Summary of main findings

The first part of the thesis is concerned with the clinical and neuropsychological features of our cohort of AD and DLB subjects. As expected, DLB was characterised by a subcortical pattern of neuropsychological impairment with attentional and executive dysfunction and less impaired memory compared to AD, consistent with the notion that subcortical change predominates in DLB. The visual system was also impaired with the majority of DLB cases reporting visual hallucinations and having difficulty with visuo-perceptual based tasks.

The main finding of the structural GM analysis was of relative preservation of medial temporal lobe structures in DLB compared to AD. This was highly significant in the bilateral parahippocampal gyri and left hippocampus (p <0.05, corrected) and consistent with the neuropsychological profile observed of relatively preserved new learning (compared to AD). There was much less regional volumetric GM loss in DLB than AD. Affected areas included the temporal, parietal, occipital and subcortical structures in DLB although only reached statistical significance when corrected for multiple comparisons in the temporal regions (including amygdala) and caudate tail. Therefore, at a similar level of dementia severity, there was more atrophy in AD than DLB, which suggests that there are differing pathological mechanisms underpinning the clinical and neuropsychological features of the conditions.

Microstructural changes in DLB were therefore investigated using diffusion tensor imaging. As expected, changes in the white matter tracts were less extensive in DLB than in AD. In DLB, the regional pattern of change (FA) compared with controls had a posterior predominance affecting the visual association areas and subcortical structures which, by contrast to the structural changes, were all highly significant, (p <0.05, corrected).

Chapter 7 Conclusions and future studies The letter fluency task was used as an executive function probe and we found a significant pattern of correlation (p<0.05, corrected) in DLB affecting frontal, parietal and subcortical structures, a pattern not observed in AD, highlighting the potential differing pathological mechanisms between the diseases.

7.2 Conclusions Cortical atrophy

Cerebral GM atrophy is largely caused by the loss of neurons and synapses. In contrast to DLB, neurodegeneration and particularly synaptic loss has been found to be associated with the clinical features of AD (Terry et al., 1991). Our finding of less global GM loss in DLB compared to AD was consistent with another large VBM study (Whitwell et al., 2007b). Given that the dementia groups were well matched for age, dementia severity and level of education, it indicates that DLB and AD have differing pathological substrates underpinning the clinical features with AD resulting in more neuronal and synaptic loss than DLB. Furthermore, medial temporal lobe atrophy on structural imaging has been associated with the presence and severity of AD neuropathology (Gosche et al., 2002; Jack et al., 2002) and is a useful biomarker in separating AD from healthy controls (Scheltens et al., 2002). We found significantly less atrophy in the medial temporal lobes structures in DLB when compared to AD, which was also consistent with the neuropsychological profile observed of relatively preserved new learning in the DLB group.

AD pathology commonly coexists in cases of DLB. Large amounts of AD neuritic pathology can mask the characteristic features of DLB (McKeith et al., 2005). Given that our DLB cohort were selected based on their clinical phenotype – having at least 2 out of 3 of the core clinical features, they were less likely to have large amounts of concomitant AD neuritic pathology. It is therefore possible that the relatively little structural GM loss observed in DLB may reflect the lesser burden of AD pathology in this group.

Subcortical structures

The thalamus organises and processes information between the subcortical and cortical structures with one of its functions being maintenance of consciousness. Similar to other studies, we did not find significant structural change in the thalamus in DLB (Whitwell et al., 2007b; Burton et al., 2002). However, we found small areas of reduced FA in the thalamus in DLB compared to AD, and we also found increased thalamic MD in DLB compared to controls. Functional imaging studies using SPECT have reported increased thalamic perfusion and a pattern of covariance with occipital hypoperfusion (Shimizu et al., 2008) and increased thalamic perfusion has also been shown to be associated with cognitive fluctuation in DLB (O'Brien et al., 2005). Given these findings, along with the prominent attentional deficits and the cognitive fluctuation observed in DLB, further studies are warranted to investigate thalamic changes in more detail using DTI ROI or tractography methods in combination with perfusion imaging.

Visual association areas

Given the early and prominent visuo-perceptual dysfunction in DLB, the finding of significant FA change preferentially affecting the parieto-occipital white matter tracts (part of the visual association areas), with relative sparing of the frontal white matter tracts was of interest. The ventral visual stream involves a connection from the primary visual cortex in the occipital lobe via the inferior longitudinal fasciculus to the inferior temporal gyrus and parahippocampal gyrus, areas which have been found to be associated with Lewy related pathology and visual hallucinations in pathological studies (Harding et al., 2002). Other DTI studies have found changes in the precuneus, inferior longitudinal fasciculus and occipital areas (Kantarci et al., 2010; Firbank et al., 2007b; Bozzali et al., 2005) and functional imaging studies using SPECT (Colloby et al., 2002) and PET (Imamura et al., 1997) have also reported precuneal and occipital hypoperfusion and occipital hypometabolism respectively without significant structural GM loss (Middelkoop et al., 2001). It is therefore possible that the functional imaging changes observed reflect damage to the white matter tracts and potentially contribute to the visuo-perceptual dysfunction observed in DLB. Further ROI studies of the dorsal and ventral visual streams

Chapter 7 Conclusions and future studies investigating the diffusion, perfusion and metabolic changes in combination along with clinical and neuropsychological correlates may help to address this.

Executive function

DLB was associated with more prominent executive dysfunction than AD. This was thought to be at least partly mediated by the striatal dopaminergic deficiency in DLB given the importance of the fronto-striatal system in executive function. Our finding of a significant correlation between letter fluency and FA and MD white matter tract change in DLB highlight the potential differing pathologic mechanisms between AD and DLB. It suggests that DTI may be a more sensitive imaging modality than structural T1 imaging to detect pathological change in DLB. Indeed, further studies are required to address this. In particular, longitudinal studies to review areas more vulnerable to white matter tract change, and pathological verification studies to help address what causes the observed diffusion tensor imaging changes observed.