Neuroimaging correlates of progressive cognitive decline and clinical symptoms in prodromal Lewy body disease. A multimodal imaging study

Ph. D. Thesis.Introduction There has been an interest in earlier diagnosis of cognitive impairment at the prodromal stage. Mild cognitive impairment (MCI) is a prodromal cognitive phenotype of dementia. Differentiating MCI with Lewy bodies (MCI-LB) and MCI due to AD (MCI-AD) using clinical features alone is challenging and biomarkers are likely to aid diagnosis. This thesis investigated whether cross-sectional structural magnetic resonance imaging (MRI) or repeat 123I-FP-CIT single photon emission tomography (SPECT) could be utilised to differentiate between MCI-LB and MCI-AD. Methods Prospective repeat 133I-FP-CIT SPECT study: 85 subjects were included in this analysis, consisting of; healthy controls (HC) (n=29), MCI-AD (n=19), possible MCI-LB (n=10), probable MCI-LB (n=27). All subjects underwent comprehensive clinical and neuropsychological assessment as well as repeat 123I-FP-CIT SPECT and baseline cardiac 123I-MIBG scintigraphy. Cross- sectional MRI study: 97 subjects were included in this analysis, consisting of; HC (n=31), MCIAD (n=32), probable MCI-LB (n=34). All subjects underwent comprehensive clinical and neuropsychological assessment as well as baseline 123I-FP-CIT SPECT, cardiac 123I-MIBG scintigraphy and structural magnetic resonance imaging. Results Progressive dopaminergic loss was detected in MCI-LB in excess of HC, with mean annual striatal decline of 6% in the MCI-LB cohorts. MCI-AD had no difference in longitudinal striatal uptake when compared to HC. Structural MRI data found: (1) grey matter volume loss in the frontal and temporal lobes in MCI-LB compared to HC, (2) bilateral cerebellar volume reduction in MCI-LB compared to iii MCI-AD, (3) no relative preservation of the medical temporal lobe in MCI-LB compared to MCI-AD, (4) no cortical thickness difference between MCI-LB and MCI-AD (5) thalamic volume loss and relative preservation of the amygdala in MCI-LB compared to MCI-AD. Conclusion Sequential 123I-FP-CIT SPECT imaging is a promising biomarker for identifying MCI-LB. Structural MRI showed no difference in cortical indexes but some differences in subcortical and cerebellar measures between MCI-LB and MCI-AD

Discovery and characterization of LRRK2: Gene responible for PARK8-linked Parkinson disease.

Parkinson disease (PD) is an incurable movement disorder clinically characterized by resting tremor, bradykinesia and other cardinal features. A Japanese kindred with autosomal dominant PD showed linkage to a novel locus on chromosome 12pl 1.2-ql3.1, subsequently given the designation PARK8. A British family showed linkage to the same region on chromosome 12, encompassing PARK8, with a maximal LOD score of 3.55. Genes within a 1-LOD support interval were subsequently prioritized for sequencing. A tyrosine to cysteine substitution at amino acid 1699 (Y1699C) that segregated with disease in the British family was discovered in the gene LRRK2. Subsequent studies demonstrated that mutations within LRRK2 are the most common genetic cause of PD, accounting for approximately 2-3% of apparently sporadic PD, 7-8% of familial PD and as much as 40% of PD in North African Arabic populations. LRRK2 is large protein consisting of multiple protein interaction motifs as well as GTPase and kinase domains. Analysis of LRRK2 suggests it is largely cytoplasmic and mutations within LRRK2 increase aggregation formation, kinase activity and neuronal toxicity. Further investigation indicates LRRK2 is able to self interact, forming at least a dimer and may represent a potential mechanism for the aggregation of LRRK2. LRRK2 also interacts with fasciculation and elongation factor zeta 2 (FEZ2), a mammalian orthologue of the Caenorhabditis elegans UNC-76 protein, which is involved in the axonal outgrowth and synaptic organisation. Although the function of LRRK2 is unknown, therapies directed towards LRRK2 are likely to have a great clinical impact and may bring us closer to understanding the pathogenic processes underlying PD