Thermally activated ion channels are known to detect the entire thermal range from extreme heat (TRPV2), painful heat (TRPV1, TRPM3 and ANO1), non-painful warmth (TRPV3 and TRPV4) and non-painful coolness (TRPM8) through to painful cold (TRPA1)^{1,2,3,4,5,6,7}. Genetic deletion of each of these ion channels, however, has only modest effects on thermal behaviour in mice^{6,7,8,9,10,11,12}, with the exception of TRPM8, the deletion of which has marked effects on the perception of moderate coolness in the range 10–25 °C¹³. The molecular mechanism responsible for detecting non-painful warmth, in particular, is unresolved. Here we used calcium imaging to identify a population of thermally sensitive somatosensory neurons which do not express any of the known thermally activated TRP channels. We then used a combination of calcium imaging, electrophysiology and RNA sequencing to show that the ion channel generating heat sensitivity in these neurons is TRPM2. Autonomic neurons, usually thought of as exclusively motor, also express TRPM2 and respond directly to heat. Mice in which TRPM2 had been genetically deleted showed a striking deficit in their sensation of non-noxious warm temperatures, consistent with the idea that TRPM2 initiates a ‘warm’ signal which drives cool-seeking behaviour.

Neurotransmitter degradation has been proposed to cause the accumulation of neurotoxic metabolites. The metabolism of these metabolites involves aldehyde dehydrogenase 2 (ALDH2). The Asian-specific single nucleotide polymorphism rs671 causes reduced enzyme activity. This study aims to explore whether Parkinson’s disease (PD) patients with reduced ALDH2 activity owing to the rs671 polymorphism are at risk for neuropsychological impairments. A total of 139 PD patients were recruited. Each participant was assessed for medical characteristics and their ALDH2 genotype. The Mini-Mental State Examination (MMSE), the Clinical Dementia Rating Scale and the Frontal Behavioral Inventory were used to measure neuropsychological functions. We found that the MMSE scores were significantly lower in patients with inactive ALDH2 (U = 1873.5, p = 0.02). The presence of cognitive impairments was significantly more frequent in the inactive ALDH2 group (46.0%) than in the active ALDH2 group (26.3%) (χ² = 5.886, p = 0.01). The inactive group showed significant deterioration in hobbies and exhibited more severe “disorganization” and “hyper-sexuality” behaviours. The additive effects of the allele on the development of cognitive impairments in PD patients may be an important finding that provides further insight into the pathogenic mechanism of cognitive dysfunction in PD.

Apathy is a common motivational deficit in neurodegenerative diseases, but lacks a culturally sensitive tool accounting for ethnic Chinese culture's impact on motivation initiation. This study developed and validated the Geriatric Apathy Scale (GAS), comprehensively incorporating cultural nuances, setting diagnostic cutoffs, and examining apathy's multi-dimensional aspects in a neurodegenerative cohort. The 16-item GAS was developed by considering ethnic Chinese cultural characteristics and conducting a literature review. The study involved 296 participants, comprising 113 with Parkinson's disease (PD), 66 with Alzheimer's disease (AD), and 117 healthy controls (HC). All participants completed the GAS, Apathy Evaluation Scale (AES), Geriatric Depression Scale (GDS-15), Mini-Mental State Examination, and Activities of Daily Living (ADLs). The GAS showed good internal consistency (r = 0.862) and test-retest reliability (r = 0.767). It correlated moderately with the AES (r = 0.639, p < .001), weakly with GDS-15 (r = 0.166, p < .01), and negatively with ADLs (r = -1.19, p < .05). Clinical diagnosis cutoff scores were identified at 15.5 for PD (sensitivity: 0.789; specificity: 0.693) and 12.5 for AD (sensitivity: 0.821; specificity: 0.632). Noteworthy disparities were observed in the Cognition and Social Motivation dimension, with elevated severity in both PD and AD compared to HC (p < .01). Interestingly, within-group comparisons revealed greater apathy severity in the Cognition and Social Motivation dimension for PD (p < .001) and AD (p = .001) versus Emotional Response and Expression and Spontaneous Behavioral Activation. The GAS, a psychometrically validated scale, assesses apathy in neurodegenerative populations, accounting for ethnic Chinese culture's influence. It establishes clinical cutoff points and explores the multi-dimensional nature of apathy.