This study investigated cerebral glucose metabolism in very early Alzheimer's disease, before a clinical diagnosis of probable Alzheimer's disease is possible, using [18F]fluorodeoxyglucose positron emission tomography. First, 66 patients with probable Alzheimer's disease with a spectrum of dementia severity (Mini-Mental State Examination score, 0-23) were recruited and studied. Cortical metabolic activity was analyzed topographically using three-dimensional stereotactic surface projections. Regression analysis was performed for each brain pixel to predict metabolic patterns of very early disease. Predictions were tested prospectively in a group of 8 patients who complained only of memory impairment without general cognitive decline (Mini-Mental State Examination score, 25 +/- 1) at the time of scanning but whose condition later progressed to probable Alzheimer's disease. Both results were compared to cerebral metabolic activity in 22 age-similar normal control subjects. Prediction and analysis of actual patients consistently indicated marked metabolic reduction (21-22%) in the posterior cingulate cortex and cinguloparietal transitional area in patients with very early Alzheimer's disease. Mean metabolic reduction in the posterior cingulate cortex was significantly greater than that in the lateral neocortices or parahippocampal cortex. The result suggests a functional importance for the posterior cingulate cortex in impairment of learning and memory, which is a feature of very early Alzheimer's disease.

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Metabolic Reduction in the Posterior Cingulate Cortex in Very Early Alzheimer's Disease

From over 100 children studied with 2-deoxy-2[18F]fluoro-D-glucose and positron emission tomography we selected 29 children (aged 5 days to 15.1 years) who had suffered transient neurological events not significantly affecting normal neurodevelopment. These 29 children were reasonably representative of normal children and provided an otherwise unobtainable population in which to study developmental changes in local cerebral metabolic rates for glucose (lCMRGlc). In infants less than 5 weeks old lCMRGlc was highest in sensorimotor cortex, thalamus, brainstem, and cerebellar vermis. By 3 months, lCMRGlc had increased in parietal, temporal, and occipital cortices; basal ganglia; and cerebellar cortex. Frontal and dorsolateral occipital cortical regions displayed a maturational rise in lCMRGlc by approximately 6 to 8 months. Absolute values of lCMRGlc for various grey matter regions were low at birth (13 to 25 mumol/min/100 gm), and rapidly rose to reach adult values (19 to 33 mumol/min/100 gm) by 2 years. lCMRGlc continued to rise until, by 3 to 4 years, it reached values of 49 to 65 mumol/min/100 gm in most regions. These high rates were maintained until approximately 9 years, when they began to decline, and reached adult rates again by the latter part of the second decade. The highest increases of lCMRGlc over adult values occurred in cerebral cortical structures; lesser increases were seen in subcortical structures and in the cerebellum. This time course of lCMRGlc changes matches that describing the process of initial overproduction and subsequent elimination of excessive neurons, synapses, and dendritic spines known to occur in the developing brain. The determination of changing metabolic patterns accompanying normal brain development is a necessary prelude to the study of abnormal brain development with positron emission tomography.

Positron emission tomography study of human brain functional development.

The availability of neuroimaging technology has spurred a marked increase in the human cognitive neuroscience literature, including the study of cognitive ageing. Although there is a growing consensus that the ageing brain retains considerable plasticity of function, currently measured primarily by means of functional MRI, it is less clear how age differences in brain activity relate to cognitive performance. The field is also hampered by the complexity of the ageing process itself and the large number of factors that are influenced by age. In this Review, current trends and unresolved issues in the cognitive neuroscience of ageing are discussed.

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The cognitive neuroscience of ageing

ContextDeficits in cerebral glucose utilization have been identified in patients
with cognitive dysfunction attributed to various disease processes, but their
prognostic and diagnostic value remains to be defined.ObjectiveTo assess the sensitivity and specificity with which cerebral metabolic
patterns at a single point in time forecast subsequent documentation of progressive
dementia.Design, Setting, and PatientsPositron emission tomography (PET) studies of [18F]fluorodeoxyglucose
in 146 patients undergoing evaluation for dementia with at least 2 years'
follow-up for disease progression at the University of California, Los Angeles,
from 1991 to 2000, and PET studies in 138 patients undergoing evaluation for
dementia at an international consortium of facilities, with histopathological
diagnoses an average of 2.9 years later, conducted from 1984 to 2000.Main Outcome MeasuresRegional distribution of [18F]fluorodeoxyglucose in each
patient, classified by criteria established a priori as positive or negative
for presence of a progressive neurodegenerative disease in general and of
Alzheimer disease (AD) specifically, compared with results of longitudinal
or neuropathologic analyses.ResultsProgressive dementia was detected by PET with a sensitivity of 93% (191/206)
and a specificity of 76% (59/78). Among patients with neuropathologically
based diagnoses, PET identified patients with AD and patients with any neurodegenerative
disease with a sensitivity of 94% and specificities of 73% and 78%, respectively.
The negative likelihood ratio of experiencing a progressive vs nonprogressive
course over the several years following a single negative brain PET scan was
0.10 (95% confidence interval, 0.06-0.16), and the initial pattern of cerebral
metabolism was significantly associated with the subsequent course of progression
overall (P<.001).ConclusionIn patients presenting with cognitive symptoms of dementia, regional
brain metabolism was a sensitive indicator of AD and of neurodegenerative
disease in general. A negative PET scan indicated that pathologic progression
of cognitive impairment during the mean 3-year follow-up was unlikely to occur.

https://jamanetwork.com/journals/jama/articlepdf/194338/JOC10908.pdf

Positron emission tomography in evaluation of dementia: Regional brain metabolism and long-term outcome.

Current knowledge is summarized about long-term memory systems of the human brain, with memory systems defined as specific neural networks that support specific mnemonic processes. The summary integrates convergent evidence from neuropsychological studies of patients with brain lesions and from functional neuroimaging studies using positron emission tomography (PET) or functional magnetic resonance imaging (fMRI). Evidence is reviewed about the specific roles of hippocampal and parahippocampal regions, the amygdala, the basal ganglia, and various neocortical areas in declarative memory. Evidence is also reviewed about which brain regions mediate specific kinds of procedural memory, including sensorimotor, perceptual, and cognitive skill learning; perceptual and conceptual repetition priming; and several forms of conditioning. Findings are discussed in terms of the functional neural architecture of normal memory, age-related changes in memory performance, and neurological conditions that affect memory such as amnesia, Alzheimeris disease, Parkinsonis disease, and Huntingtonis disease.

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Cognitive neuroscience of human memory

The cerebral blood flow, oxygen extraction and oxygen utilization has been measured regionally in 22 dements, and 14 aged normal volunteers. Ten demented patients were studied twice at a six-month interval from initial measurements. The use of a steady-state 15O technique and positron tomography for measuring regional cerebral blood flow, regional oxygen extraction fraction and mean cerebral oxygen utilization is discussed. The limitations of measurements are reviewed in the light of the present results and the current state of technological development in positron emission tomography is discussed. A decline in cerebral blood flow and mean cerebral oxygen utilization was correlated with increasing severity of dementia in both degenerative and vascular dements. The decline was coupled, both for the cerebral hemisphere as a whole and regionally. There was no increase in oxygen extraction ratio globally, and therefore no evidence to support the existence of a chronic ischaemic brain syndrome. Focal abnormalities in oxygen utilization were observed for both vascular and degenerative groups. In the vascular group, parietal defects were the most pronounced. Individual derangements of the regional pattern varied, reflecting the different unique patterns of ischaemic damage in these patients. In the degenerative group, parietal and temporal defects were seen in the less severe group, but a profound depression in the frontal regions with relative sparing of occipital area characterized the severe degenerative dements.

Regional cerebral oxygen supply and utilization in dementia. A clinical and physiological study with oxygen-15 and positron tomography.

The oxygen-15 inhalation technique has been applied to the quantitation of regional CBF, CMRO2 and OER with positron emission tomography. The introduction of corrections for gamma-ray attenuation, and for recirculation, has allowed us to obtain values for CBF, CMRO2 and OER in close agreement with values obtained using other techniques. In 27 normal volunteers mean CMRO2 shows values ranging from 4.98 to 3.79 ml/100/min, depending on the region evaluated. Mean CBF values range from 55.3 to 38.8 ml/100ml/min. Mean OER is more constant, ranging from 0.56 to 0.49, with a mean of 0.53 +/- 0.04, thus reflecting the close matching between metabolism and blood supply. We have further identified corrections for cerebral blood volume, which is measurable, and for water partition coefficient, which remains uncertain. In preliminary studies these corrections decrease the OER over the physiological range of flow by 10%, with a 15% lower CMRO2. The reproducibility of the results and the effects of aging have been studied. A series of 27 studies on acute ischaemic CVD are reported. The course of the clinical condition has been correlated with the quantitation of oxygen utilization and blood flow performed at different intervals from the onset of symptoms.

C. Pozzilli

Papers

Regional cerebral oxygen supply and utilization in dementia. A clinical and physiological study with oxygen-15 and positron tomography.

CMRO2 and CBF by the oxygen-15 inhalation technique. Results in normal volunteers and cerebrovascular patients.

Cerebral energy relationships in dementia: a prospective study with positron emission tomography.