Biomedical subjects

Bruno Giordani

Publications and source records attributed to Bruno Giordani.

13 recordsLinked to original sources

PubMed2011

Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease.

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

Adaptor Proteins, Signal Transducing↗

PubMed2007

Patterns of cognitive change over time and relationship to age following successful treatment of Cushing's disease.

Chronically elevated levels of cortisol have been associated with changes in cognitive functioning and brain morphology. Using Cushing's disease as a model to assess the effects of high levels of cortisol on cognitive functioning, 27 patients with Cushing's disease were examined at baseline and three successive follow-up periods up to 18 months after successful surgical treatment. At all follow-up periods, patients were administered cognitive tests as well as measures of plasma and urinary free cortisol. Structural MRIs and a depression measure were taken at baseline and one-year follow-up. Results showed that there is a specific pattern of significant cognitive and morphological improvement following successful treatment. Verbal fluency and recall showed recovery, although brief attention did not. Age of participants was a significant factor as to when recovery of function occurred; younger patients regained and sustained their improvement in cognitive functioning more quickly than older participants. Improvement in verbal recall also was associated with a decrease in cortisol levels as well as an increase in hippocampal formation volume one year after treatment. Overall, these findings suggest that at least some of the deleterious effects of prolonged hypercortisolemia on cognitive functioning are potentially reversible, up to at least 18 months post treatment.

Adolescent↗

PubMed2006

Improvement in mood and ideation associated with increase in right caudate volume.

BACKGROUND: The basal ganglia, particularly caudate, are hypothesized to play a role in affective and obsessive-compulsive disorders. The depressive syndrome is a feature of untreated Cushing's disease. The objective of this study was to test the hypothesis that after treatment of Cushing's disease reduces elevated cortisol, improvement in mood and related ideations are associated with increase in caudate volume. METHODS: In this longitudinal, interventional study of 23 patients with Cushing's disease, 24-hour urinary free cortisol, structural magnetic resonance imaging and behavioral measures were obtained prior to treatment and approximately one year after pituitary microadenomectomy. Five SCL-90-R subscales measuring change in mood, related ideations and physical symptoms were utilized. RESULTS: Partial correlations (adjusted for age and time since surgery) showed change in caudate, but not hippocampal, volume was significantly associated with change in behavioral SCL-90-R subscales, indicating selectivity for structure. Right but not left caudate showed associations, suggesting selectivity for lateralization. Right caudate volume increase was significantly associated with decreases in Depression, Anxiety, Obsessive-Compulsive, and Paranoid scores, but not with Somatization (physical symptoms), indicating specificity for behavioral but not physical variables. LIMITATIONS: A limitation is that relatively low-resolution scans were utilized. Although most likely not diminishing the significant findings, less sensitive methodology could lead to an increased probability of a type 2 error. CONCLUSIONS: These findings support the concept that caudate, and likely right caudate, participates in human brain circuitry regulating mood.

Adenoma↗

PubMed2006

A statistical approach for classifying change in cognitive function in individuals following pharmacologic challenge: an example with alprazolam.

INTRODUCTION: The effects of any drug treatment on cognitive function are typically studied in groups of subjects. Observations made about the behavior of the drug, in the study sample, are then generalized to the population from which the sample was drawn. However, the magnitude and pharmacodynamic qualities of the response to many central nervous system-active drugs are known to vary in the population. Therefore, it is useful to consider statistical models for the detection of cognitive change in response to a drug treatment in individual subjects. MATERIALS AND METHODS: In this report, we first outline the statistical assumptions and requirements for the reliable estimation of clinically relevant individual change in cognition. We then used the sedative benzodiazepine, alprazolam, as a pharmacologic challenge in healthy volunteer subjects to test our statistical model, using a parallel groups placebo-controlled study design. After treatment, the nature and severity of alprazolam-induced cognitive change was determined for each individual. RESULTS: Our proposed method and analysis showed an excellent sensitivity and specificity for alprazolam-related cognitive deterioration in individuals. DISCUSSION AND CONCLUSIONS: These findings, although preliminary, suggest that statistically reliable decisions about the effects of sedative drugs on cognition can be made for individuals.

Adult↗

PubMed2005

Deep brain stimulation for refractory obsessive-compulsive disorder.

BACKGROUND: Neurosurgery (anterior capsulotomy) has been beneficial to many patients with debilitating, refractory obsessive-compulsive disorder (OCD), but the irreversibility of the procedure is an important limitation to its use. Nondestructive, electrical stimulation (deep brain stimulation; DBS) has proven an effective alternative to ablative surgery for neurological indications, suggesting potential utility in place of capsulotomy for OCD. METHODS: The effects of DBS for OCD were examined in four patients in a short-term, blinded, on-off design and long-term, open follow-up. The patients had incapacitating illness, refractory to standard treatments. Hardware developed for movement disorder treatment was surgically implanted, with leads placed bilaterally in the anterior limbs of their internal capsules. Patients received stimulation in a randomized "on-off" sequence of four 3-week blocks. Ongoing, open stimulation was continued in consenting patients after the controlled trial. RESULTS: Patients tolerated DBS well. Dramatic benefits to mood, anxiety, and OCD symptoms were seen in one patient during blinded study and open, long-term follow-up. A second patient showed moderate benefit during open follow-up. CONCLUSIONS: It appears that DBS has potential value for treating refractory psychiatric disorders, but additional development work is needed before the procedure is utilized outside of carefully controlled research protocols.

Adult↗

PubMed2005

A method for determining the magnitude of change across different cognitive functions in clinical trials: the effects of acute administration of two different doses alprazolam.

While there is no doubt that benzodiazepine administration leads to transient cognitive impairment in healthy adults, the nature and magnitude of such impairment has not been well described. The cognitive effects of a single dose of alprazolam 0.5 and 1 mg were therefore assessed in 36 healthy adults on measures of psychomotor function, visual attention, working memory, planning and learning in a double-blind parallel-groups study. Measures of these different cognitive functions were selected on the basis of their brevity and because they yielded distributions of performance data that were without skew, floor or ceiling effects of range restriction (i.e. normal distributions). With data satisfying the assumptions for parametric analysis, measures of effect size could be computed in addition to significance testing, thus allowing for direct and meaningful comparison between the different performance measures used. Alprazolam 0.5 mg reduced only the speed of attentional performance although the magnitude of this reduction was large (d = 0.8). At 1.0 mg, impairments in psychomotor function, equivalent to that seen for attentional function at the lower dose, were observed. In addition, moderate (d approx = 0.5) impairments in working memory, and learning also became obvious. When considered together, these results suggest that low-dose alprazolam primarily alters visual attentional function. At the higher dose psychomotor functions also become impaired, and it is likely that the combination of these led to the observed moderate impairments in higher level executive and memory processes. The current study also illustrates a method for directly comparing the magnitude of change in cognitive function between measures with different performance metrics.

Adult↗

PubMed2005

Differentiation of Alzheimer's disease from dementia with Lewy bodies utilizing positron emission tomography with [18F]fluorodeoxyglucose and neuropsychological testing.

We compared the relative utility of neuropsychological testing and positron emission tomography (PET) with [18F]fluorodeoxyglucose ([18F]FDG) in differentiating Alzheimer's disease (AD) from dementia with Lewy bodies (DLB). We studied 25 patients with AD, 20 with DLB, and 19 normal elderly controls. There was no difference between patient groups for MMSE, confrontational naming, or verbal learning. The DLB group was significantly more impaired than the AD group for verbal fluency, and the AD group was significantly more impaired than the DLB group for verbal delayed recall. The DLB group had greater difficulty than the AD group on a visual discrimination task that does not require motor functioning, but the difference did not reach significance. Family ratings of motor functioning suggested significantly greater impairment in DLB patients than in AD patients. PET studies revealed significantly lower local cerebral metabolic rates for glucose (lCMRglc) for visual cortex (Brodmann areas 17, 18, and 19) in the DLB than the AD group, but no differences for other regions commonly affected in AD, including posterior cingulate, superior parietal lobe, lateral temporal lobe, and the prefrontal region. Motor ratings were significantly correlated with lCMRglc in all areas of cerebral cortex, including Brodmann areas 17, 18, and 19. The results demonstrate a similar profile of cerebral hypometabolism in the two patient groups except in the visual cortex, where the DLB group shows markedly lower lCMRglc than the AD group. Neuropsychological testing also differentiates the groups, and family ratings of motor functioning are as robust as PET in these later stages of the disorders.

Aged↗

PubMed2005

Age differences in timed accurate stepping with increasing cognitive and visual demand: a walking trail making test.

BACKGROUND: Impaired vision, cognition, and divided attention performance predict falls. Requiring both visual and cognitive input, the ability to step accurately is necessary to safely traverse challenging terrain conditions such as uneven or slippery surfaces. We compared healthy young and older adults in the time taken to step accurately under conditions of increasing cognitive and visual demand. METHODS: Healthy Young (n = 42, mean age 21) and Older (n = 37, mean age 70) participants were required to step accurately on an instrumented walkway under conditions of increasing visual and cognitive demand. Based on the paper-and-pencil neuropsychological test, the Trail Making Test (P-TMT) A and B, participants stepped on instrumented targets with increasing sequential numbers (Walking Trail Making Test A [W-TMT A]) and increasing sequential numbers and letters (Walking Trail Making Test B [W-TMT B]), under conditions of Low as well as Normal lighting. RESULTS: W-TMT performance time increased with increased age (Older vs Young), decreased light (Low vs Normal), and increased cognitive demand (Trails B vs Trails A). W-TMT performance time was disproportionately increased in Low light and in the Older group under the highest cognitive demand (W-TMT B) conditions. Paired W-TMT A-B differences were three times higher in the Older group than in the Young group. In the Older group, the correlation between W-TMT results and P-TMT B was particularly strong (p <.001). CONCLUSIONS: The time to perform a stepping accuracy task, such as may be required to avoid environmental hazards, increases under reduced lighting and with increased cognitive demand, the latter disproportionately so in older adults.

Adolescent↗

PubMed2004

Striatal monoamine terminals in Lewy body dementia and Alzheimer's disease.

We used positron emission tomography (PET) with (+)-[(11)C]dihydrotetrabenazine ([+]-[(11)C]DTBZ) to examine striatal monoaminergic presynaptic terminal density in 20 patients with dementia with Lewy bodies (DLB), 25 with Alzheimer's disease (AD), and 19 normal elderly controls. Six DLB patients developed parkinsonism at least 1 year before dementia (DLB/PD) and 14 developed dementia before parkinsonism or at about the same time (DLB/AD). Striatal mean binding potential was decreased by 62 to 77% in the DLB/PD group and 45 to 67% in the DLB/AD compared to AD and control. Binding was lower in the DLB/PD group than the DLB/AD, but the differences reached only marginal significance in the caudate nucleus. No differences were found between AD and control groups though a few AD patients had binding values below the range of the controls. Subsequent neuropathological examination in one AD patient revealed both AD and DLB changes despite the absence of clinical parkinsonism. Both DLB groups had an anterior to posterior binding deficit gradient relative to controls, largest in posterior putamen, smaller in anterior putamen, smallest in caudate nucleus. The DLB/AD group showed significant binding asymmetry only in posterior putamen. We conclude that PET with (+)-[(11)C]DTBZ differentiates DLB from AD, and decreased binding in AD may indicate subclinical DLB pathology in addition to AD pathology.

Aged↗

PubMed2004

The effects of occupational exposure to chlorpyrifos on the neurologic examination of central nervous system function: a prospective cohort study.

Questions persist about adverse effects such as impaired cognition and attention, incoordination, spasticity, or parkinsonism from chronic, low-level exposures to organophosphate (OP) compounds. In a prospective cohort study, we evaluated chlorpyrifos-manufacturing workers and a referent group on 2 occasions, 1 year apart, to determine whether occupational exposure to chlorpyrifos produced clinically evident central nervous system (CNS) dysfunction. Chlorpyrifos subjects had significantly higher TCP excretion and lower average BuChE activity than referents in a range in which physiological effects on B-esterases exist. Few subjects had neurologic symptoms or signs, and there were no significant group differences in terms of signs at baseline or second examinations. Chronic chlorpyrifos exposure produced no clinical evidence of cortical, pyramidal tract, extrapyramidal, or other CNS dysfunction among chlorpyrifos subjects compared with referents, either at baseline or after 1 year of additional chlorpyrifos exposure.

Adult↗

PubMed2004

Cognitive executive dysfunction in children with mild sleep-disordered breathing.

In children, moderate or severe sleep-disordered breathing (SDB) may impair cognitive executive functions (EFs), including working memory, attention, and mental flexibility. The main objective of this study was to assess EFs in children with mild levels of SDB. Subjects for this descriptive study were 12 children (5 girls, 7 boys) aged 8.0 to 11.9 years (M = 9.0 +/- 0.85) participating in an ongoing study of the effects of adenotonsillectomy on behavior. Each subject had a nocturnal polysomnogram (PSG) and a multiple sleep latency test (MSLT). Mild SDB was considered present if the child's apnea/hypopnea index (AHI) was > or = 1 and < 10. Between MSLT nap attempts, each child completed standardized tests of EFs. The sample showed significant impairment of sustained attention and vigilance on a computerized continuous performance test. Children with low mental flexibility scores on the Children's Category Test (CCT) spent more time in stage 1 sleep (12.2% v. 9.5%, P = 0.028 on PSG) and showed a marginally higher arousal index (9.7 v. 6.5, P = 0.06 on PSG) than children with average or above-average CCT scores. AHI accounted for a significant proportion of the variance in CCT scores when 1 outlier was removed (N = 11, Rsq = 0.67, P = 0.002). Mild levels of SDB and associated sleep architecture disruptions may be associated with impairment of EFs in children.

Analysis of Variance↗

PubMed2003

Improvement in learning associated with increase in hippocampal formation volume.

BACKGROUND: Patients with spontaneous Cushing's syndrome are exposed to elevated levels of endogenous cortisol for months to years. We previously reported that hippocampal formation volume (HFV) increased in such patients after treatment lowered cortisol to normal concentrations. In the present study, we examined whether the structural increase was associated with improvement in cognition. METHODS: Twenty-four patients with Cushing's disease were studied before treatment and following treatment. Magnetic resonance imaging was used to measure HFV and caudate head volume. Neuropsychologic tests of verbal cognition, learning, and memory were also administered. RESULTS: Patients showed variability in improvement on neuropsychologic test performance. After partialing out age, education, duration of illness, and time since surgical treatment, greater improvement in word list learning, as measured by the Selective Reminding Test was associated with greater increase in HFV (r =.59, p <.02). There were no significant associations between improvement in paragraph or paired-word learning or memory tasks and increase in HFV. Improvement in other verbal tasks not strongly dependent on the hippocampus were not significantly associated with increase in HFV. CONCLUSIONS: After cortisol levels decline to normal concentrations, structural volumetric increase in HFV is accompanied by functional improvement in learning of unrelated words.

Adenoma↗

PubMed2003

Environmental influences on primary memory development: a cross-cultural study of memory span in Lao and American children.

Although research examining Auditory-Verbal and Visual Memory Span in adults has failed to provide compelling evidence for the modality specificity of such tasks, Fastenau, Conant, and Lauer (1998) suggested that these processes may be dissociable in children until around the age of 8 years when visuospatial memory span appears to become more verbally mediated perhaps as a function of formal reading training. A subsequent cross-cultural study in Zaïre (now Democratic Republic of Congo) by Conant and colleagues (1999) supported that hypothesis. However, other differences in the sociocultural environments of American and rural Zaïrian children such as nutritional and health care factors could potentially account for the findings. The present study examines the relationships among Auditory-Verbal, Visual, and Cross-Modal Memory Span tasks with 46 Lao and 56 American children. Both samples were divided into younger and older groups, and separate partial correlational analyses were performed on Kaufman Assessment Battery for Children (K-ABC) data from each group. In younger Lao and American children, Auditory-Verbal Memory Span was not significantly correlated with Visual Memory Span or Cross-Modal Memory Span, whereas significant correlations were found between Auditory-Verbal Memory Span and these other tasks in older children from both countries. The similar pattern in both cultures, together with findings from Zaïre, supports the hypothesis that the relationship between Auditory-Verbal and Visual Memory Span may change with reading training.

Aging↗