and temporal lobes was measured from an identically positioned slab of seven contiguous 3-mm-thick coronal images. Follow-up measures of the gray and white matter subcomponents of these volumes were also obtained. Both CD and Am groups had a significantly smaller temporal lobe volumes, but only the CD group demonstrated a significantly greater decline in temporal lobe volume with age (intracranial volume, education, and race were controlled for in all statistical analyses). Segmenting the brain regions into gray and white matter revealed that the negative correlation between age and temporal lobe volume of CD patients was mostly due to a significant age-related decline in the gray matter subcomponent. Negative trends between age and gray matter volumes were also observed in the Am and normal groups. In the frontal lobes, age was negatively correlated with gray matter volume in the control, CD, and Am groups. Unlike the consistent decreases in gray matter volumes, white matter showed non-significant increases in volume with age. The data suggest that CD patients may have an accelerated age-related decline in temporal lobe gray matter volume and a smaller temporal lobe volume compared to normal controls. In the frontal lobe, age-related gray matter volume reductions occur in all three groups. These age-related cortical gray matter volume reductions may be a biological marker for the risk of addictive behavior, which also decreases with age.

Effects of selegiline pretreatment on response to experimental cocaine administration

Several medications have been reported to alter the subjective effects of experimentally administered cocaine. We studied the effects of selegiline, a monoamine oxidase B inhibitor, on the subjective effects of experimentally administered cocaine in chronically cocaine-dependent subjects. Eight subjects completed a protocol that involved repeated administrations of cocaine before and after treatment with selegiline, given in extended release form, 10 mg per day. Four days of treatment with selegiline was associated with decreased self-reported 'high' and 'stimulated' feelings after cocaine administration, measured as the area under the curve. Changes in other subjective effects were less pronounced. Selegiline pretreatment had minimal effects on the cardiovascular responses to cocaine administration.

The incidence of T2-weighted MR imaging signal abnormalities in the brain of cocaine-dependent patients is age-related and region-specific.

BACKGROUND AND PURPOSE: Cocaine and its metabolites can produce vasospasm, and cocaine-dependent patients are at increased risk for stroke. Based on previous case reports, we hypothesized that the incidence of hyperintense brain lesions observed on T2-weighted MR images would also be increased in asymptomatic cocaine-dependent individuals. METHODS: Sixty-two male "crack" (smoked) cocaine-dependent participants ranging in age from 25 to 66 years were compared with 116 normal male control participants ranging in age from 25 to 80 years. Those with histories of neurologic symptoms or illnesses were excluded. The severity of hyperintense lesions was rated on a 0- to 3-point scale, and ratings of 3 were used in the data analysis as an indicator of a probable pathologic process. Three regions were separately rated: the cerebral white matter, insular subcortex white matter, and subcortical gray matter (basal ganglia and thalamus region). RESULTS: Significantly increased risk of severe lesions was observed in the two white matter regions of the cocaine-dependent group (odds ratio of 16.7 and 20.3) but not in the subcortial gray matter region (odds ratio of 1.4). In the insula subcortex white matter, the risk of lesions increased with age in the cocaine-dependant sample, but remained essentially absent among normal controls through the age of 80 years. In the cerebral white matter, the relationship of age and risk of lesion among normal participants was similar in shape to that in cocaine-dependent participants, but equivalent risk was seen 20 years earlier among cocaine-dependent participants. CONCLUSIONS: Cocaine-dependent participants had a significantly increased age-related risk of white matter damage. The possible clinical implications of this damage are discussed.

Choreoathetoid movements in cocaine dependence.

BACKGROUND: To evaluate the severity of choreoathetoid movements in cocaine dependent (CD) subjects and age-matched normal control subjects. METHODS: Choreoathetoid movements were evaluated using the Abnormal Involuntary Movement Scale (AIMS) in samples of 71 CD, 56 normal control, and 9 amphetamine-dependent male subjects. RESULTS: The CD subjects had a significantly increased nonfacial (limbs plus body) AIMS subscore. When the nonfacial AIMS scores of the two groups were compared in relation to age, a significant age by diagnosis interaction was observed, indicating that the differences between groups were most marked in the younger age groups. The facial AIMS scores were also increased but only in the youngest CD cohort (under 32 years of age). The comparison group of 9 younger amphetamine-dependent subjects also showed increased AIMS scores. CONCLUSIONS: Increases in choreoathetoid movements in younger cocaine and amphetamine-dependent subjects may be related to their psychostimulant use. The absence of differences in choreoathetoid movements between the older CD subjects and normal control subjects may represent an age-related self-selection effect.

Selegiline effects on cocaine-induced changes in medial temporal lobe metabolism and subjective ratings of euphoria.

To test the effect of selegiline, a specific monoamine oxidase B (MAO-B) inhibitor, on the cerebral metabolic and euphorigenic effects of cocaine in experienced users, eight cocaine-dependent (CD) subjects were evaluated using a within-subjects design. Each subject participated in two pairs of [F-18]-fluorodeoxyglucose (FDG)-positron emission tomography (PET) scans (baseline scan followed 24 h later by a second scan obtained in conjunction with a 40-mg cocaine infusion) performed before and after a 1-week period of daily treatment with 10 mg selegiline administered orally. The hippocampus and amygdala were evaluated because of their hypothesized involvement in the addiction process, and the thalamus was evaluated as a comparison region. Following 7 days of selegiline treatment, the magnitude of the subjective euphoria ("high") produced by cocaine infusion was reduced by 40% (cocaine by selegiline interaction F = 7.15, df = 1.21, p = .014). Selegiline treatment also altered glucose utilization (normalized against whole brain counts) in the two limbic regions, but not the thalamus. In the amygdala, the effects of cocaine differed, depending upon whether or not patients were being treated with selegiline (cocaine by selegiline interaction F = 4.67, df = 1,19.8, p = .043). A different effect was observed in the hippocampus, where selegiline treatment decreased metabolic activity irrespective of whether cocaine was given (main effect F = 7.70, df = 1.20, p = .012). The concomitant changes in both the subjective experience of the "high" and normalized amygdala glucose utilization after selegiline treatment, suggest that a relationship exists between cocaine-induced euphoria and limbic metabolism. The data suggest that selegiline may be a useful adjunct in the treatment of cocaine dependence.

Magnetic resonance imaging evidence of "silent" cerebrovascular toxicity in cocaine dependence.

BACKGROUND: Cocaine and its metabolites can produce vasospasm. Cocaine-dependent (CD) patients are at increased risk for stroke, and a high frequency of brain perfusion defects has been observed in clinically asymptomatic CD subjects. This is the first controlled magnetic resonance imaging (MRI) study of clinically asymptomatic CD subjects. METHODS: Two age-matched groups of male subjects (61 CD and 57 control) participated in the study. Subjects with a history of neurologic symptoms or major medical or neurologic illness, such as hypertension, diabetes, or significant head trauma, were excluded. The severity of hyperintense lesions observed on T2-weighted MRI images were rated on a 0-3-point scale by an experienced radiologist who was blind to all clinical data. Ratings of 3 were felt to be significant indicators of a possible disease process and were used in the data analysis. Three regions were separately rated: the cerebral white matter, subinsular white matter, and subcortical gray matter (basal ganglia and thalamus region). RESULTS: Despite the exclusion criteria minimizing risk factors for cerebrovascular events, 17 of the 61 (27.9%) CD subjects and 4 of 57 (7%) of the control subjects had severe hyperintense lesions suggestive of subclinical or "silent" anoxic vascular events. Significant group differences were observed in the two white matter regions but not in the subcortical gray matter region. The risk of severe white matter lesions in the CD group increased with age, reaching 50% in the oldest age quartile (46-58 years), and this increase was not related to the number of years cocaine was used. CONCLUSIONS: The data suggest that asymptomatic CD patients are a heterogeneous population with a significantly increased age-related risk of white matter neurovascular toxicity. Premature neurovascular damage may impact treatment outcomes and, as the CD population ages, may manifest as an increased incidence of cognitive deficits.

MR evaluation of age-related increase of brain iron in young adult and older normal males.

The purposes of this study were to extend the investigation of age-related increases in brain iron to a younger age group, replicate previously published results, and further evaluate the validity of a novel noninvasive magnetic resonance (MR) method for measuring tissue iron (ferritin) levels with specificity. The method consists of measuring the dependence of tissue transverse relaxation rates (R2) on the field strength of MR instruments. Two MR instruments operating at 1.5 and 0.5 T were used to measure the field-dependent R2 increase (FDRI) in the frontal white matter, caudate, putamen, and globus pallidus. A group of 13 normal adult males (ages 21-77), with seven subjects below and six above age 35, was examined. As expected from postmortem and prior FDRI data, robust and significant age-related increases in FDRI were observed in the caudate, putamen, and globus pallidus, with the globus pallidus FDRI increasing sharply in the second decade and reaching a plateau after age 30. In addition, we replicated previous reports showing very high correlations between FDRI and published brain iron levels for the four regions examined. The data replicate and extend previous FDRI observations on brain aging and are consistent with postmortem data on age-related increases in brain iron. These results are relevant to the investigation of age-related neurodegenerative diseases in which iron may catalyze toxic free radical reactions.

A multicenter trial of bupropion for cocaine dependence in methadone-maintained patients.

We conducted a multi-site, placebo-controlled, randomized double-blind clinical trial comparing bupropion HCL (300 mg/day) to placebo for the treatment of cocaine dependence in methadone-maintained subjects. A total of 149 subjects at three sites participated in a 12-week study. Outcome measures included cocaine use, level of depression, and psychosocial functioning. Results showed no significant differences between placebo and bupropion. Exploratory analyses suggested a medication effect for the subset of subjects depressed at study entry. The need to target subgroups of cocaine abusers in future pharmacotherapy trials and the possible role of treatment readiness are discussed.

Prosopagnosia: a bihemispheric disorder.

A 54-year-old, right-handed male suffered three sequential infarcts. The first two destroyed much of the right posterior parietal area, the posterior-medial portion of the right temporal lobe and virtually the entire right occipital lobe producing left homonymous hemianopsia and left visual neglect but no prosopagnosia. A third vascular accident involved the left parieto-occipital lobe and immediately produced prosopagnosia that has persisted. The sequential correlations of lesion and symptomatology in this case demonstrate that development of persistent prosopagnosia occurred only after bilateral damage.

Neuropsychiatric aspects of stroke.

Neuropsychiatric disorders following stroke are common, and pathologic involvement of specific regions or functional systems results in behavioral syndromes similar to idiopathic psychiatric syndromes. Depression occurs in up to half of all stroke patients and is most frequently associated with left anterior cortical and subcortical infarctions. Mood changes interfere with cognitive, functional and social recovery. Treatment with heterocyclic antidepressants, stimulants, and electroconvulsive therapy is efficacious in most patients. Mania, delusions, hallucinations, personality alterations, obsessive-compulsive disorder, and changes in sexual behavior are less common but have also been described in post-stroke patients. Each behavioral syndrome is associated with a specific pattern of brain involvement. Investigation of these phenomena contributes to understanding the cerebral basis of psychiatric disorders.

Identification of the viral sequence required for the generation of recovered avian sarcoma viruses and characterization of a series of replication-defective recovered avian sarcoma viruses.

The ability of transformation-defective deletion mutants of Schmidt-Ruppin Rous sarcoma virus to induce tumors and generate recovered sarcoma viruses (rASVs) was correlated with the partial src sequences retained in the transformation-defective viral genomes. Since all the transformation-defective viruses that were capable of generating rASVs retained a portion of the 3' src sequence, regardless of the extent of the 5' src deletion, and those lacking the 3' src were unable to generate rASVs, it appears that the 3', but most likely not the 5', src sequence retained in the transformation-defective viral genome is essential for rASV formation. However, rASVs derived from a particular mutant, td109, which retained a portion of the 3' src sequence, but lacked most (if not all) of the 5' src sequence, were all found to be defective in replication. Analyses of the genomic sequences of 13 isolates of td109-derived rASVs revealed that they contained various deletions in viral envelope (env), polymerase (pol), and structural protein (gag) genes. Ten isolates of rASVs contained env deletions. One isolate (rASV3812) contained a deletion of env and the 3' half of pol, and one isolate (rASV398) contained a deletion of env and pol. The one with the most extensive deletion (rASV374) had a deletion from the p12-coding sequence through pol and env. In addition, the 5' src region of td109-derived rASVs were heterogeneous. Among the 7 isolates analyzed in detail, one isolate of rASV had a small deletion of the 5' src sequence, whereas three other isolates contained extra new sequences upstream from src. Both env- and env- pol- rASVs were capable of directing the synthesis of precursor and mature gag proteins in the infected nonproducer cells. We attribute the deletions in the replication-defective rASVs to the possibility that the 5' recombination site between the td109 and c-src sequence, involved regions of only partial homology due to lack of sufficient 5' src sequence in the td109 genome for homologous recombination. A model of recombination between the viral genome and the c-src sequence is proposed to account for the requirement of the 3' src sequence and the basis for the generation of deletions in td109-derived rASVs.