Recent imaging evidence in Alzheimer's disease suggests that neural involvement in early-stage disease is more complex than is encapsulated in the commonly held position of predominant mesial temporal lobe degeneration-there is also early posterior cingulate cortex and diencephalic damage. These findings suggest that early clinical Alzheimer's disease is underpinned by damage to an inter-connected network. If correct, this hypothesis would predict degeneration of the white matter pathways that connect this network. This prediction can be tested in vivo by diffusion magnetic resonance imaging. Most diffusion tensor imaging studies of white matter in neurodegenerative disorders such as Alzheimer's disease have concentrated on fractional anisotropy reductions and increased 'apparent' diffusivity; however, there is a lack of empirical biological evidence to assume that fractional anisotropy changes will necessarily capture the full extent of white matter changes in Alzheimer's disease. In this study, therefore, we undertook a comprehensive investigation of diffusion behaviour in Alzheimer's disease by analysing each of the component eigenvalues of the diffusion tensor in isolation to test the hypothesis that early Alzheimer's disease is associated with degeneration of a specific neural network. Using tract-based spatial statistics, we performed voxel-wise analyses of fractional anisotropy, axial, radial and mean diffusivities in 25 Alzheimer's disease patients compared with 13 elderly controls. We found that increased absolute (axial, radial and mean) diffusivities in Alzheimer's disease were concordant in a distribution consistent with the network hypothesis, highly statistically significant and far more sensitive than fractional anisotropy reductions. The former three measures identified confluent white matter abnormalities in parahippocampal gyrus and posterior cingulum, extending laterally into adjacent temporo-parietal regions as well as splenium and fornix. The caudal occipital lobe, temporal pole, genu and prefrontal white matter were relatively preserved. This distribution is highly consistent with expected predictions of tract degeneration from grey matter lesions identified by fluorodeoxyglucose positron emission tomography and structural magnetic resonance imaging. Concordant with results from these other imaging modalities, this pattern predominantly involves degeneration of the tracts connecting the circuit of Papez. These findings also highlight that early neuropathological processes are associated with changes of the diffusion ellipsoid that are predominantly proportional along all semi-principal axes.

The study of patients with semantic dementia, a variant of frontotemporal lobar degeneration, has emerged over the last two decades as an important lesion model for studying human semantic memory. Although it is well-known that semantic dementia is associated with temporal lobe degeneration, controversy remains over whether the semantic deficit is due to diffuse temporal lobe damage, damage to only a sub-region of the temporal lobe or even less severe damage elsewhere in the brain. The manner in which the right and left temporal lobes contribute to semantic knowledge is also not fully elucidated. In this study we used unbiased imaging analyses to correlate resting cerebral glucose metabolism and behavioural scores in tests of verbal and non-verbal semantic memory. In addition, a region of interest analysis was performed to evaluate the role of severely hypometabolic areas. The best, indeed the only, strong predictor of semantic scores across a set of 21 patients with frontotemporal lobar degeneration with semantic impairment was degree of hypometabolism in the anterior fusiform region subjacent to the head and body of the hippocampus. As hypometabolism in the patients' rostral fusiform was even more extreme than the abnormality in other regions with putative semantic relevance, such as the temporal poles, the significant fusiform correlations cannot be attributed to floor-level function in these other regions. More detailed analysis demonstrated more selective correlations: left anterior fusiform function predicted performance on two expressive verbal tasks, whereas right anterior fusiform metabolism predicted performance on a non-verbal test of associative semantic knowledge. This pattern was further supported by an additional behavioural study performed on a wider cohort of patients with semantic dementia, in which the patients with more extensive right-temporal atrophy (when matched on degree of naming deficit to a set of cases with more extensive left temporal atrophy) were significantly more impaired on the test of non-verbal semantics. Our preferred interpretation of this laterality effect involves differential strength of connectivity between different regions of a widespread semantic network in the human brain.

Objective To evaluate a cognitive test, the TYM (“test your memory”), in the detection of Alzheimer’s disease.Design Cross sectional study.Setting Outpatient departments in three hospitals, including a memory clinic.Participants 540 control participants aged 18-95 and 139 patients attending a memory clinic with dementia/amnestic mild cognitive impairment.Intervention Cognitive test designed to use minimal operator time and to be suitable for non-specialist use.Main outcome measures Performance of normal controls on the TYM. Performance of patients with Alzheimer’s disease on the TYM compared with age matched controls. Validation of the TYM with two standard tests (the mini-mental state examination (MMSE) and the Addenbrooke’s cognitive examination-revised (ACE-R)). Sensitivity and specificity of the TYM in the detection of Alzheimer’s disease.Results Control participants completed the TYM with an average score of 47/50. Patients with Alzheimer’s disease scored an average of 33/50. The TYM score shows excellent correlation with the two standard tests. A score of ≤42/50 had a sensitivity of 93% and specificity of 86% in the diagnosis of Alzheimer’s disease. The TYM was more sensitive in detection of Alzheimer’s disease than the mini-mental examination, detecting 93% of patients compared with 52% for the mini-mental state exxamination. The negative and positive predictive values of the TYM with the cut off of ≤42 were 99% and 42% with a prevalence of Alzheimer’s disease of 10%. Thirty one patients with non-Alzheimer dementias scored an average of 39/50.Conclusions The TYM can be completed quickly and accurately by normal controls. It is a powerful and valid screening test for the detection of Alzheimer’s disease.

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