Prodromal Motoric Cognitive Risk Syndrome and Everyday Function.

BACKGROUND: Motoric cognitive risk syndrome (MCR), a pre-dementia syndrome characterized by subjective cognitive complaints and slow gait, is associated with disability in instrumental activities of daily living. It is unknown whether these functional limitations occur even before this pre-dementia syndrome is diagnosed. OBJECTIVE: To assess profiles of complex and instrumental activities of daily living in the prodromal stages of MCR. METHODS: We examined functional profiles in 46 older adults (mean age 79 years, 59% women) living in the community with normal cognition at baseline who developed MCR over follow-up ('pre-MCR') with 264 older adults (mean age 75 years, 57% women) who remained cognitively intact over the follow-up period. RESULTS: Pre-MCR individuals had more limitations on complex everyday function at baseline compared to normal controls in multivariable logistic regression models (odds ratio 1.21). Pre-MCR cases at baseline had limitations in handling finances (odds ratio 3.0) and performing hobbies (odds ratio 5.5) as compared to normal controls. Pre-MCR cases had a greater difference in the number of complex functional limitations from baseline to MCR compared to the difference from baseline to final visit for the controls (1.2±3.0 versus 0.5±2.2, p < 0.001). CONCLUSIONS: Limitations in complex everyday tasks arise in the prodromal stages of MCR and can assist in risk prognostication.

Olfactory Dysfunction and Incidence of Motoric Cognitive Risk Syndrome: A Prospective Clinical-Pathologic Study.

BACKGROUND AND OBJECTIVES: To examine associations between olfactory dysfunction, Alzheimer's disease (AD) pathology, and motoric cognitive risk syndrome (MCR), a predementia syndrome characterized by cognitive complaints and slow gait that is associated with risk for AD and other dementias. METHODS: We conducted a retrospective analysis of a prospective cohort study to examine if baseline olfactory function was associated with risk of incident MCR in 1,119 adults aged 60 and older (75.1% female). The association between performance on the Brief Smell Identification Test (BSIT) and incident MCR risk was computed using Cox models and reported as Hazard ratio (HR) with 95% confidence intervals (CI) adjusted for demographic, comorbidity, and cognitive factors. Furthermore, we assessed the relationship between postmortem AD pathology as well as non-AD pathology and olfactory function at the time of MCR diagnosis using linear regression models adjusted for sex, education, age at death, and time from diagnosis to death. RESULTS: There were 544 (48.6%) incident cases of MCR over a median follow-up of 3.94 years. Lower BSIT scores (poor olfaction) at baseline were associated with an increased risk of incident MCR (HR for a 1-point increase in BSIT score, 0.92; 95% CI, 0.88-0.96) in fully adjusted models. Those with hyposmia (scores of ≤8 on the BSIT) at baseline (26.6%) were at increased risk of MCR (HR, 1.44; 95% CI, 1.19-1.74) compared to those with normal olfactory function. A composite measure of global AD pathology as well as presence of Lewy body pathology were both inversely and independently associated with BSIT scores at the time of incident MCR diagnosis (n=118). τ tangle density, a specific component of AD pathology, was inversely associated with olfactory function and the correlation remained after controlling for mild cognitive impairment syndrome as well as presence of Lewy body pathology. DISCUSSION: The results provide evidence that olfactory dysfunction precedes MCR incidence and is related to Alzheimer pathology; providing a clinical approach to risk stratify as well as subtype MCR.

Involvement of Neural Transient Receptor Potential Channels in Peripheral Inflammation.

Transient receptor potential (TRP) channels are a superfamily of non-selective cation channels that act as polymodal sensors in many tissues throughout mammalian organisms. In the context of ion channels, they are unique for their broad diversity of activation mechanisms and their cation selectivity. TRP channels are involved in a diverse range of physiological processes including chemical sensing, nociception, and mediating cytokine release. They also play an important role in the regulation of inflammation through sensory function and the release of neuropeptides. In this review, we discuss the functional contribution of a subset of TRP channels (TRPV1, TRPV4, TRPM3, TRPM8, and TRPA1) that are involved in the body's immune responses, particularly in relation to inflammation. We focus on these five TRP channels because, in addition to being expressed in many somatic cell types, these channels are also expressed on peripheral ganglia and nerves that innervate visceral organs and tissues throughout the body. Activation of these neural TRP channels enables crosstalk between neurons, immune cells, and epithelial cells to regulate a wide range of inflammatory actions. TRP channels act either through direct effects on cation levels or through indirect modulation of intracellular pathways to trigger pro- or anti-inflammatory mechanisms, depending on the inflammatory disease context. The expression of TRP channels on both neural and immune cells has made them an attractive drug target in diseases involving inflammation. Future work in this domain will likely yield important new pathways and therapies for the treatment of a broad range of disorders including colitis, dermatitis, sepsis, asthma, and pain.