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Reductions in regional cerebral perfusion, particularly in the posterior temporo-parietal lobes, are well recognized in Alzheimer's disease. We set out to correlate perfusion changes, using (99m)Tc-HMPAO single photon emission tomography (SPET), with the pathological stage of Alzheimer's disease. The 'Braak stage' of the distribution of neurofibrillary pathology in post-mortem brains was used to classify SPET scans taken in life from a mixed (dementia and control) elderly population into the entorhinal stage (n = 23 subjects), limbic stage (n = 30 subjects) and neocortical stage (n = 36 subjects) Alzheimer's disease pathology. The SPET scans were then registered to a common, standard Talaraich space, and single template scans produced for each pathological stage. Comparison of these templates revealed an evolution in the pattern of reduction in regional perfusion. Additional comparisons were performed using earlier SPET scans obtained 5 years before death. For comparisons between templates, a threshold of 10% perfusion change was chosen so as to be clinically relevant as well as statistically significant. Reduced perfusion appears between the entorhinal and limbic stages in the anterior medial temporal lobe, subcallosal area, posterior cingulate cortex, precuneus and possibly the supero-anterior aspects of the cerebellar hemispheres. Large posterior temporo-parietal perfusion defects then appear between the limbic and neocortical stages, before finally large frontal lobe perfusion defects. The time course of these perfusion defects appears relatively long, suggesting that perfusion changes may have scope to be a diagnostic aid in staging Alzheimer's disease in life. The reduction in anterior medial temporal lobe perfusion may have future relevance on modern high resolution SPET and PET systems and also perfusion-type MRI sequences.

Because the clinical picture of Alzheimer disease (AD) is often difficult to discriminate from other dementing illnesses, the diagnosis of AD requires neuropathological confirmation. However, for the pathological diagnosis of AD, there are no unanimously accepted criteria. The three currently used sets of pathological criteria (Khachaturian: Khachaturian, Arch Neurol 1985;42:1097-105; Tiemy: Tierney et al., Can J Neurol Sci 1986; 13:424-6; CERAD: Mirra et al., Neurology 1991;41:479-86) for the disease differ from each other considerably. We applied these criteria to the first 43 consecutive subjects (37 demented) with no neuropathology other than AD-type pathology from autopsies after longitudinal prospective clinical study in the Oxford Project to Investigate Memory and Ageing (OPTIMA). The results show that the CERAD category of definite AD corresponds closely with the cases that fulfill Tierney A3 inclusion criteria for AD. The combined CERAD categories of possible, probable, and definite AD correspond closely to cases fulfilling Khachaturian criteria forAD. The influence of a clinical diagnosis of dementia when Khachaturian and CERAD criteria were applied was considerable because between 9.3% and 90.7% of patients would have been categorized differently depending on whether clinical dementia was present or absent.

There is evidence consistent with the hypothesis that inflammatory and immune mechanisms are involved in the pathogenesis of Alzheimer disease (AD). We have investigated whether the levels of inflammatory associated proteins in serum or lumbar cerebrospinal fluid (CSF) reflect the progressive cognitive decline and brain atrophy of AD-patients. Levels of interleukin-1beta(IL-1beta), IL-1 receptor antagonist (IL-1ra), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), the soluble TNF receptors type I and II (sTNFR I and II), and the acute phase protein alpha1-antichymotrypsin (x1-ACT) were determined in paired serum and CSF samples taken yearly over a period of 2-5 years from pathologically confirmed AD patients (n = 8) and normal controls or non-AD subjects with other CNS pathology (n = 9). No significant differences were found between AD subjects and controls in the mean levels of the above mediators. There was also no correlation in either subject group between the levels of these inflammatory mediators in serum or CSF, and the change in cognitive status or the progression of the atrophy of the medial temporal lobe measured by X-ray computed tomography (CT). The concentrations of IL-1beta, IL-6, and TNF-alpha were determined in brain tissue specimens of five to nine different brain regions in six of the AD patients and four of the non-AD subjects. The levels of IL-1beta and IL-6 in the various brain regions were not significantly different in the AD and the non-AD group. However, in AD patients the level of TNF-alpha was significantly lower in the frontal cortex (32%, p = 0.024), the superior temporal gyrus (57%, p = 0.021), and the entorhinal cortex (49%, p = 0.009) compared with non-AD subjects. Low levels of TNF-alpha in the brain areas that showed neuropathology in AD may indicate a dysregulation of the inflammatory process in AD. Despite this finding, this study does not support the use of measurements of any of the inflammatory mediators investigated here as a diagnostic parameter for AD, due the large overlap in the levels of these factors between AD patients and other subjects, and the poor relation to clinical signs of AD.

We have analyzed the tendency of amyloid load, neuritic plaques and neurofibrillary tangles (NFT) in the hippocampus and neocortex to occur in clusters in 49 consecutive cases of Alzheimer's disease (AD). This clustering tendency of the pathology was analysed in relation to severity of clinical disease assessed within 6 months before death, duration and age at onset of disease and at death. Amyloid plaques showed only a slight tendency to cluster together while neuritic plaques and, even more, NFT were clearly clustered. A greater clustering tendency was associated with more severe clinical impairment with particularly strong correlations being found between the clustering tendency of NFT in the hippocampus and clinical memory deficit, and between the clustering tendency of NFT in the parietal neocortex and overall cognitive deficit. Neuritic plaques showed similar but less pronounced and robust correlations between clustering and cognitive status. In the hippocampus NFT clustering was also negatively correlated with age at death, but not duration of disease nor age of disease onset. We conclude that clustering characterises neuritic pathology but not diffuse amyloid deposits and significantly affects cognition. The discrepancies between the group diagnosed as AD-only and the patient group that contained all patients, including the ones with mixed pathology, lead us to believe that any additional pathology might have a significant effect on the cognitive status of AD patients.