Hemispheric asymmetries of hypometabolism associated with semantic memory impairment in Alzheimer's disease: a study using positron emission tomography with fluorodeoxyglucose-F18

Considerable disagreement exists about the neuroanatomical basis of conceptual-semantic impairments observed in a subgroup of patients with Alzheimer's disease (AD) at mild to moderate stages of the disease. Several studies of groups of patients have shown correlations between focal hypometabolism or hypoperfusion in left hemispheric areas and measures of verbal semantic memory impairment in AD patients. The question remains, however, whether left hemispheric hypometabolism is sufficient to produce such impairment in the single case and whether nonverbal semantic knowledge is also affected. We used positron emission tomography (PET) with fluorodeoxyglucose-F18 (FDG), statistical parametric mapping (SPM), and tests of verbal and nonverbal semantic memory in 11 AD patients with a mean score on the Mini-Mental State Examination of 22.6 (+/-2.8). Naming impairment was significantly associated with left hemispheric asymmetry of hypometabolism on a single-case basis. Our correlation analysis showed that metabolism in left anterior temporal, posterior inferior temporal, inferior parietal and medial occipital areas (Brodmann areas: 21/38, 37, 40 and 19) correlated with both verbal and nonverbal semantic performance. We conclude that left hemispheric synaptic dysfunction, as measured by regional glucose hypometabolism, was sufficient to produce semantic impairments in our patients. The majority of areas affected in our patients with semantic impairments were involved in multimodal or supramodal (verbal and nonverbal) semantic knowledge.     

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.     

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.     

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.     

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.     

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.     

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.     

Parkinson's disease in twins studied with 18F-dopa and positron emission tomography.

We used 18F-dopa PET to examine concordance for dysfunction of the nigrostriatal dopaminergic system in 18 co-twins of patients with Parkinson's disease (PD) and scanned one clinically concordant monozygotic (MZ) twin pair, 17 asymptomatic co-twins (10 MZ, 7 dizygotic [DZ]), and 13 twins with PD (8 MZ, 5 DZ). Mean 18F-dopa uptake of the twins with PD was significantly reduced in putamen to 38% and in caudate to 66% of normal. Mean putamen 18F-dopa uptake for the 17 asymptomatic co-twins was also significantly reduced (86% of normal), as was putamen tracer uptake for the 10 MZ (87% of normal) and seven DZ (83% of normal) asymptomatic co-twin subgroups. Four of 10 MZ and two of seven DZ asymptomatic co-twins had putamen 18F-dopa uptake reduced more than 2 SDs below the normal mean. Three of these four asymptomatic MZ co-twins had tremor on examination at the time of PET and one has now developed PD 2 years later. Our PET findings give concordances for nigral dysfunction of 45% in the MZ pairs and 29% in the DZ pairs at a 2-SD threshold, and 18% in MZ and 0% in DZ pairs at a 3-SD threshold of significance. These data suggest that the concordance for nigral pathology in PD twins may be higher than previously realized and that the presence of an isolated postural or rest tremor may be a phenotypic expression of PD.     

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.     

Dyskinesias in Parkinson's disease: views from positron emission tomography studies

Levodopa‐induced dyskinesias (LIDs) and graft‐induced dyskinesias (GIDs) are serious and common complications of Parkinson's disease (PD) management following chronic treatment with levodopa or intrastriatal transplantation with dopamine‐rich foetal ventral mesencephalic tissue, respectively. Positron emission tomography (PET) molecular imaging provides a powerful in vivo tool that has been employed over the past 20 years for the elucidation of mechanisms underlying the development of LIDs and GIDs in PD patients. PET used together with radioligands tagging molecular targets has allowed the functional investigation of several systems in the brain including the dopaminergic, serotonergic, glutamatergic, opioid, endocannabinoid, noradrenergic and cholinergic systems. In this article the role of PET imaging in unveiling pathophysiological mechanisms underlying the development of LIDs and GIDs in PD patients is reviewed.     

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.     

The effect of diazepam sedation on cerebral glucose metabolism in Alzheimer's disease as measured using positron emission tomography

The effect of sedation induced by intravenous diazepam on cerebral glucose metabolic activity was examined with [18F]2-fluoro-2-deoxy-D-glucose (FDG) and positron emission tomography (PET) in five patients with probable Alzheimer's disease. Each subject was studied on 2 separate days: on one occasion at rest with eyes patched and ears open, and on the second when sedated with intravenous diazepam titrated to maintain stage II sleep by clinical and EEG criteria. Similar patterns of glucose uptake were observed in both the presence and the absence of sedation, but overall glucose utilization was depressed an average of 20% and was closely correlated with the amount of diazepam administered prior to the injection of FDG. The predominant temporoparietal hypometabolism and relative sparing of frontal metabolism observed in this disease are therefore not explained by differences in anxiety or activity level in this patient group. Utilization of diazepam sedation for PET study appears to be safe and may permit the study of patients otherwise unable to cooperate with FDG-PET procedures.     

Positron emission tomography in Alzheimer's disease

Twenty-one patients with a clinical diagnosis of dementia of the Alzheimer's type (DAT) and 29 healthy, age-matched controls were studied using positron emission tomography (PET) and [18F]2-fluoro-2-deoxy-D-glucose to measure regional cerebral glucose consumption in the resting state. Reductions in ratio measures of relative metabolism in some parietal, temporal, and frontal regions were found in mild, moderate, and severe DAT groups. A significant increase in right/left metabolic asymmetry, particularly in parietal regions, also was seen in mild and moderate groups. Only in the severely demented patients was the absolute cerebral metabolic rate reduced significantly from control values. Fourteen patients had repeated PET studies, but only those patients with moderate to severe dementia showed a decline in IQ over 6 to 15 months. There were no significant changes in metabolic measures over time. PET is useful in quantifying regional cerebral dysfunction in DAT, even in the early stages of the disease.     

Parkinson's disease: in vivo assessment of disease progression using positron emission tomography

Over the past two decades, positron emission tomography (PET) has provided valuable insights into the mechanisms of nigrostriatal degeneration in Parkinson's disease (PD). Furthermore, it allows the in vivo assessment of disease progression and the evaluation of treatment interventions. In this review, we shall discuss some of the issues and concerns that arise with the use of PET as a surrogate marker of disease progression in Parkinson's disease.     

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.     

[18F]T807, a novel tau positron emission tomography imaging agent for Alzheimer's disease

ObjectiveWe wished to develop a highly selective positron emission tomography (PET) imaging agent targeting PHF-tau in human Alzheimer's disease (AD) brains.MethodsTo screen potential tau binders, human AD brain sections were used as a source of native paired helical filament (PHF)-tau and Aβ rather than synthetic tau aggregates or Aβ fibrils generated in vitro to measure the affinity and selectivity of [¹⁸F]T807 to tau and Aβ. Brain uptake and biodistribution of [¹⁸F]T807 in mice were also tested.ResultsIn vitro autoradiography results show that [¹⁸F]T807 exhibits strong binding to PHF-tau-positive human brain sections. A dissociation constant (K_d) of [¹⁸F]T807 (14.6 nM) was measured using brain sections from the frontal lobe of AD patients. A comparison of autoradiography and double immunohistochemical staining of PHF-tau and Aβ on adjacent sections demonstrated that [¹⁸F]T807 binding colocalized with immunoreactive PHF-tau pathology, but did not highlight Aβ plaques. In vivo studies in mice demonstrated that [¹⁸F]T807 was able to cross the blood–brain barrier and washed out quickly.Conclusions[¹⁸F]T807 demonstrates high affinity and selectivity to PHF-tau as well as favorable in vivo properties, making this a promising candidate as an imaging agent for AD.