Dysregulation of hair-strand-based elemental biodynamics in amyotrophic lateral sclerosis.

backgroundAmyotrophic lateral sclerosis (ALS) is a rare motor neurodegenerative disorder and is predominantly diagnosed in older adults. Altered levels of essential and toxic elements have been implicated in ALS pathophysiology; however, little is known about the longitudinal biodynamic patterns of these elements in patients with ALS.

methodsUsing a single individual hair strand, we generated time series data of 400-800 time points approximately at 2 to 4 hourly resolution on 17 elemental intensities in ALS-positive cases and ALS-negative controls from a national collection and a regional centre in the US (on a total sample of 391, with 295 cases and 96 controls, with median age at hair collection over 60 years). The elements included were Li, Mg, P, S, Ca, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Sr, Sn, Ba, and Pb. We analysed the growth increments in single hair strands using laser ablation-inductively coupled plasma-mass spectrometry to create time-resolved signals of elemental exposure and intensity along the hair strand. Two complementary information-theoretic methods, cross-recurrence quantification analysis and transfer entropy-based network analysis, were employed to generate time-resolved features that quantify the synchronisation of multi-element biodynamics.

findingsMale ALS-positive cases had significantly lower synchronicity in Cu-Zn temporal biodynamics than ALS-negative controls (recurrence: log(β) = -1.64, p-value < 0.001, q-value = 0.03). Female ALS-positive cases had lower synchronicity in Cr-Ni temporal biodynamics than ALS-negative controls (recurrence: log(β) = -1.59, p-value < 0.001, q-value = 0.46). In both males and females, multiple centrality measures of Cu (that quantify the importance of Cu within a network of all elemental intensities) were significantly lower in ALS-positive cases than in ALS-negative controls [in males, closeness centrality of Cu: log(β) = -0.64, p-value = 0.002, q-value = 0.04; in females, eigenvector centrality of Cu: log(β) = -0.53, p-value = 0.02, q-value = 0.97].

interpretationWe demonstrate that ALS-positive cases have significantly higher odds of collapse in the synchronisation of elemental biodynamics and worse connectedness in copper-based networks compared to ALS-negative controls.

fundingUS National Institutes of Health (P30ES023515, R01ES026033, U2CES030859, U2CES026561, R35ES030435, UL1TR004419, 1OT2NS136938-01, 1R01ES034133-01) and CDC/ATSDR (R01TS000331, R01TS000324 and R01TS000285).