Choice of reference area in studies of Alzheimer's disease using positron emission tomography with fluorodeoxyglucose-F18

At present, there is still no consensus on the choice of the reference area in positron emission tomography (PET) studies of Alzheimer's disease (AD). In this study, PET scans with fluorodeoxyglucose-F18 were carried out in the following groups of subjects: 47 patients with probable AD, 8 patients with mild cognitive impairment, and 15 age-similar healthy subjects. Scans normalized to the cerebral global mean (CGM), cerebellum (CBL), and the primary sensorimotor cortex (SMC). We evaluated the effect of the different count normalization procedures on the accuracy of (18)F-FDG PET to detect AD-specific metabolic abnormalities (voxel-based group comparison) and to differentiate between patients and healthy subjects (ROI-based discriminant analysis) with regard to the degree of clinical deterioration. Metabolic reductions in groups of very mildly, mildly and moderate-to-severely affected patients appeared, respectively, 2.2, 2.6, and 2.7 times greater in spatial extent when tracer uptake was normalized to SMC rather than to CGM. The overall accuracy of discrimination was 94%, 91%, and 80% after normalization to SMC, CBL, and CGM, respectively. In general, normalization to SMC was somewhat superior to cerebellar normalization, allowing the detection of more pronounced metabolic deficits and the more accurate discrimination of patients from non-patients. Normalization to CGM should be used with great caution not only in advanced stages of dementia, but also in very mild AD cases.     

Neuronal substrates for semantic memory: a positron emission tomography study in Alzheimer's disease

We examined 57 patients with mild Alzheimer's disease by using three kinds of verbal semantic memory tests (category fluency, confrontation naming and generation of verbal definition) and correlated each score with regional cerebral glucose metabolism determined by (18)F-fluorodeoxyglucose and positron emission tomography. The scores of all three verbal semantic memory tests correlated significantly with regional cerebral glucose metabolism in the left inferior temporal gyrus, even after controlling for the effects of age, sex and educational attainment. In contrast, the scores of the word recall test did not correlate significantly with regional cerebral glucose metaboliosm in the left inferior temporal gyrus, neither before nor after controlling for these confounders. Our results suggested that the left inferior temporal lobe contributes to verbal semantic memory.     

The psychotic phenomenon in probable Alzheimer's disease: a positron emission tomography study

Positron emission tomography was used to examine the mechanisms of the psychotic phenomenon in Alzheimer's disease (AD). Data from 2 patients with delusions and 2 with hallucinations were compared with those of 5 AD patients without psychosis. The patients with paranoid delusions had diminished relative regional cerebral blood flow (rel-CBF) in the left dorsolateral prefrontal and left medial temporal cortices. The patients with visual hallucinations showed diminished rel-CBF in the right parietal, left medial temporal, and left dorsolateral prefrontal cortices. These findings support the hypothesis that a frontal-temporal abnormality is associated with paranoid delusions in AD. By contrast, visual hallucinations are associated with parietal as well as frontal and temporal lobe dysfunction. In these patients, a left prefrontal-temporal cortex dysfunction appears to be a common denominator for the development of the psychotic phenomenon in AD.     

Functional imaging of cognition in Alzheimer's disease using positron emission tomography

Positron emission tomography in Alzheimer's disease (AD) demonstrates a metabolic decrease, predominantly in associative posterior cortices (comprising the posterior cingulate cortex), and also involving medial temporal structures and frontal regions at a lesser degree. The level of activity in this wide network is roughly correlated with dementia severity, but several confounds (such as age, education or subcortical ischemic lesions) may influence the brain-behaviour relationship. Univariate analyses allow one to segregate brain regions that are particularly closely related to specific neuropsychological performances. For example, a relationship was established between the activity in lateral associative cortices and semantic performance in AD. The role of semantic capacities (subserved by temporal or parietal regions) in episodic memory tasks was also emphasized. The residual activity in medial temporal structures was related to episodic memory abilities, as measured by free recall performance, cued recall ability and recognition accuracy. More generally, AD patients' performance on episodic memory tasks was correlated with the metabolism in several structures of Papez's circuit (including the medial temporal and posterior cingulate regions). Multivariate analyses should provide complementary information on impaired metabolic covariance in functional networks of brain regions and the consequences for AD patients' cognitive performance. More longitudinal studies are being conducted that should tell us more about the prognostic value of initial metabolic impairment and the neural correlates of progressive deterioration of cognitive performance in AD.     

Hemiballismus: study of a case using positron emission tomography with 18fluoro-2-deoxyglucose

A 64-year-old man had right-sided persistent hemiballismus. Cerebral computed tomography (CT) and 0.5-T magnetic resonance imaging (MRI) showed no abnormalities, but 1.5-T MRI showed decreased signal intensity of the putamina, greater on the left than on the right. The subthalamic area was normal on CT and MRI. Positron emission tomography with 18fluoro2-deoxyglucose showed marked hypometabolism of the left putamen (60% of the right) and hypermetabolism of the left parietal lobe (138% of the right). The decreased metabolism of the left putamen may indicate a reduction in neuronal firing. The pathophysiology of the hemiballismus in this case may be loss of tonic inhibition of the lateral globus pallidus from the putamen, leading in turn to greater inhibition of the subthalamic nucleus, less excitation of the medial globus pallidus, and less inhibition of the thalamus and motor cortex, and thus allowing expression of the ballistic movements.     

Cerebral hypometabolism in progressive supranuclear palsy studied with positron emission tomography

Progressive supranuclear palsy (PSP) is characterized by supranuclear palsy of gaze, axial dystonia, bradykinesia, rigidity, and a progressive dementia. Pathological changes in this disorder are generally restricted to subcortical structures, yet the type and range of cognitive deficits suggest the involvement of many cerebral regions. We examined the extent of functional impairment to cerebral cortical and subcortical structures as measured by the level of glucose metabolic activity at rest. Fourteen patients with PSP were compared to 21 normal volunteers of similar age using 18F-2-fluoro-2-deoxy-D-glucose and positron emission tomography. Glucose metabolism was reduced in the caudate nucleus, putamen, thalamus, pons, and cerebral cortex, but not in the cerebellum in the patients with PSP as compared to the normal subjects. Analysis of individual brain regions revealed significant declines in cerebral glucose utilization in most regions throughout the cerebral cortex, particularly those in the superior half of the frontal lobe. Declines in the most affected regions of cerebral cortex were greater than those in any single subcortical structure. Although using conventional neuropathological techniques the cerebral cortex appears to be unaffected in PSP, significant and pervasive functional impairments in both cortical and subcortical structures are present. These observations help to account for the constellation of cognitive symptoms in individual patients with PSP and the difficulty encountered in identifying a characteristic psychometric profile for this group of patients.     

Imaging the pathology of Alzheimer's disease: amyloid-imaging with positron emission tomography

The steep rise in the incidence of Alzheimer's disease (AD) has further added to the considerable public health burden caused by aging of the United States population. Among the most characteristic pathologic hallmarks of AD are neuritic plaques and neurofibrillary tangles. The capability to use positron emission tomography and selective markers for amyloid protein deposition promises to substantially alter the way we diagnosis and manage patients who have AD.     

Positron emission tomography with fluorodeoxyglucose-F18 in an animal model of mania

Intracerebroventricular (ICV) administration of ouabain to young adult rats has been suggested to model human bipolar mania. In the human condition, mania and bipolar depression are both associated with reductions in frontal cerebral metabolism. We utilized [(18)F]-fluorodeoxyglucose [(18)FDG] positron emission tomography (PET) to visualize glucose uptake in animals receiving ICV ouabain. Animals received 5 microl of 10(-)(3) M ouabain ICV, were anesthetized with isoflurane inhalation, and administered intraperitoneally with 0.5 mCi of (18)FDG. PET data were collected over 20 min 1 hour later. Additionally, the effect of lithium was examined in animals receiving lithium in their diet for 1 week before the ICV ouabain injection. Data were analyzed with IDL Virtual Machine software. Brain glucose utilization as measured by (18)FDG uptake was significantly reduced in animals receiving ICV ouabain compared with those receiving equal volumes of artificial cerebrospinal fluid. Pretreatment with lithium normalized (18)FDG uptake. These results mirror human studies.     

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.     

Alzheimer's disease: focal cortical changes shown by positron emission tomography

Local rates of cortical glucose metabolism were estimated by positron emission tomography in 13 right-handed patients with Alzheimer's disease. Individuals with disproportionate failure of language function had markedly diminished metabolism in the left frontal, temporal, and parietal regions. Patients with predominant visuo-constructive dysfunction evidenced a hypometabolic focus in the right parietal cortex. Patients with memory failure as the most apparent feature had no significant metabolic asymmetry in cortical regions. In all subjects, verbal competency generally correlated with metabolic activity in the left frontal and temporal areas, while visuo-constructive test performance was linked to glucose utilization in the right parietal lobe.     

Patterns of regional brain hypometabolism associated with knowledge of semantic features and categories in Alzheimer's disease

The study of semantic memory in patients with Alzheimer's disease (AD) has raised important questions about the representation of conceptual knowledge in the human brain. It is still unknown whether semantic memory impairments are caused by localized damage to specialized regions or by diffuse damage to distributed representations within nonspecialized brain areas. To our knowledge, there have been no direct correlations of neuroimaging of in vivo brain function in AD with performance on tasks differentially addressing visual and functional knowledge of living and nonliving concepts. We used a semantic verification task and resting 18-fluorodeoxyglucose positron emission tomography in a group of mild to moderate AD patients to investigate this issue. The four task conditions required semantic knowledge of (1) visual, (2) functional properties of living objects, and (3) visual or (4) functional properties of nonliving objects. Visual property verification of living objects was significantly correlated with left posterior fusiform gyrus metabolism (Brodmann's area [BA] 37/19). Effects of visual and functional property verification for non-living objects largely overlapped in the left anterior temporal (BA 38/20) and bilateral premotor areas (BA 6), with the visual condition extending more into left lateral precentral areas. There were no associations with functional property verification for living concepts. Our results provide strong support for anatomically separable representations of living and nonliving concepts, as well as visual feature knowledge of living objects, and against distributed accounts of semantic memory that view visual and functional features of living and nonliving objects as distributed across a common set of brain areas.     

Contribution of positron emission tomography to functional neuroimaging in Alzheimer's disease

When combined with cognitive investigations, functional neuroimaging methods such as positron emission tomography allow to depict the neural substrates that underlie the neuropsychological alterations in Alzheimer's disease. Capitalising on the variance in both cognitive performances and resting cerebral metabolic rate of glucose (CMRGlc) in Alzheimer's disease, it is possible to correlate these two quantitative variables on a pixel-by-pixel basis and to generate maps showing the significant correlations in stereotaxic space. Some examples using this approach in the domain of memory disorders are presented in this brief review. We notably show that the localisation of the significant correlations differs from one memory system to another, as evaluated by clinical memory tasks. This approach also unravels the compensatory mechanisms that take place with evolution of the disease. Over and above its interest in clinical neuropsychology, this method constitutes a new source of inferences complementary to the classic activation paradigm in normal subjects, as the latter identifies the cerebral structures that are involved with, but not necessarily indispensable for, the normal execution of the task. This approach highlights the interest of combining functional neuroimaging and neuropsychology to better understand the neural substrates of cognitive deficits in both patients with memory disorders and elderly normal subjects.     

A single-photon emission computed tomography imaging study of driving impairment in patients with Alzheimer's disease

Single-photon emission computed tomography (SPECT) was used in this study to examine the neurophysiologic basis of driving impairment in 79 subjects with dementia. Driving impairment, as measured by caregiver ratings, was significantly related to regional reduction of right hemisphere cortical perfusion on SPECT, particularly in the temporo-occipital area. With increased severity of driving impairment, frontal cortical perfusion was also reduced. Clock drawing was more significantly related to driving impairment than the Mini-Mental State Examination (MMSE). Driving impairment in Alzheimer's disease is related to changes in cortical function which vary according to the severity of the disease. Cognitive tests of visuoperceptual and executive functions may be more useful screening tools for identifying those at greatest risk for driving problems than examinations like the MMSE that are weighted toward left-hemisphere-based verbal tasks.     

Progressive loss of cortical acetylcholinesterase activity in association with cognitive decline in Alzheimer's disease: a positron emission tomography study

We measured brain acetylcholinesterase activity in 30 patients with Alzheimer's disease (AD) and 14 age-matched controls by positron emission tomography (PET) and using a carbon 11-labeled acetylcholine analogue. Seven AD patients had repeat PET scans. The k3 values were calculated as an index of acetylcholinesterase activity in a three-compartment analysis using the metabolite corrected arterial input function. Twenty-eight of the 30 AD patients (14 each in the early and late onset subgroups) were retained in the study so as to equalize the range and average severity of cognitive impairment within the early and late onset subgroups. The k3 values were significantly reduced in the neocortex, hippocampus, and amygdala in the early onset AD patients, although the k3 values were significantly reduced only in the temporoparietal cortex and amygdala in the late onset AD patients. In the longitudinal study, all 7 repeat AD patients showed further reduction of cortical k3 values in the second PET scans, with a mean interval of 2 years, suggesting a progressive loss of the ascending cholinergic system from the nucleus basalis of Meynert in AD. In 37 AD patients, there was a highly significant correlation between the cortical k3 values and Mini-Mental State Examination scores, supporting the cholinergic hypothesis in AD.     

Cerebral mapping of apraxia in Alzheimer's disease by positron emission tomography

The ability to mimic skilled movements or to pantomime them in response to spoken command was compared with psychometric performance and with regional glucose utilization as estimated by [18F]fluorodeoxyglucose positron emission tomography in 17 right-handed patients with Alzheimer's disease and 6 age-matched normal subjects. Apraxia scores, both on tests to command and to imitation, were significantly lower in the Alzheimer patients. Imitation scores correlated best with performance on tests of visual--spatial ability and with cortical metabolism in the right parietal lobe; command scores related most closely with the results of tests reflecting verbal proficiency and with cortical metabolism in the left inferior hemisphere, especially frontally. Apraxia to command and imitation may thus reflect neuronal dysfunction in distinct cerebral regions in patients with Alzheimer's disease.     

Cerebellar and frontal hypometabolism in alcoholic cerebellar degeneration studied with positron emission tomography

Local cerebral metabolic rate for glucose was studied utilizing 18F-2-fluoro-2-deoxy-D-glucose and positron emission tomography (PET) in 14 chronically alcohol-dependent patients and 8 normal control subjects of similar age and sex. Nine of the 14 patients (Group A) had clinical signs of alcoholic cerebellar degeneration, and the remaining 5 (Group B) did not have signs of alcoholic cerebellar degeneration. PET studies of Group A revealed significantly decreased local cerebral metabolic rates for glucose in the superior cerebellar vermis in comparison with the normal control subjects. Group B did not show decreased rates in the cerebellum. Both Groups A and B showed decreased local cerebral metabolic rates for glucose bilaterally in the medial frontal area of the cerebral cortex in comparison with the normal control subjects. The severity of the clinical neurological impairment was significantly correlated with the degree of hypometabolism in both the superior cerebellar vermis and the medial frontal region of the cerebral cortex. The degree of atrophy detected in computed tomography scans was significantly correlated with local cerebral metabolic rates in the medial frontal area of the cerebral cortex, but not in the cerebellum. The data indicate that hypometabolism in the superior cerebellar vermis closely follows clinical symptomatology in patients with alcoholic cerebellar degeneration, and does not occur in alcohol-dependent patients without clinical evidence of cerebellar dysfunction. Hypometabolism in the medial frontal region of the cerebral cortex is a prominent finding in alcohol-dependent patients with or without alcoholic cerebellar degeneration.     

Young-onset Parkinson disease with and without parkin gene mutations: a fluorodopa F 18 positron emission tomography study

BACKGROUND: Mutations of the parkin gene are frequently encountered in patients with young-onset Parkinson disease (YOPD), but the effects of this mutation on the nigrostriatal dopaminergic degeneration are not well established. OBJECTIVE: To analyze, using positron emission tomography and fluorodopa F 18, the severity and profile of striatal dopaminergic metabolism in YOPD patients with and without parkin gene mutations. METHODS: We performed positron emission tomography with fluorodopa F 18 in 19 YOPD patients with parkin gene mutations (parkin patients), 6 YOPD patients without parkin gene mutations (nonparkin patients), and 9 healthy controls. Putamen and caudate nucleus fluorodopa F 18 uptake was assessed using regions of interest analysis. RESULTS: In parkin patients, the striatal fluorodopa F 18 uptake reduction was 36.3%, 51.3%, and 66.7%, respectively, for the caudate nucleus, anterior putamen, and posterior putamen compared with controls. In nonparkin patients, this reduction was 23.0%, 43.6%, and 73.0%, respectively. This reduction was asymmetrical according to the most affected hemibody for the anterior and posterior putamen in parkin patients and for the posterior putamen in nonparkin patients. A rostrocaudal gradient was observed with a severe decrease in fluorodopa F 18 uptake in the putamen and relative sparing of the caudate nucleus. There was no significant difference of striatal fluorodopa F 18 uptake between our 2 YOPD populations. In parkin patients, no significant correlation was found among fluorodopa F 18 uptake, motor disability, and the type of mutations. In nonparkin patients, there was a significant correlation between fluorodopa F 18 uptake and clinical severity. CONCLUSIONS: The pattern of fluorodopa F 18 uptake in the striatum of YOPD patients is similar to that of patients with idiopathic Parkinson disease and does not depend on the presence or absence of mutations of the parkin gene.