Impairment of nonverbal recognition in Alzheimer disease: a PET O-15 study.

OBJECTIVE: To characterize deficits in nonverbal recognition memory and functional brain changes associated with these deficits in Alzheimer disease (AD). METHODS: Using O-15 PET, we studied 11 patients with AD and 17 cognitively intact elders during the combined encoding and retrieval periods of a nonverbal recognition task. Both task conditions involved recognition of line drawings of abstract shapes. In both conditions, subjects were first presented a list of shapes as study items, and then a list as test items, containing items from the study list and foils. In the titrated demand condition, the shape study list size (SLS) was adjusted prior to imaging so that each subject performed at approximately 75% recognition accuracy; difficulty during PET scanning in this condition was approximately matched across subjects. A control task was used in which SLS = 1 shape. RESULTS: During performance of the titrated demand condition, SLS averaged 4.55 (+/-1.86) shapes for patients with AD and 7.53 (+/-4.81) for healthy elderly subjects (p = 0.031). However, both groups of subjects were closely matched on performance in the titrated demand condition during PET scanning with 72.17% (+/-7.98%) correct for patients with AD and 72.25% (+/-7.03%) for elders (p = 0.979). PET results demonstrated that patients with AD showed greater mean differences between the titrated demand condition and control in areas including the left fusiform and inferior frontal regions (Brodmann areas 19 and 45). CONCLUSIONS: Relative fusiform and inferior frontal differences may reflect the Alzheimer disease (AD) patients' compensatory engagement of alternate brain regions. The strategy used by patients with AD is likely to be a general mechanism of compensation, rather than task-specific.

Metabolic correlates of levodopa response in Parkinson's disease.

OBJECTIVE: To assess the effects of levodopa on resting-state brain metabolism in PD. BACKGROUND: In previous studies the authors used [18F] fluorodeoxyglucose (FDG) and PET to quantify regional metabolic abnormalities in PD. They found that this disease is characterized reproducibly by a specific abnormal PD-related pattern (PDRP). In this study the authors used IV levodopa infusion to quantify the effects of dopamine replacement on regional metabolism and PDRP network activity. They tested the hypothesis that clinical response to dopaminergic therapy correlates with these metabolic changes. METHODS: The authors used FDG/PET to measure resting-state regional brain metabolism in seven patients with PD (age, 59.4 +/- 4.2 years; Hoehn and Yahr stage, 1.9 +/- 0.7, mean +/- SD); subjects were scanned both off levodopa and during an individually titrated constant-rate IV levodopa infusion. The authors used statistical parametric mapping to identify significant changes in regional brain metabolism that occurred with this intervention. They also quantified levodopa-induced changes in PDRP expression. Metabolic changes with levodopa correlated with clinical improvement as measured by changes in Unified PD Rating Scale (UPDRS) motor scores. RESULTS: Levodopa infusion improved UPDRS motor ratings (30.6% +/- 12.0%, p < 0.002) and significantly decreased regional glucose metabolism in the left putamen, right thalamus, bilateral cerebellum, and left primary motor cortex (p < 0.001). Changes in pallidal metabolism correlated significantly with clinical improvement in UPDRS motor ratings (p < 0.01). Levodopa infusion also resulted in a significant (p = 0.01) decline in PDRP expression. The changes in PDRP activity mediated by levodopa correlated significantly with clinical improvement in UPDRS motor ratings (r = -0.78, p < 0.04). CONCLUSION: Levodopa reduces brain metabolism in the putamen, thalamus, and cerebellum in patients with PD. Additionally, levodopa reduces PD-related pattern activity, and the degree of network suppression correlates with clinical improvement. The response to dopaminergic therapy in Patients with PD may be determined by the modulation of cortico-striato-pallido-thalamocortical pathways.

Metabolic network abnormalities in early Huntington's disease: an [(18)F]FDG PET study.

UNLABELLED: The identification of discrete patterns of altered functional brain circuitry in preclinical Huntington's disease (HD) gene carriers is important to understanding the pathophysiology of this disorder and could be useful as a biologic disease marker. The purpose of this study was to use PET imaging of regional cerebral glucose metabolism to identify abnormal networks of brain regions that are specifically related to the preclinical phase of HD. METHODS: Eighteen presymptomatic HD gene carriers, 13 early-stage HD patients, and 8 age-matched gene-negative relatives were scanned using PET with [(18)F]FDG to quantify regional glucose utilization. A network modeling strategy was applied to the FDG PET data to identify disease-related regional metabolic covariance patterns in the preclinical HD cohort. The outcome measures were the region weights defining the metabolic topography of the HD gene carriers and the subject scores quantifying the expression of the pattern in individual subjects. RESULTS: Network analysis of the presymptomatic carriers and the gene-negative control subjects revealed a significant metabolic covariance pattern characterized by caudate and putamenal hypometabolism but also included mediotemporal metabolic reductions as well as relative metabolic increases in the occipital cortex. Subject scores for this pattern were abnormally elevated in the preclinical group compared with those of the control group (P < 0.005) and in the early symptomatic group compared with those of the presymptomatic group (P < 0.005). CONCLUSION: These findings show that FDG PET with network analysis can be used to identify specific patterns of abnormal brain function in preclinical HD. The presence of discrete patterns of metabolic abnormality in preclinical HD carriers may provide a useful means of quantifying the rate of disease progression during the earliest phases of this illness.

Metabolic changes following subthalamotomy for advanced Parkinson's disease.

We studied 6 advanced-stage Parkinson's disease patients with [18F] fluorodeoxyglucose/positron emission tomography before and 3 months after unilateral ablation of the subthalamic nucleus performed with microelectrode mapping. Operative changes in glucose metabolism were assessed by comparing baseline and postoperative scans. We also quantified operative changes in the activity of an abnormal Parkinson's disease-related metabolic network that we had identified in previous [18F] fluorodeoxyglucose/positron emission tomography studies. Following unilateral subthalamic nucleus ablation, a highly significant reduction in glucose utilization was present in the midbrain ipsilateral to the lesion site, most pronounced in the vicinity of the substantia nigra pars reticularis. Significant metabolic reductions were also present in the ipsilateral internal globus pallidus, ventral thalamus, and pons. Operative changes in Parkinson's disease network activity differed significantly for the lesioned and unlesioned hemispheres. In the lesioned hemisphere, network activity declined significantly following surgery, but was unaltered in the contralateral, unlesioned hemisphere. These results suggest that subthalamotomy reduces basal ganglia output through internal globus pallidus/substantia nigra pars reticularis and also influences downstream neural activity in the pons and ventral thalamus. This procedure also reduces the activity of abnormal Parkinson's disease-related metabolic brain networks, suggesting a widespread modulation of motor circuitry.

Networks mediating the clinical effects of pallidal brain stimulation for Parkinson's disease: a PET study of resting-state glucose metabolism.

Employing [(18)F]fluorodeoxyglucose (FDG) and PET, we have found previously that stereotaxic ablation of the internal globus pallidus (GPi) for Parkinson's disease causes resting metabolic changes in brain regions remote from the lesion site. In this study we determined whether similar metabolic changes occur in Parkinson's disease patients treated with deep brain stimulation (DBS) of the GPi. We studied seven Parkinson's disease patients with FDG-PET to measure resting regional cerebral glucose utilization on and off GPi stimulation. We used statistical parametric mapping to identify significant changes in regional brain metabolism that occurred with this intervention. We also quantified stimulation-related changes in the expression of a specific abnormal Parkinson's disease-related pattern of metabolic covariation (PDRP) that had been identified in earlier FDG-PET studies. Metabolic changes with DBS were correlated with clinical improvement as measured by changes in Unified Parkinson's Disease Rating Scale (UPDRS) motor ratings off medication. GPi DBS improved UPDRS motor ratings (36%, P < 0.001) and significantly increased regional glucose metabolism in the premotor cortex ipsilateral to stimulation and in the cerebellum bilaterally. GPi DBS also resulted in a significant (P < 0.01) decline in PDRP activity ipsilateral to stimulation, which correlated significantly with clinical improvement in UPDRS motor ratings (P < 0.03). Clinical improvement with GPi DBS is associated with reduced expression of an abnormal Parkinson's disease-related metabolic network involving elements of the cortico-striato-pallido-thalamocortical and the cerebello-cortical motor loops.

Functional networks in motor sequence learning: abnormal topographies in Parkinson's disease.

We examined the neural circuitry underlying the explicit learning of motor sequences in normal subjects and patients with early stage Parkinson's disease (PD) using 15O-water (H2 15O) positron emission tomography (PET) and network analysis. All subjects were scanned while learning motor sequences in a task emphasizing explicit learning, and during a kinematically controlled motor execution reference task. Because different brain networks are thought to subserve target acquisition and retrieval during motor sequence learning, we used separate behavioral indices to quantify these aspects of learning during the PET experiments. In the normal cohort, network analysis of the PET data revealed a significant covariance pattern associated with acquisition performance. This topography was characterized by activations in the left dorsolateral prefrontal cortex (PFdl), rostral supplementary motor area (preSMA), anterior cingulate cortex, and in the left caudate/putamen. A second independent covariance pattern was associated with retrieval performance. This topography was characterized by bilateral activations in the premotor cortex (PMC), and in the right precuneus and posterior parietal cortex. The normal learning-related topographies failed to predict acquisition performance in PD patients and predicted retrieval performance less accurately in the controls. A separate network analysis was performed to identify discrete learning-related topographies in the PD cohort. In PD patients, acquisition performance was associated with a covariance pattern characterized by activations in the left PFdl, ventral prefrontal, and rostral premotor regions, but not in the striatum. Retrieval performance in PD patients was associated with a covariance pattern characterized by activations in the right PFdl, and bilaterally in the PMC, posterior parietal cortex, and precuneus. These results suggest that in early stage PD sequence learning networks are associated with additional cortical activation compensating for abnormalities in basal ganglia function.

Regional cerebral blood flow in mood disorders, V.: Effects of antidepressant medication in late-life depression.

Twenty elderly outpatients with major depression were treated with either nortriptyline or sertraline. Resting regional cerebral blood flow (rCBF) was assessed by the planar (133)Xenon inhalation technique after a medication washout and following 6- 9 weeks of antidepressant treatment. At baseline, the depressed sample had reduced rCBF in frontal cortical regions when compared with 20 matched normal-control subjects. After treatment, Responders and Nonresponders differed in the expression of a specific topographic alteration, with Responders manifesting reduced perfusion in frontal regions. These findings are consistent with this group's previous report of reduced rCBF after response to electroconvulsive therapy (ECT) and suggest a common mechanism of action.

Different brain networks mediate task performance in normal aging and AD: defining compensation.

OBJECTIVE: To determine whether the pathologic mechanisms of AD alter the brain networks subserving performance of a verbal recognition task. BACKGROUND: Functional imaging studies comparing task-related activation in AD patients and controls generally have not used network analysis and have not controlled for task difficulty. METHODS: H2 15O PET was used to measure regional cerebral blood flow in 14 patients and 11 healthy elders during the performance of a serial verbal recognition task under two conditions: low demand, with study list size (SLS) equal to one; and titrated demand, with SLS adjusted so that each subject recognized words at 75% accuracy. The Scaled Subprofile Model was used to identify networks of regionally covarying activity across these task conditions. RESULTS: In the elders, higher SLS was associated with the recruitment of a network of brain areas involving left anterior cingulate and anterior insula (R2 = 0.94; p < 0.0001). Three patients also expressed this network. In the remaining patients, higher SLS was associated with the recruitment of an alternate network consisting of left posterior temporal cortex, calcarine cortex, posterior cingulate, and the vermis (R2 = 0.81, p < 0.001). Expression of this network was unrelated to SLS in the elders and more intact AD patients. CONCLUSIONS: The patients' use of the alternate network may indicate compensation for processing deficits. The transition from the normal to the alternate network may indicate a point where brain disease has irreversibly altered brain function and thus may have important implications for therapeutic intervention.

Quantitative EEG during seizures induced by electroconvulsive therapy: relations to treatment modality and clinical features. I. Global analyses.

This study examined the effects of electroconvulsive therapy (ECT) treatment conditions, patient individual difference factors, and clinical outcome on global electroencephalogram (EEG) power during and immediately following ECT-induced seizures. Sixty-two patients were randomized to ECT conditions differing in electrode placement (right unilateral versus bilateral) and stimulus dosage (just above seizure threshold versus 2.5 times seizure threshold). At the second and penultimate treatments, global total power (1.5-28.5 Hz) and global power in specific frequency bands were quantified in 19-lead EEG recordings of the generalized seizure and the immediate postictal period. Seizures induced with high dosage, and to lesser extent, with bilateral electrode placement, resulted in greater global power. Patient age, initial seizure threshold, and baseline depression severity were inversely related to global power during seizures. While superior clinical outcome following ECT was associated with greater global power during seizures, this effect was small. The factors associated with more robust seizure expression also resulted in greater postictal bioelectric suppression. Associations with treatment parameters and patient variables were stronger at the second than penultimate treatment. We conclude that manipulations of ECT technique strongly determine the magnitude of seizure expression, but relations with clinical outcome are weak. The findings raise doubt about the clinical utility of algorithms based on analysis of EEG features to guide ECT parameter selection.

Quantitative EEG during seizures induced by electroconvulsive therapy: relations to treatment modality and clinical features. II. Topographic analyses.

This study tested three alternative theories of the mechanisms of therapeutic action of electroconvulsive therapy (ECT). The theories differed in predictions about the global and topographic effects of effective and ineffective forms of ECT on electroencephalogram (EEG) seizure expression. At the second treatment, 19-lead EEG recordings were obtained in 57 depressed patients randomized to conditions that differed in ECT electrode placement and stimulus dosage. Power in the delta frequency band was quantified during the seizure and analyzed with traditional multivariate methods and the Scaled Subprofile Model. Electrical dosage of the ECT stimulus had a powerful effect on ictal global delta power and, more so, than electrode placement. Greater ictal global delta power was associated with superior therapeutic outcome, but the magnitude of this effect was small. Effective forms of ECT resulted in a topography where delta power was accentuated in prefrontal EEG sites. High dosage right unilateral ECT also resulted in stronger asymmetry in prefrontal regions than the ineffective, low dosage right unilateral ECT. Greater bilateral generalization of seizure expression does not appear to be a prerequisite for therapeutic effects. Instead, more intense seizure expression in prefrontal regions may be critical for efficacy.

The metabolic topography of essential blepharospasm: a focal dystonia with general implications.

OBJECTIVE: To determine the metabolic topography of essential blepharospasm (EB). BACKGROUND: EB is a cranial dystonia of unknown etiology and anatomic localization. The authors have used 18F-fluorodeoxyglucose (FDG) and PET with network analysis to identify distinctive patterns of regional metabolic abnormality associated with idiopathic torsion dystonia (ITD), as well as sleep induction during PET imaging to suppress involuntary movements, thereby reducing this potential confound in the analysis. METHODS: Six patients with EB and six normal volunteers were scanned with FDG-PET. Scans were performed twice: once in wakefulness and once following sleep induction. The authors used statistical parametric mapping to compare glucose metabolism between patients with EB and control subjects in each condition. They also quantified the expression of the previously identified ITD-related metabolic networks in each subject in both conditions. RESULTS: With active involuntary movements during wakefulness, the EB group exhibited hypermetabolism of the cerebellum and pons. With movement suppression during sleep, the EB group exhibited superior-medial frontal hypometabolism in a region associated with cortical control of eyelid movement. Network analysis demonstrated a specific metabolic covariance pattern associated with ITD was also expressed in the patients with EB in both the sleep and wake conditions. CONCLUSION: These findings suggest that the clinical manifestations of EB are associated with abnormal metabolic activity in the pons and cerebellum, whereas the functional substrate of the disorder may be associated with abnormalities in cortical eyelid control regions. Furthermore, ITD-related networks are expressed in patients with EB, suggesting a functional commonality between both forms of primary dystonia.

Electrophysiological correlates of the adverse cognitive effects of electroconvulsive therapy.

Resting state, eyes closed, 19-lead EEG recordings were obtained at pre-ECT baseline and just prior to penultimate treatment and during the week following the ECT course in 59 patients with major depression. Patients had been randomized to ECT conditions that varied in electrode placement and stimulus intensity. The EEG data were submitted to power spectral analysis, and global and topographic effects were characterized for the delta and theta frequency bands. Relations between the EEG changes and scores on three cognitive measures were examined. The period of disorientation immediately following RUL ECT was associated with an accentuation of delta power in anterior frontal and temporal regions. Across the electrode placements, increased theta activity in left frontotemporal regions was associated with longer recovery of orientation. Post-ECT decrements in global cognitive status, as assessed by the modified Mini-Mental State exam, were associated with a greater increase in delta relative to theta power, globally across the cortex. The magnitude of retrograde amnesia for autobiographical events correlated with increased theta activity in left frontotemporal regions. The findings suggest that distinct neurophysiological changes subserve the therapeutic and adverse cognitive effects of ECT. Postictal disorientation and post-ECT retrograde amnesia appear to share a common physiological substrate.

Individual differences in PET activation of object perception and attention systems predict face matching accuracy.

We sought to investigate how individual differences in the regional patterns of cerebral blood flow (rCBF) relate to task performance during the perceptual matching of faces. We analyzed rCBF data obtained by PET and H2150 from nine young healthy, right-handed, adult males (mean age 29i3 years) using a statistical model of regional covariance, the Scaled Subprofile Model (SSM). SSM analysis performed on a voxel-basis for scan subtractions comparing face-matching and control tasks extracted two patterns whose subject expression in a multiple regression analysis was highly predictive of task accuracy (R2 = 0.87, p < 0.002). The pattern reflecting this linear combination was principally characterized by higher rCBF in regions of bilateral occipital and occipitotemporal cortex, right orbitofrontal cortex, left thalamus, basal ganglia, midbrain, and cerebellum with relatively lower rCBF in anterior cingulate, regions in bilateral prefrontal and temporal cortex, right thalamus, and right inferior parietal cortex. The results indicate that individual subject differences in face matching performance are specifically associated with the functional interaction of cortical and subcortical brain regions previously implicated in aspects of object perception and visual attentional processing.

Reproducibility of regional metabolic covariance patterns: comparison of four populations.

UNLABELLED: In a previous [18F]fluorodeoxyglucose (FDG) PET study we analyzed regional metabolic data from a combined group of Parkinson's disease (PD) patients and healthy volunteers (N), using network analysis. By this method, we identified a unique pattern of regional metabolic covariation with an expression which accurately discriminated patients from healthy volunteers. To assess the reproducibility of this pattern as a potential marker for PD, we compared the pattern's topography with that of the disease-related covariance patterns identified in three other independent populations of patients with PD and healthy individuals studied in different PET laboratories. METHODS: The following patient populations were studied: group A (original cohort: 22 PD, 20 N; resolution: 7.5 mm full width at half maximum [FWHM]); group B (18 PD, 12 N; resolution: 4.2 mm FWHM); group C (25 PD, 15 N; resolution: 8.0 mm FWHM); and group D (14 PD, 10 N; resolution: 10 mm FWHM). Region weights for the PD-related covariance pattern (PDRP) identified in the group A analysis were correlated with those for the disease-related patterns identified in the analyses of groups B, C and D. In addition, subject scores for the group A PDRP were computed prospectively for every individual in each of the study populations. PDRP scores for PD and N within each cohort were compared. RESULTS: The PDRP topography identified in group A was highly correlated with each of the corresponding topographies identified in the other populations (r2 approximately 0.60, P < 0.0001). Prospectively computed subject scores for the group A PDRP significantly discriminated PD from N in each population (P < 0.004). CONCLUSION: The PDRP topography identified previously in Group A is highly reproducible across patient populations and tomographs. Prospectively computed PDRP scores can accurately discriminate patients from controls in multiple populations studied with different tomographs. Brain network imaging with FDG PET can provide robust metabolic markers for the diagnosis of PD.

Functional brain networks in DYT1 dystonia.

Early-onset idiopathic torsion dystonia (ITD) is an autosomal dominant hyperkinetic movement disorder with incomplete penetrance, associated with a 3 base-pair deletion in the DYT1 gene on chromosome 9q34. To determine the metabolic substrates of brain dysfunction in DYT1 dystonia, we scanned 7 nonmanifesting and 10 affected DYT1 carriers and 14 normal volunteers with [18F]fluorodeoxyglucose and positron emission tomography. We found that DYT1 dystonia is mediated by the expression of two independent regional metabolic covariance patterns. The first pattern, identified in an analysis of nonmanifesting gene carriers was designated movement free (MF). This abnormal pattern was characterized by increased metabolic activity in the lentiform nuclei, cerebellum, and supplementary motor areas. The MF pattern was present in DYT1 carriers with and without clinical manifestations and persisted in DYT1 dystonia patients in whom involuntary movements were suppressed by sleep. The second pattern, identified in an analysis of affected gene carriers with sustained contractions at rest, was designated movement related (MR). This pattern was characterized by increased metabolic activity in the midbrain, cerebellum, and thalamus. The expression of the MR pattern was increased in waking DYT1 patients with sustained dystonia, compared with DYT1 carriers who were unaffected or who had dystonia only on action, as well as normal controls. MR subject scores declined significantly with sleep in affected DYT1 patients but not in normal controls. These findings indicate the penetrance of the DYT1 gene is considerably greater than previously assumed. ITD is mediated through the interaction of functional brain networks relating separately to gene status and to abnormal movement.

The metabolic anatomy of tremor in Parkinson's disease.

OBJECTIVE: To identify regional metabolic brain networks related specifically to the presence of tremor in PD. BACKGROUND: The pathophysiology of parkinsonian tremor is unknown. Because tremor in PD occurs mainly in repose, we used resting state PET with 18F-fluorodeoxyglucose (FDG) to identify specific metabolic brain networks associated with this clinical manifestation. METHODS: We studied two discrete groups of eight PD patients with and without tremor using FDG/PET. Both patient groups were matched for gender, age, and Unified Parkinson Disease Rating Scale ratings for akinesia and rigidity. Ten normal volunteer subjects served as controls. RESULTS: Network analysis with the Scaled Subprofile Model was performed in two steps. 1) We computed the expression of the PD-related pattern (PDRP) identified by us previously in each of the PD patients and control subjects. Although PDRP subject scores were abnormally elevated in the combined PD cohort (p < 0.005), these values did not differ in the PD patient groups with and without tremor (p = 0.36). 2) We used SSM to analyze the data from the combined PD cohort comprising both patient groups. We found that PD patients with tremor were characterized by increased expression of a metabolic network comprising the thalamus, pons, and premotor cortical regions. Subject scores for this pattern were elevated in the tremor group compared with the atremulous patient group and the normal control group (p < 0.005). CONCLUSIONS: The findings suggest that PD patients with tremor are characterized by distinct increases in the functional activity of thalamo-motor cortical projections. Modulation of this functional anatomic pathway is likely to be the mechanism for successful interventions for the relief of parkinsonian tremor.

Preoperative indicators of clinical outcome following stereotaxic pallidotomy.

We assessed the utility of preoperative clinical assessment and functional brain imaging with 18F-fluorodeoxyglucose (FDG) and positron emission tomography (PET) in predicting the clinical outcome of stereotaxic pallidotomy for the treatment of advanced Parkinson's disease (PD). Twenty-two PD patients undergoing posteroventral pallidotomy were assessed preoperatively with the Core Assessment Program for Intracerebral Transplantation (CAPIT) ratings measured on and off levodopa; quantitative FDG/PET was also performed before surgery. Preoperative clinical and metabolic measurements were correlated with changes in off-state CAPIT ratings determined 3 months after surgery. Clinical outcome following pallidotomy was also correlated with intraoperative measures of spontaneous pallidal single-unit activity as well as postoperative MRI measurements of lesion volume and location. We found that unilateral pallidotomy resulted in variable clinical improvement in off-state CAPIT scores for the contralateral limbs (mean change 30.9 +/- 15.5%). Postoperative MRI revealed that pallidotomy lesions were comparable in location and volume across the patients. Clinical outcome following surgery correlated significantly with preoperative measures of CAPIT score change with levodopa administration (r = 0.60, p < 0.005) and with preoperative FDG/PET measurements of lentiform glucose metabolism (r = 0.71, p < 0.0005). Operative outcome did not correlate with intraoperative measures of spontaneous pallidal neuronal firing rate. We conclude that preoperative measurements of lentiform glucose metabolism and levodopa responsiveness may be useful indicators of motor improvement following pallidotomy. Both preoperative quantitative measures, either singly or in combination, may be helpful in selecting optimal candidates for surgery.

Metabolic correlates of pallidal neuronal activity in Parkinson's disease.

We have used [18F]fluorodeoxyglucose and PET to identify specific metabolic covariance patterns associated with Parkinson's disease and related disorders previously. Nonetheless, the physiological correlates of these abnormal patterns are unknown. In this study we used PET to measure resting state glucose metabolism in 42 awake unmedicated Parkinson's disease patients prior to unilateral stereotaxic pallidotomy for relief of symptoms. Spontaneous single unit activity of the internal segment of the globus pallidus (GPi) was recorded intraoperatively in the same patients under identical conditions. The first 24 patients (Group A) were scanned on an intermediate resolution tomograph (full width at half maximum, 8 mm); the subsequent 18 patients (Group B) were scanned on a higher resolution tomograph (full width half maximum, 4.2 mm). We found significant positive correlations between GPi firing rates and thalamic glucose metabolism in both patient groups (Group A: r = 0.41, P < 0.05; Group B: r = 0.69, P < 0.005). In Group B, pixel-based analysis disclosed a significant focus of physiological-metabolic correlation involving the ventral thalamus and the GPi (statistical parametric map: P < 0.05, corrected). Regional covariance analysis demonstrated that internal pallidal neuronal activity correlated significantly (r = 0.65, P < 0.005) with the expression of a unique network characterized by covarying pallidothalamic and brainstem metabolic activity. Our findings suggest that the variability in pallidal neuronal firing rates in Parkinson's disease patients is associated with individual differences in the metabolic activity of efferent projection systems.

The metabolic anatomy of Tourette's syndrome.

The functional brain networks underlying the clinical manifestations of Gilles de la Tourette's syndrome (TS) are currently unknown. To identify these networks, we studied TS patients and normal subjects with 18F-fluorodeoxyglucose (FDG) and PET employing a statistical model of regional metabolic covariation. We studied 10 TS patients (mean age, 41.5 +/- 12.7 years) who were either drug naive or medication free for at least 2 years. Ten normal volunteers (mean age, 42.5 +/- 11.5) served as controls. We used quantitative FDG/PET to calculate global, regional, and normalized rates of glucose metabolism (GMR, rCMRGlc, and rCMRGlc/GMR) in all subjects. The Scaled Subprofile Model (SSM) was used to identify specific patterns of regional metabolic covariation associated with TS. We found that global and regional metabolic rates were normal in TS. SSM analysis identified two TS-related brain networks. One pattern (15.8% variance accounted for, VAF) was characterized by covariate bilateral metabolic increases in lateral premotor and supplementary motor association cortices and in the midbrain. Individual patient expression of this pattern (subject score) was abnormally increased in the TS group (p < 0.01). A second pattern (10.5% VAF) was characterized by covariate decreases in caudate and thalamic metabolism associated with smaller reductions in lentiform and hippocampal metabolic activity. Subject scores for this pattern correlated with Tourette Syndrome Global Scale (TSGS) global ratings (r = 0.85, p < 0.005). We conclude that the metabolic landscape of TS is characterized by a nonspecific pattern of increased motor cortical activity identified in other hyperkinetic disorders. TS is also associated with a specific brain network characterized by a reduction in the activity of limbic basal ganglia-thalamocortical projection systems.

Questionable dementia: clinical course and predictors of outcome.

OBJECTIVE: To evaluate the clinical course and predictors of outcome in outpatients with cognitive impairment who do not meet criteria for dementia at initial evaluation. DESIGN: Naturalistic longitudinal study. METHODS: Cognitively impaired patients in a memory disorders clinic who fell between the "normal" and "dementia" categories were defined broadly as "questionable dementia" (QD). Of 127 consecutive QD patients, 75 were followed for a minimum of 1 year (mean 2.5 years, SD 1.7). Baseline neuropsychological testing was conducted in 62 of these 75 QD patients. RESULTS: At the final follow-up time-point, 41.3% met diagnostic criteria for dementia (27 of 31 patients with dementia had possible or probable Alzheimer's Disease, AD), 44% were rated as not demented, and 14.7% remained as "uncertain" dementia. Increased age was associated with the final diagnosis of dementia, but duration of follow-up, Clinical Dementia Rating, and modified Mini Mental State (mMMS) scores were not predictive. Low scores on the mMMS delayed recall subtest, consistent long-term retrieval on the Selective Reminding Test, category naming for animals, and the WAIS-R digit symbol, picture arrangement, and block design subtests were predictive of the final diagnosis of dementia (all P < or = .01). mMMS delayed recall showed 66.7% sensitivity and 71.4% specificity, the other five neuropsychological subtests together showed 66.7% sensitivity and 66.7% specificity, and the six tests together showed 81% sensitivity and 76.9% specificity. Similar predictive accuracy was obtained for the final diagnosis of AD. CONCLUSIONS: In QD patients, poor performance on the mMMS delayed recall item may be a useful predictor of the diagnosis of dementia (and AD) on follow-up. Combining a screening instrument like the mMMS with specific neuropsychological tests may provide good predictive accuracy. In QD patients, the observed heterogeneity in diagnostic outcome, with most patients in the "dementia" and "no dementia" categories at follow-up, enhances the feasibility of evaluating early markers with predictive accuracy for dementia and AD.