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Alzheimer's Disease (AD) in elderly adds substantially to socio-economic burden necessitating early diagnosis. While recent studies in rodent models of AD have suggested diagnostic and therapeutic value for gamma rhythms in brain, the same has not been rigorously tested in humans. In this case-control study, we recruited a large population (N=244; 106 females) of elderly (>49 years) subjects from the community, who viewed large gratings that induced strong gamma oscillations in their electroencephalogram (EEG). These subjects were classified as healthy (N=227), mild-cognitively-impaired (MCI; N=12) or AD (N=5) based on clinical history and Clinical Dementia Rating scores. Surprisingly, stimulus-induced gamma rhythms, but not alpha or steady-state visually evoked responses, were significantly lower in MCI/AD subjects compared to their age and gender matched controls. This reduction was not due to differences in eye-movements or baseline power. Our results suggest that gamma could be used as potential screening tool for MCI/AD in humans.

AbstractGamma rhythms (∼20-70 Hz) have been reported to be abnormal in mental disorders such as autism and schizophrenia in humans, and Alzheimer’s disease (AD) models in rodents. However, the effect of normal aging on these oscillations is not known, especially for elderly subjects (>49 years) for which AD is most prevalent. In a first large-scale (236 subjects; 104 females) electroencephalogram (EEG) study on gamma oscillations on elderly subjects (aged 50-88 years), we presented full-screen Cartesian gratings that induced two distinct gamma oscillations (slow: 20-34 Hz and fast: 36-66 Hz). Power and centre frequency significantly decreased with age for both slow and fast gamma, but not alpha (8-12 Hz). Reduction was more salient for fast gamma than slow. These results were independent of microsaccades and pupillary reactivity to stimulus, as well as variations in power spectral density with age. Steady-state visual evoked potentials (SSVEPs) also reduced with age. These results are crucial first steps towards using gamma/SSVEPs as biomarkers of cognitive decline in elderly.Significance statementNo study in humans has examined visual narrow-band gamma oscillations with healthy aging in elderly subjects. In a first large-scale (236 subjects) EEG study on stimulus-induced narrow band gamma in cognitively normal elderly (>49 years) humans, we show that both power and centre frequency of slow and fast gamma (20-34 Hz and 36-66 Hz respectively) decrease with age, but alpha power does not. Steady-state visual evoked potential (SSVEPs) in gamma range also decrease with age. Any EEG-based biomarker is accessible and affordable to patients of a wide socio-economic spectrum. Our results are important steps for developing such screening/diagnostic tests for aging-related diseases, like Alzheimer’s disease.

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Lithium is an effective, well-established treatment for bipolar disorder (BD). However, the mechanisms of its action, and reasons for variations in clinical response, are unclear. We used neural precursor cells (NPCs) and lymphoblastoid cell lines (LCLs), from BD patients characterized for clinical response to lithium (using the “Alda scale” and “NIMH Retrospective Life chart method”), to interrogate cellular phenotypes related to both disease and clinical lithium response. NPCs from two biologically related BD patients who differed in their clinical response to lithium were compared with healthy controls. RNA-Seq and analysis, mitochondrial membrane potential (MMP), cell viability, and cell proliferation parameters were assessed, with and without in vitro lithium. These parameters were also examined in LCLs from 25 BD patients (16 lithium responders and 9 non-responders), and 12 controls. MMP was lower in both NPCs and LCLs from BD; but it was reversed with in vitro lithium only in LCLs, and this was unrelated to clinical lithium response. The higher cell proliferation observed in BD was unaffected by in vitro lithium. Cell death was greater in BD. However, LCLs from clinical lithium responders could be rescued by addition of in vitro lithium. In vitro lithium also enhanced BCL2 and GSK3B expression in these cells. Our findings indicate cellular phenotypes related to the disease (MMP, cell proliferation) in both NPCs and LCLs; and those related to clinical lithium response (cell viability, BCL2/GSK3B expression) in LCLs.