Abnormal network oscillations in patients with Dementia with Lewy bodies and a mouse model of alpha-synucleinopathy

Ph. D. Thesis.Electrophysiology can reveal changes in neuronal oscillatory activity in the brain in relation to neurodegenerative disorders, including dementia with Lewy bodies (DLB). DLB, characterised by abnormal α-synuclein (α-syn) aggregation within neurons, is the second most common cause of dementia after Alzheimer’s disease (AD). This thesis had two aims. Firstly, to identify resting-state EEG changes that reflect cognitive fluctuations, a DLB core symptom, and differentiate DLB from AD and Parkinson’s disease dementia (PDD) patients and healthy controls. Secondly, to detect electrophysiological alterations in young mice over-expressing human mutant α-syn while under urethane-induced anaesthesia, mimicking deep-sleep. The resulting slowoscillation (SO) composed of Up-states (neuronal firing) and Down-states (neuronal “silence”), was recorded intra-cortically, from the hippocampus and medial prefrontal cortex (mPFC). The human EEG analysis replicated reports of a shift of power and dominant frequency (DF) from alpha to theta frequencies, in DLB/PDD patients compared to AD patients and controls. Contrary to previous work, the DF variability (DFV) over time was increased in AD and not in DLB/PDD patients, although a DLBspecific correlation between the DFV and cognitive fluctuations persisted. The DFV and power/DF distribution could differentiate between AD and DLB patients with high sensitivity (92.26%) and specificity (83.3%). Analysis of sleep patterns in α-syn mice in both the mPFC and hippocampus revealed increased SO frequency, aberrant neuronal firing activity on Down-states, altered power distribution on Up-states and disturbed sleep spindle activity, compared to WTs. A novel infra-slow modulation (ISM) was described in WTs, presenting as bursts of power across frequencies every ~ 3.5 min. In α-syn mice, the ISM induced abnormally high levels of high frequency oscillatory power in the hippocampus. Our findings indicate altered neuronal oscillatory activity in DLB patients and α-syn mice during rest and sleep respectively, suggesting that α-syn affects the integrity of the networks underlying widespread, synchronous activity.Alzheimer’s Societ