R. S. J. Frackowiak

Regional cerebral blood flow during volitional expiration in man: a comparison with volitional inspiration.

1. Positron emission tomographic (PET) imaging of regional cerebral blood flow (rCBF), using a new 3‐dimensional technique of data collection, was used to identify areas of neuronal activation associated with volitional inspiration and separately with volitional expiration in five normal male subjects. A comparison of the activated areas was also undertaken to isolate regions specific for one or other active task. 2. Scans were performed during intravenous infusion of H2(15)O under conditions of (a) volitional inspiration with passive expiration, (b) passive inspiration with volitional expiration and (c) passive inspiration with passive expiration. Four measurements in these three conditions were performed in each subject. Breathing pattern was well matched between conditions. 3. Regional increases in brain blood flow, due to increased neural activity associated with either active inspiration or active expiration, were derived using a pixel by pixel comparison of images obtained during the volitional and passive ventilation phases. Data were pooled from all runs in all subjects and were then processed to detect statistically significant (P < 0.05) increases in rCBF comparing active inspiration with passive inspiration and active expiration with passive expiration. 4. During active inspiration significant increases in rCBF were found bilaterally in the primary motor cortex dorsally just lateral to the vertex, in the supplementary motor area, in the right lateral pre‐motor cortex and in the left ventrolateral thalamus. 5. In active expiration significant increases in rCBF were found in the right and left primary motor cortices dorsally just lateral to the vertex, the right and left primary motor cortices more ventrolaterally, the supplementary motor area, the right lateral pre‐motor cortex, the ventrolateral thalamus bilaterally, and the cerebellum. 6. Using this modified and more sensitive PET technique, these findings essentially replicate those for volitional inspiration obtained in a previous study. For volitional expiration the areas activated are more extensive, but overlap with those involved in volitional inspiration. 7. The technique used has been successful in demonstrating the regions of the brain involved in the generation of volitional breathing, and probably in the volitional modulation of automatic breathing patterns such as would be required for the production of speech.

Progressive degeneration of the right temporal lobe studied with positron emission tomography.

A 79 year old man with a twelve year progressive history of prosopagnosia and recent naming difficulty, in whom other intellectual skills were preserved, is described. Positron emission tomography (PET) revealed an area of right temporal lobe hypometabolism, with an additional area of less severe hypometabolism at the left temporal pole. This may represent an example of progressive focal cortical degeneration similar to that associated with primary progressive dysphasia, but affecting the right temporal lobe.

Progressive loss of speech output and orofacial dyspraxia associated with frontal lobe hypometabolism.

Three patients are described with slowly progressive loss of speech and dysarthria associated with orofacial dyspraxia, initially with intact written language, who subsequently developed more widespread cognitive abnormalities. Positron emission tomography (PET) revealed bifrontal hypometabolism in all of the patients, most marked in the inferior and lateral portions of both frontal lobes, with some extension into the parietal and temporal cortices in one case. These patients may represent a further example of focal progressive cortical degeneration.

Alzheimer's Disease Families with Amyloid Precursor Protein Mutationsa

Early onset Familial Alzheimers Disease (FAD) is an autosomal dominant disease with apparent complete penetrance. It is genetically heterogeneous with some families carrying mutations in the amyloid precursor protein (APP) gene which segregate with the disease. In addition, there is allelic heterogeneity with four mutations associated with FAD. Three mutations have been reported at APP 717, just distal to the C‐terminus of the β‐amyloid domain, APP 717 val‐ile, APP 717 val‐phe, and APP 717 val‐gly, which are associated with autopsy‐proven Alzheimers disease (AD). APP 670/671 lies at the N terminus of the β‐amyloid domain and is associated with clinically diagnosed FAD in two Swedish families. FAD tends to have prominent myoclonus and this is shared by the cases with APP mutations. In two unrelated UK families with APP 717 val‐ile mutations there was early prominent memory impairment with dyscalculia proceeding to generalized cognitive impairment with a lack of insight. There was a late development of a gait disturbance with extrapyramidal features in some members. Positron emission tomography (PET) with fluorodeoxyglucose demonstrated posterior bitemporal biparietal hypometabolism in one case. Magnetic resonance imaging (MRI) showed generalized cerebral atrophy particularly affecting the temporal lobes and hippocampus. At autopsy, a single case showed extensive β‐amyloid deposition with congophilic angiopathy and widespread senile plaques and neurofibrillary tangles. The cytoskeletal pathology associated with abnormally phosphorylated tau was similar to cases of sporadic AD. In addition, there were widespread cortical and subcortical Lewy bodies. A single family with the APP 717 val‐gly mutation also showed prominent myoclonus, lack of insight, and seizures, PET, in a single case, showed classical biparietal bitemporal hypometabolism. Autopsy, in a single case, showed diffuse deposits of β‐amyloid throughout the cortex with frequent neuritic plaques and neurofibrillary tangles. No other inclusion bodies were seen. There was severe congophilic angiopathy. The age at onset of APP mutations is around 50 years of age by contrast to other early onset FAD pedigrees.

Clinical and Neuroimaging Features of Familial Alzheimer's Diseasea

Subtle phenotypic differences between familial Alzheimers disease (FAD) pedigrees can be identified which may reflect the genetic and allelic heterogeneity of the disease. Positron emission tomography (PET) of APP mutation and chromosome 14‐linked FAD pedigree members reveals biparietal bitemporal hypometabolism. Scanning of asymptomatic at‐risk individuals reveals a similar, but quantitatively less severe, pattern of hypometabolism.

Positron emission tomography in familial Alzheimer disease.

SummaryThere is increasing evidence for genetic heterogeneity in Alzheimer disease. A longitudinal clinical and imaging study had been established in order to determine whether specific phenotypic profiles are present in aetiologically distinct familial Alzheimer disease (FAD) pedigrees. [18F]fluorodeoxyglucose positron emission tomography has been used in conjunction with statistical parametric mapping to determine the relative distribution of hypometabolism. A parietotemporal deficit has been observed in individuals from both amyloid precursor protein mutation and chromosome 14 linked FAD families. Preliminary data from asymptomatic individuals at risk of FAD shows similar, although a less extensive pattern of deficit.

Patterns of Cerebral Metabolism in Degenerative Dementia

Alzheimer’s disease is the commonest cause of primary degenerative dementia and classically presents with early memory disturbance and subsequent impairment of language and visuospatial functions. Characteristically positron emission tomography (PET) scanning reveals posterior biparietal and bitemporal hypometabolism. Increasingly, clinical subtypes of Alzheimer’s disease are being recognized, although it is not yet clear whether these represent biological distinctions. The most clearly defined is the distinction between familial and sporadic cases. PET studies to date, however, reveal no obvious differences. Similarly, both early- and late-onset cases may demonstrate posterior biparietal hypometabolism. A further distinction is that drawn between rigid and non-rigid cases. It has been argued that Parkinsonian features are a frequent finding in Alzheimer’s disease and may be due to coincidental Lewy body formation. We have examined 20 patients for the presence of extrapyramidal features and confirm that rigidity may be demonstrated in a number of these cases, but this is not always accompanied by the bradykinesia that is characteristic of Parkinson’s disease. In addition, [18F]fluorodopa uptake studied with PET shows no significant differences between rigid and non-rigid Alzheimer’s patients, or between patients and healthy controls, in contrast to the marked reduction in putamen uptake in Parkinson’s disease. These findings suggest that extranigral factors contribute to the rigidity in this group. In addition to Alzheimer’s disease, non-Alzheimer primary degenerative dementias are being increasingly recognized. These include the frontal lobe dementias and focal cortical degenerations, such as primary progressive dysphasia, which may progress to a late generalized cognitive impairment. PET scanning in these groups reveals neither diffuse frontal lobe hypometabolism in the frontal lobe dementia group or focal hypometabolism in the left temporal lobe in patients with primary progressive dysphasia.

Oxygen metabolism in the degenerative dementias

Positron Emission Tomography (PET) is a quantitative technique which can be used to measure regional values of cerebral metabolism in the living human at rest. While structural scans (CT or MRI) may be normal in the degenerative dementias, or show generalised atrophy, functional imaging techniques allow differentiation of subtypes of dementias according to patterns of dysmetabolism. This paper describes some of the variety of alterations in patterns of oxygen metabolism that may be observed in degenerative cognitive disorders, and their correlations with clinical subtypes.