The advance of Parkinson's disease is associated with the existence of abnormal oscillations within the basal ganglia with frequencies in the beta band (13-30 Hz). While the origin of these oscillations remains unknown, there is some evidence suggesting that oscillations observed in the basalgangliaariseduetointeractionsoftwonuclei:thesubthalamicnucleus(STN)andtheglobuspallidusparsexterna(GPe).Toinvestigatethis hypothesis, we develop a computational model of the STN-GPe network based upon anatomical and electrophysiological studies. Significantly, our study shows that for certain parameter regimes, the model intrinsically oscillates in the beta range. Through an analytical study of the model, we identify a simple set of necessary conditions on model parameters that guarantees the existence of beta oscillations. These conditions for generation of oscillations are described by a set of simple inequalities and can be summarized as follows: (1) The excitatory connections from STN to GPe and the inhibitory connections from GPe to STN need to be sufficiently strong. (2) The time required by neurons to react to their inputs needs to be short relative to synaptic transmission delays. (3) The excitatory input from the cortex to STN needs to be high relative to the inhibition from striatum to GPe. We confirmed the validity of these conditions via numerical simulation. These conditions describe changes in parameters that are consistent with those expected as a result of the development of Parkinson's disease, and predict manipulations that could inhibit the pathological oscillations.

Failure to translate successful neuroprotective preclinical data to a clinical setting in Alzheimer's disease (AD) indicates that amyloidopathy and tauopathy alone provide an incomplete view of disease. We have tested here the relevance of additional homeostatic deviations that result from loss of activity of transcription factor NRF2, a crucial regulator of multiple stress responses whose activity declines with ageing. A transcriptomic analysis demonstrated that NRF2-KO mouse brains reproduce 7 and 10 of the most dysregulated pathways of human ageing and AD brains, respectively. Then, we generated a mouse that combines amyloidopathy and tauopathy with either wild type (AT-NRF2-WT) or NRF2-deficiency (AT-NRF2-KO). AT-NRF2-KO brains presented increased markers of oxidative stress and neuroinflammation as well as higher levels of insoluble phosphorylated-TAU and Aβ*56 compared to AT-NRF2-WT mice. Young adult AT-NRF2-KO mice exhibited deficits in spatial learning and memory and reduced long term potentiation in the perforant pathway. This study demonstrates the relevance of normal homeostatic responses that decline with ageing, such as NRF2 activity, in the protection against proteotoxic, inflammatory and oxidative stress and provide a new strategy to fight AD.

In Parkinsonism, subthalamic nucleus (STN) neurons and two types of external globus pallidus (GP) neuron inappropriately synchronise their firing in time with slow (∼1 Hz) or beta (13–30 Hz) oscillations in cortex. We recorded the activities of STN, Type-I GP (GP-TI) and Type-A GP (GP-TA) neurons in anaesthetised Parkinsonian rats during such oscillations to constrain a series of computational models that systematically explored the effective connections and physiological parameters underlying neuronal rhythmic firing and phase preferences in vivo. The best candidate model, identified with a genetic algorithm optimising accuracy/complexity measures, faithfully reproduced experimental data and predicted that the effective connections of GP-TI and GP-TA neurons are quantitatively different. Estimated inhibitory connections from striatum were much stronger to GP-TI neurons than to GP-TA neurons, whereas excitatory connections from thalamus were much stronger to GP-TA and STN neurons than to GP-TI neurons. Reciprocal connections between GP-TI and STN neurons were matched in weight, but those between GP-TA and STN neurons were not; only GP-TI neurons sent substantial connections back to STN. Different connection weights between and within the two types of GP neuron were also evident. Adding to connection differences, GP-TA and GP-TI neurons were predicted to have disparate intrinsic physiological properties, reflected in distinct autonomous firing rates. Our results elucidate potential substrates of GP functional dichotomy, and emphasise that rhythmic inputs from striatum, thalamus and cortex are important for setting activity in the STN–GP network during Parkinsonian beta oscillations, suggesting they arise from interactions between most nodes of basal ganglia–thalamocortical circuits.

Introduction Plasma biomarkers for Alzheimer's disease (AD) diagnosis/stratification are a “Holy Grail” of AD research and intensively sought; however, there are no well-established plasma markers. Methods A hypothesis-led plasma biomarker search was conducted in the context of international multicenter studies. The discovery phase measured 53 inflammatory proteins in elderly control (CTL; 259), mild cognitive impairment (MCI; 199), and AD (262) subjects from AddNeuroMed. Results Ten analytes showed significant intergroup differences. Logistic regression identified five (FB, FH, sCR1, MCP-1, eotaxin-1) that, age/APOε4 adjusted, optimally differentiated AD and CTL (AUC: 0.79), and three (sCR1, MCP-1, eotaxin-1) that optimally differentiated AD and MCI (AUC: 0.74). These models replicated in an independent cohort (EMIF; AUC 0.81 and 0.67). Two analytes (FB, FH) plus age predicted MCI progression to AD (AUC: 0.71). Discussion Plasma markers of inflammation and complement dysregulation support diagnosis and outcome prediction in AD and MCI. Further replication is needed before clinical translation.