Objective: To investigate the extent and the nature of white matter tissue damage of patients with Alzheimer's disease using diffusion tensor magnetic resonance imaging (DT-MRI). Background: Although Alzheimer's disease pathology mainly affects cortical grey matter, previous pathological and MRI studies showed that also the brain white matter of patients is damaged. However, the nature of Alzheimer's disease associated white matter damage is still unclear. Methods: Conventional and DT-MRI scans were obtained from16 patients with Alzheimer's disease and 10 sex and age matched healthy volunteers. The mean diffusivity (D), fractional anisotropy (FA), and inter-voxel coherence (C) of several white matter regions were measured. Results: D was higher and FA lower in the corpus callosum, as well as in the white matter of the frontal, temporal, and parietal lobes from patients with Alzheimer's disease than in the corresponding regions from healthy controls. D and FA of the white matter of the occipital lobe and internal capsule were not different between patients and controls. C values were also not different between patients and controls for any of the regions studied. Strong correlations were found between the mini mental state examination score and the average overall white matter D (r=0.92, p<0.001) and FA (r=0.78; p<0.001). Conclusions: White matter changes in patients with Alzheimer's disease are likely to be secondary to wallerian degeneration of fibre tracts due to neuronal loss in cortical associative areas.

Fluency tasks have been widely used to tap the voluntary generation of responses. The anatomical correlates of fluency tasks and their sensitivity and specificity have been hotly debated. However, investigation of the cognitive processes involved in voluntary generation of responses and whether generation is supported by a common, general process (e.g. fluid intelligence) or specific cognitive processes underpinned by particular frontal regions has rarely been addressed. This study investigates a range of verbal and non-verbal fluency tasks in patients with unselected focal frontal (n=47) and posterior (n=20) lesions. Patients and controls (n=35) matched for education, age and sex were administered fluency tasks including word (phonemic/semantic), design, gesture and ideational fluency as well as background cognitive tests. Lesions were analysed by standard anterior/posterior and left/right frontal subdivisions as well as a finer-grained frontal localization method. Thus, patients with right and left lateral lesions were compared to patients with superior medial lesions. The results show that all eight fluency tasks are sensitive to frontal lobe damage although only the phonemic word and design fluency tasks were specific to the frontal region. Superior medial patients were the only group to be impaired on all eight fluency tasks, relative to controls, consistent with an energization deficit. The most marked fluency deficits for lateral patients were along material specific lines (i.e. left-phonemic and right-design). Phonemic word fluency that requires greater selection was most severely impaired following left inferior frontal damage. Overall, our results support the notion that frontal functions comprise a set of specialized cognitive processes, supported by distinct frontal regions.

Memory loss is one of the first symptoms of typical Alzheimer's disease (AD), for which there are no effective therapies available. The precuneus (PC) has been recently emphasized as a key area for the memory impairment observed in early AD, likely due to disconnection mechanisms within large-scale networks such as the default mode network (DMN). Using a multimodal approach we investigated in a two-week, randomized, sham-controlled, double-blinded trial the effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) of the PC on cognition, as measured by the Alzheimer Disease Cooperative Study Preclinical Alzheimer Cognitive Composite in 14 patients with early AD (7 females). TMS combined with electroencephalography (TMS-EEG) was used to detect changes in brain connectivity. We found that rTMS of the PC induced a selective improvement in episodic memory, but not in other cognitive domains. Analysis of TMS-EEG signal revealed an increase of neural activity in patients' PC, an enhancement of brain oscillations in the beta band and a modification of functional connections between the PC and medial frontal areas within the DMN. Our findings show that high-frequency rTMS of the PC is a promising, non-invasive treatment for memory dysfunction in patients at early stages of AD. This clinical improvement is accompanied by modulation of brain connectivity, consistently with the pathophysiological model of brain disconnection in AD.