Cerebellar and brainstem hypometabolism in olivopontocerebellar atrophy detected with positron emission tomography

We studied local cerebral metabolic rates for glucose (1CMRglc) with 18F-2-fluoro-2-deoxy-D-glucose and positron emission tomography (PET) in 30 patients with olivopontocerebellar atrophy (OPCA) and 30 age-matched control subjects without neurological disease. The diagnosis of OPCA was based on the history and physical findings and on the exclusion of other causes of cerebellar ataxia by means of laboratory investigations. Computed tomographic scans revealed some degree of atrophy of the cerebellum in most patients with OPCA, and many also had atrophy of the brainstem. PET studies in these patients revealed significant hypometabolism in the cerebellar hemispheres, cerebellar vermis, and brainstem in comparison with the normal control subjects. A significant relationship was found between the degree of atrophy and the level of 1CMRglc in the cerebellum and brainstem. Nevertheless, several patients had minimal atrophy and substantially reduced 1CMRglc, suggesting that atrophy does not fully account for the finding of hypometabolism. 1CMRglc was within normal limits for the thalamus and cerebral cortex. The data suggest that PET/1CMRglc may be useful as a diagnostic test in patients with the adult onset of cerebellar ataxia.     

Speech disorders in olivopontocerebellar atrophy correlate with positron emission tomography findings

We compared the severity of ataxic and spastic dysarthria with local cerebral metabolic rates for glucose (lCMRGlc) in 30 patients with olivopontocerebellar atrophy (OPCA). Perceptual analysis was used to examine the speech disorders, and rating scales were devised to quantitate the degree of ataxia and spasticity in the speech of each patient. lCMRGlc was measured with 18F-2-fluoro-2-deoxy-D-glucose and positron emission tomography (PET). PET studies revealed marked hypometabolism in the cerebellar hemispheres, cerebellar vermis, and brainstem of OPCA patients compared with 30 control subjects. With data normalized to the cerebral cortex, a significant inverse correlation was found between the severity of ataxia in speech and the lCMRGlc within the cerebellar vermis, cerebellar hemispheres, and brainstem, but not within the thalamus. No significant correlation was found between the severity of spasticity in speech and lCMRGlc in any of these structures. The findings support the view that the severity of ataxia in speech in OPCA is related to the functional activity of the cerebellum and its connections in the brainstem.     

Motor dysfunction in olivopontocerebellar atrophy is related to cerebral metabolic rate studied with positron emission tomography

We compared the severity of motor dysfunction with local cerebral metabolic rates for glucose (lCMRGlc) and the; degree of tissue atrophy in 30 patients with olivopontocerebellar atrophy (OPCA). We devised a scale to quantitate the degree of ataxia in the neurological examinations. lCMRGlc was measured with¹⁸F-2-fluoro-2-deoxy-D-glucose and positron emission tomography (PET). Tissue atrophy was assessed by visual rating of computed tomographic scans. PET studies revealed Marchked hypometabolism in the cerebellar vermis, cerebellar hemispheres, and brainstem of OPCA patients compared with 30 control subjects. A significant correlation was found between severity of motor impairment and lCMRGlc within the cerebellar vermis, both cerebellar hemispheres, and the brainstem. A significant but weaker relationship was noted between the degree of tissue atrophy in these regions and clinical severity. Partial correlation analysis revealed that motor dysfunction in OPCA correlated more strongly with lCMRGlc than with the amount of tissue atrophy. These results suggest that the clinical manifestations of OPCA are more closely related to the metabolic state of the tissue than to the structural changes in the cerebellum.     

Analysis of cerebellar functions in spinocerebellar degeneration using positron emission tomography (PET)

We quantitatively evaluated the cerebellar functions of 23 patients with spinocerebellar degeneration (SCD) and 10 normal controls using positron emission tomography (PET). Statistical analysis was performed using the Student's test. Regional cerebral blood flow (CBF) and regional cerebral metabolic rate (CMR) of the cerebellar hemisphere and cerebellar vermis were significantly lower in patients with SCD than in normal subjects (p less than 0.001). However, no significant difference between the both groups was seen in the CBFs and the CMRs of the occipital cortex and frontal cortex. Even in the patients with SCD who had not apparent cerebellar atrophy on CT, their CBFs and CMRs of the cerebellum were significantly low, and with advance of cerebellar atrophy, they tended to fall. In the patients with SCD, the fall of CMR was more prominent than that of CBF. Neither CBF, nor CMR of the cerebellum showed correlation to the duration of the illness. The present investigation suggested that PETs were valuable for the early diagnosis and the research on the pathogenesis of SCD.     

Positron emission tomographic studies of cerebral benzodiazepine-receptor binding in chronic alcoholics

Positron emission tomography was used with [¹¹C] flumazenil (FMZ) and [¹⁸F] fluorodeoxyglucose to study GABA type A/benzodiazepine (GABA-A/BDZ) receptors and cerebral metabolic rates for glucose (1CMRglc) in 17 male patients with severe chronic alcoholism (ALC), 8 with (ACD) and 9 without alcoholic cerebellar degeneration (non-ACD). In comparison with male normal controls of similar ages, the ALC group had significantly reduced FMZ ligand influx (K₁), FMZ distribution volume (DV), and 1CMRglc bilaterally in the medial frontal lobes, including superior frontal gyrus and rostral cingulate gyrus; the ACD group had significant reductions of K₁, DV, and ICMRglc bilaterally in the same distribution, and also in the superior cerebellar vermis; and the non-ACD group had significant reductions of K₁, DV, and ICMRglc bilaterally in the same regions of the frontal lobes but not in the superior cerebellar vermis. When compared with the non-ACD group, the ACD group had significant reductions of K₁ and DV bilaterally in the superior cerebellar vermis. The results suggest that severe chronic alcoholism damages neurons containing GABA-A/BDZ receptors in the superior medial apsects of the frontal lobes, and in patients with clinical signs of ACD, neurons containing GABA-A/BDZ receptors in the superior cerebellar vermis.     

High-Resolution Fluorodeoxyglucose Positron Emission Tomography Shows Both Global and Regional Cerebral Hypometabolism in Multiple Sclerosis

The authors study brain regional glucose metabolism prospectively in multiple sclerosis (MS) using high-resolution 2-[18-F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) in 25 MS patients of the Dent Neurologic Institute compared with 6 healthy subjects. Glucose metabolism is measured in 20 regions of interest using a line-profile technique. Compared with control subjects, a 9% reduction in total brain glucose metabolism is noted in MS patients (p < 0.05). Hypometabolism is widespread, including the cerebral cortex, subcortical nuclei, supratentorial white matter, and infratentorial structures. This reduction represents absolute regional decreases ranging from 3% to 18%. The most dramatic absolute reductions occur in the superior mesial frontal cortex, superior dorsolateral frontal cortex, mesial occipital cortex, lateral occipital cortex, deep inferior parietal white matter, and pons. The regional hypometabolism in the superior mesial frontal cortex and superior dorsolateral frontal cortex is statistically significant (p < 0.05), whereas the changes in the mesial occipital cortex (p = 0.07) and the lateral occipital cortex (p = 0.09) approach significance. The authors' findings suggest that widespread cerebral dysfunction occurs in MS, and that diaschisis or neuronal system disconnection resulting from white matter disease plays a major role. Cortical gray matter hypometabolism may also reflect direct MS involvement. The quantitative cerebral abnormalities detected by FDG PET may serve as a marker of disease activity in understanding the pathophysiological expression and therapeutic response of MS.     

Ictal Patterns of Cerebral Glucose Utilization in Children with Epilepsy

Summary: To determine seizure propagation patterns, we analyzed ictal positron emission tomography (PET) studies of regional cerebral glucose utilization in 18 children (11 male and 7 female aged weeks to 16 years) with epilepsy (excluding infantile spasms IS). Three major metabolic patterns were determined based on degree and type of subcortical involvement: Nine children had type I; asymmetric glucose metabolism of striatum and thalamus. Of these, the 7 oldest children showed unilateral cortical hypermetabolism (always including frontal cortex) and crossed cerebellar hypermetabolism. Two infants (aged <1 year) had a similar ictal PET pattern but no cerebellar asymmetry, presumably owing to immaturity of corticopontocerebellar projections. Five children had type II, symmetric metabolic abnormalities of striatum and thalamus; this pattern was accompanied by hippocampal or insular cortex hypermetabolism, diffuse neocortical hypometabolism, and absence of any cerebellar abnormality. Four children had type III, hypermetabolism restricted to cerebral cortex. This classification can accommodate ictal PET and single photon emission computed tomography (SPECT) patterns described by other investigators. Future studies should be directed at the clinical relevance of this classification, particularly with regard to epilepsy surgery.     

Neurobiology of non-REM sleep in depression: further evidence for hypofrontality and thalamic dysregulation

OBJECTIVE: Sleep disturbances characterize depression and may reflect the abnormal persistence of brain activity from wakefulness into non-REM sleep. The goal of this study was to investigate the functional neuroanatomical correlates of non-REM sleep relative to presleep wakefulness in depressed patients and healthy subjects. METHOD: Twelve medication-free depressed patients and 13 healthy subjects underwent polysomnography and [(18)F]fluorodeoxyglucose positron emission tomography scans during presleep wakefulness and non-REM sleep. Statistical parametric mapping contrasts were performed to detect differences in relative regional cerebral glucose metabolism between presleep wakefulness and non-REM sleep in each group as well as interactions across states and between groups. RESULTS: Relative to healthy subjects, depressed patients showed less of a decrease in relative regional cerebral glucose metabolism from presleep wakefulness to non-REM sleep in the left and right laterodorsal frontal gyri, right medial prefrontal cortex, right superior and middle temporal gyri, insula, right posterior cingulate cortex, lingual gyrus, striate cortex, cerebellar vermis, and left thalamus. CONCLUSIONS: Patterns of relative regional cerebral glucose metabolism changes from presleep wakefulness to non-REM sleep differ in healthy subjects and depressed patients. Specifically, the transition from wakefulness to non-REM sleep was characterized by the relative persistence of elevated metabolic activity in frontoparietal regions and thalamus in depressed patients compared with healthy subjects. These findings suggest that abnormal thalamocortical network function may underlie sleep anomalies and complaints of nonrestorative sleep in depressed patients.     

Reduced cerebellar blood flow and oxygen metabolism in spinocerebellar degeneration: a combined PET and MRI study

Fourteen patients with spinocerebellar degeneration (SCD) were subjected to MRI and PET studies. The quantitative MRI data revealed significant cerebellar and pontine atrophy in the patients with olivopontocerebellar atrophy (OPCA), and cerebellar atrophy in the patients with late cerebellar cortical atrophy (LCCA). We failed to demonstrate significant differences in the pons between LCCA patients and normal controls. PET measurements revealed decreases in cerebral oxygen metabolic rate (CMRO₂) in the cerebellar hemisphere and vermis in both groups of patients. The markedly decreased cerebral blood flow (CBF) and CMRO₂ in the pons were found only in the patients with OPCA. PET data corrected for the tissue shrinkage on the basis of MRI morphometry indicated a net reduction in cerebellar CMRO₂ and CBE The present study has demonstrated that a combination of functional and anatomical data offers further evidence in favour of the current acceptable classification of SCD based on clinicopathological grounds. Our data further suggest that the amount of atrophy in the cerebellum could not fully account for the decreased metabolic rates observed in PET studies.     

A relationship between metabolism in frontal lobes and cerebellum in normal subjects studied with PET

Lesions of one cerebral hemisphere are associated with decreased glucose metabolism, oxygen metabolism, and blood flow in the contralateral cerebellar hemisphere. We used positron emission tomography to look for a functional relationship in cerebral metabolism between the cerebral cortex and the contralateral cerebellum in normal human subjects. Twenty-four normal subjects were scanned with [18F]fluoro-2-deoxy-D-glucose while in a resting state. Asymmetry in local CMRglu (LCMRglu) in the frontal cortex was strongly correlated with asymmetry in LCMRglu in the opposite direction in the cerebellar hemispheres (r = -0.60, p less than 0.001). Widespread subregions of the frontal cortex were found to contribute to this relationship. Considering these results together with previous studies demonstrating that frontal lesions are associated with decreased metabolism in the contralateral cerebellum, we conclude that the frontal cortex exerts a strong modulating influence on metabolism in the contralateral cerebellum in normal subjects, and that this influence may be asymmetrical.     

Decreased glucose utilization in the striatum and frontal lobe in probable striatonigral degeneration

Nine positron emission tomography studies of regional cerebral glucose metabolism were performed in 7 patients with probable striatonigral degeneration, a disorder characterized by parkinsonian features and absent or poor response to L-dopa. When compared with values obtained in normal volunteers, mean cerebral glucose metabolism was slightly reduced in subjects with striatonigral degeneration who, in addition, had a marked (20.5%, +/- 3 SD) relative hypometabolism in putaminal and caudate nuclei. Significant hypometabolism was also found in motor/premotor as well as in prefrontal cortex. In 2 subjects who were studied twice a deterioration of relative striatal metabolism paralleled clinical evolution. Magnetic resonance imaging disclosed the presence of abnormal iron deposits in the putamen in all cases but showed no cortical anomalies. These results suggest that positron emission tomography with [18F]fluorodeoxyglucose may provide an index of cell and processes degeneration in the striatum in striatonigral degeneration and is able to detect functional deficits in frontal cortex. The presence of striatal hypometabolism might be a predictor of a poor response to L-dopa.     

Proton magnetic resonance spectroscopy (1H MRS) in patients with sporadic cerebellar degeneration.

The authors studied 23 patients with cerebellar degeneration including multiple systemic atrophy (MSA) and cerebellar cortical atrophy (CCA) by proton magnetic resonance spectroscopy (1H-MRS). 1H-MRS allowed noninvasive measurement of the signal intensities derived from N-acetylaspartate (NAA), creatine + phosphocreatine (CRE), and choline-containing compounds (CHO). There was significant reduction of the NAA/CRE level in the frontal cortex, putamen, cerebellar hemisphere and cerebellar vermis of patients with MSA, and in the frontal cortex, cerebellar hemisphere and cerebellar vermis of patients with CCA as compared with those of normal controls. There was significant reduction of the NAA/CRE level also in the putamen of patients with MSA as compared with that of patients with CCA. These results indicated the presence of a degenerative process and/or functional impairment in the frontal cortex and putamen of patients with MSA and in the frontal cortex of patients with CCA, in addition to a degenerative process in the cerebellum. There was a significant correlation between the NAA/CRE level and the severity of clinical signs. 1H-MRS is valuable in providing information regarding the pathophysiology and the progress of cerebellar degenerative diseases.     

Metabolic Changes of Cerebrum by Repetitive Transcranial Magnetic Stimulation over Lateral Cerebellum: A Study with FDG PET

To better understand the functional role of cerebellum within the large-scale cerebellocerebral neural network, we investigated the changes of neuronal activity elicited by cerebellar repetitive transcranial magnetic stimulation (rTMS) using (18)F-fluorodeoxyglucose (FDG) and positron emission tomography (PET). Twelve right-handed healthy volunteers were studied with brain FDG PET under two conditions: active rTMS of 1?Hz frequency over the left lateral cerebellum and sham stimulation. Compared to the sham condition, active rTMS induced decreased glucose metabolism in the stimulated left lateral cerebellum, the areas known to be involved in voluntary motor movement (supplementary motor area and posterior parietal cortex) in the right cerebral hemisphere, and the areas known to be involved in cognition and emotion (orbitofrontal, medial frontal, and anterior cingulate gyri) in the left cerebral hemisphere. Increased metabolism was found in cognition- and language-related brain regions such as the left inferior frontal gyrus including Broca's area, bilateral superior temporal gyri including Wernicke's area, and bilateral middle temporal gyri. Left cerebellar rTMS also led to increased metabolism in the left cerebellar dentate nucleus and pons. These results demonstrate that rTMS over the left lateral cerebellum modulates not only the target region excitability but also excitability of remote, but interconnected, motor-, language-, cognition-, and emotion-related cerebral regions. They provide further evidence that the cerebellum is involved not only in motor-related functions but also in higher cognitive abilities and emotion through the large-scale cerebellocereberal neural network.     

PET study in subjects from two Italian FAD families with APP717 Val to Ileu mutation

Cerebral glucose metabolism was investigated with 2-[¹⁸F]-fluoro-2-deoxy-D-glucose ([¹⁸F]FDG) and positron emission tomography (PET) in seven members belonging to two Italian families with familial Alzheimer's disease (FAD) and APP717 Val to Ileu mutation. The aim of the study was to identify the pattern of cerebral hypometabolism in the affected patients and the possible occurrence of brain metabolic changes in the APP mutated subjects. The two patients with FAD, when compared with normal age matched controls, showed a severe bilateral hypometabolism in parietal and temporal regions, as well as in the prefrontal areas, which were more affected on the left side. Subcortical thalamic structures were also involved in one patient. In a comparison with a group of patients with sporadic AD, the most affected cerebral areas in the FAD patients were the prefrontal regions and the thalamus, bilaterally. One of the four mutated subjects, with an age close to the family age of disease onset, in a comparison with normals, showed metabolic reductions in the right thalamus, in the left dorsolateral frontal cortex and, bilaterally, in the frontal orbital regions. This regional brain hypometabolism was present in a preclinical phase, 1 year before the onset of dementia. In the three younger subjects carrying the mutation, a metabolic reduction was detected in the thalamus, bilaterally. These results demonstrate that a pattern of cerebral hypometabolism involving cortical and subcortical structures is present in FAD patients with APP717 Val to Ileu mutation. Cerebral hypometabolism may occur in pre-symptomatic and young asymptomatic APP717 mutated FAD subjects and it can be detected by a highly sensitive procedure such as PET.     

Cerebral glucose metabolism in five patients with Lennox-Gastaut syndrome

Regional cerebral glucose metabolic rates were estimated by positron emission tomography, in parallel with electroencephalography and cranial computed tomography in 5 patients with Lennox-Gastaut syndrome. The 5 patients, 3 boys and 2 girls, ranged in age from 10-15 years. Computed tomography revealed no gross abnormalities. Each patient received 2-5 mCi of 2-(18F)-fluoro-2-deoxy-D-glucose (18F-FDG) intravenously. Averaged cerebral glucose metabolic rates were reduced in each cerebral region as compared with controls. Unilateral hypometabolism was present in 4 patients: one in the inferior frontal gyrus as well as the posterior portion of the superior temporal gyrus; one in the inferior frontal gyrus; one in the posterior portion of the superior temporal gyrus; and one demonstrated diffuse hemispheric hypometabolism including the inferior frontal and posterior portion of the superior temporal gyrus. The side of hypometabolism was the same as the epileptogenic focus on the electroencephalogram. No focal changes were demonstrated on the electroencephalogram of a patient whose positron emission tomography revealed hemispheric hypometabolism. Hypometabolism of the inferior frontal and posterior portion of the superior temporal gyrus may relate to the possible pathogenesis of Lennox-Gastaut syndrome. Positron emission tomography has the potential to reveal a latent focal or lateralized abnormality in some patients with non-localized electroencephalographic changes.     

Voxel-based comparison of regional cerebral glucose metabolism between PSP and corticobasal degeneration

OBJECTIVES: Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neurodegenerative disorders that may be accompanied by dementia and parkinsonism as clinical symptoms. The purpose of this study was to elucidate cerebral metabolic differences of these two diseases with cognitive impairments by [18F] fluorodeoxyglucose (FDG) and positron emission tomography (PET). METHODS: A total of 12 patients with PSP (age: 62.8+/-6.0 years old, m: 7, f: 5, Mini-Mental State Examination (MMSE): 23.4+/-2.6), 12 patients with CBD (age: 64.8+/-6.3 years old, m: 6, f: 6, MMSE: 22.9+/-4.5), and age-matched healthy subjects (normal control (NC)) (age: 63.8+/-7.7 years old, m: 7, f: 5) were subjected to FDG-PET to obtain glucose metabolic images. We compared regional cerebral metabolic images by a voxel-by-voxel analysis with statistical parametric mapping (SPM) among PSP, CBD, and NC subjects, and evaluated differences of hypometabolic regions. RESULTS: The patients with PSP showed reduced cerebral glucose metabolism in the medial and lateral frontal gyri, basal ganglia, and midbrain compared with NC, whereas the patients with CBD showed significant reduction in the parietal lobes (p<0.001). SPM also revealed parietal hypometabolism in CBD patients compared with PSP patients (p<0.001). CONCLUSIONS: The predominant parietal glucose metabolic reduction in CBD patients was different from previously reported findings. This finding would be the characteristic substance of patients with CBD accompanying cognitive impairments. Our findings suggest that measurement of glucose metabolism by PET and a voxel-based analysis is useful to understand the pathophysiology of these two diseases with cognitive impairments.     

A PET study of the pathophysiology of negative symptoms in schizophrenia. Positron emission tomography

OBJECTIVE: Positron emission tomography (PET) was used to compare cerebral metabolic patterns in schizophrenic subjects with predominantly negative symptoms (alogia, affective flattening, avolition, and attentional impairment) and in those with predominantly positive symptoms. METHOD: Fourteen right-handed male subjects with DSM-IV schizophrenia were assigned to groups with predominantly negative or predominantly positive symptoms on the basis of their post-drug-washout scores on the Positive and Negative Syndrome Scale. The patients were compared to seven age- and gender-matched normal volunteers. PET scans with [(18)F]fluorodeoxyglucose were obtained during a degraded Continuous Performance Task to measure absolute glucose metabolic rates. Statistical parametric mapping was used to estimate the regional metabolic differences between groups. RESULTS: The subjects with predominantly negative symptoms had significant differences in glucose metabolic rates, compared to both the subjects with predominantly positive symptoms and the normal subjects. Negative symptom subjects had a lower glucose metabolic rate in the right hemisphere, especially in the temporal and ventral prefrontal cortices, compared to the other groups, and higher metabolic rates in the cerebellar cortex and in the lower deep cerebellar nuclei. Negative symptom subscale scores were negatively correlated with glucose metabolic rates for most of the brain areas that differentiated subjects with predominantly negative symptoms from those with predominantly positive symptoms. CONCLUSIONS: Schizophrenic subjects with predominantly negative symptoms have greater metabolic abnormalities than subjects with predominantly positive symptoms, particularly in frontal, temporal, and cerebellar circuitry. These results are consistent with abnormalities in corticocortical, corticobasal ganglia, mesocortical dopamine, and cerebellar-thalamic-prefrontal circuits, which may underlie the negative symptoms of schizophrenia.     

Lowered cerebral glucose utilization in amyotrophic lateral sclerosis

Regional cerebral metabolic rates for glucose (rCMRGlc) were analyzed in 19 studies of 12 patients with amyotrophic lateral sclerosis (ALS) by positron emission tomography (PET) with [18F]2-fluoro-2-deoxy-D-glucose. In the 8 ALS patients with upper motor neuron signs, the mean cortical rCMRGlc was significantly lower than in 11 age-matched control subjects (p less than 0.01). The degree of hypometabolism correlated with the duration of the clinical signs and extended throughout the cortex and basal ganglia, but not to the cerebellum. Of the 4 such patients who had repeat PET scans, 3 demonstrated significant subsequent reduction in the rCMRGlc, corresponding to the worsening of the clinical picture. In contrast, 4 ALS patients with disease confined to lower motor neurons and 3 patients with lower motor neuron disease from old paralytic poliomyelitis had normal or near-normal rCMRGlc throughout the brain. Because histological evidence shows no generalized neuronal cell loss in the cortex of ALS patients, including in some cases the primary motor regions, the demonstration of severe generalized hypometabolism in structurally normal cortex indicates that some cortical neurons exist in a state of neuronal nonfunction, rather than cell death, and that anatomoclinical correlations may be more complex. The data also indicate that ALS with upper motor neuron involvement extends beyond the corticospinal tracts and differs in cortical function from the ALS confined to lower motor neurons or the other lower motor neuron disorders.     

Glucose metabolism and serotonin receptors in the frontotemporal lobe degeneration

In patients with the frontal variant of frontotemporal lobar degeneration (fv-FTLD), behavioral abnormalities may vary from apathy with motor slowness (apathetic form) to disinhibition with agitation (disinhibited form). These clinical presentations may be related to specific regional cerebral dysfunction and to deficit in the serotoninergic system. We studied cerebral glucose uptake using (18)F-fluorodeoxyglucose and positron emission tomography in 18 patients fulfilling clinical criteria for fv-FTLD and showing, respectively, an apathetic or disinhibited behavioral syndrome. In eight of these patients, we also evaluated the 5-hydroxytryptamine-2A receptor cerebral receptor distribution with [(11)C]MDL and positron emission tomography. We found a reduction of frontal glucose metabolism in the whole group of fv-FTLD patients. Apathetic syndrome was associated with a prevalent dorsolateral and frontal medial hypometabolism, whereas the disinhibited syndrome demonstrated a selective hypometabolism in interconnected limbic structures (the cingulate cortex, hippocampus/amygdala, and accumbens nucleus). The in vivo measurements of [(11)C]MDL indicated a significant reduction of 5-hydroxytryptamine-2A receptors in orbitofrontal, frontal medial, and cingulate cortices. These (18)F-fluorodeoxyglucose positron emission tomography changes can be considered as specific functional markers of the different behavioral presentations in fv-FTLD. The serotoninergic system dysfunction provides a rationale for therapeutic trials with selective serotonin reuptake inhibitors.