Chen, Honglei

Background: Olfactory identification (OI) impairment appears early in the course of Alzheimer’s disease dementia (AD), prior to detectable cognitive impairment. However, the neuroanatomical correlates of impaired OI in cognitively normal older adults (CN) and persons with mild cognitive impairment (MCI) are not fully understood. Objective: We examined the neuroanatomic correlates of OI impairment in older adults from the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). Methods: Our sample included 1,600 older adults without dementia who completed clinical assessment and structural brain imaging from 2011 to 2013. We characterized OI impairment using the 12-item Sniffin’ Sticks odor identification test (score ≤6). We used voxel-based morphometry (VBM) and region of interest (ROI) analyses to examine the neuroanatomic correlates of impaired OI in CN and MCI, after adjusting for potential confounders. Analyses were also separately stratified by race and sex. Results: In CN, OI impairment was associated with smaller amygdala gray matter (GM) volume ( p < 0.05). In MCI, OI impairment was associated with smaller GM volumes of the olfactory cortex, amygdala, entorhinal cortex, hippocampus, and insula (ps < 0.05). Differential associations were observed by sex in MCI; OI impairment was associated with lower insular GM volumes among men but not among women (p-interaction = 0.04). There were no meaningful interactions by race. Conclusion: The brain regions associated with OI impairment in individuals without dementia are specifically those regions known to be the primary targets of AD pathogenic processes. These findings highlight the potential utility of olfactory assessment in the identification and stratification of older adults at risk for AD.

Introduction: Impairment in the sense of smell is associated with plaques and tangles in the olfactory region of the brain, which connects to the hippocampus where neuropathologic changes related to mild cognitive impairment (MCI) and dementia due to Alzheimer’s disease are first sited. Olfactory impairments may thus be a marker for poor cognitive function and MCI. We assessed olfaction and cognitive function in 6055 White and Black men and women aged 60-99 years. Methods: Sense of smell was measured in ARIC-NCS participants (2011-2013) by the 12-item Sniffin’ Sticks screening test (score range: 0-12, median: 10). A clinically validated threshold (smell score <6) defined olfactory impairment (OI). A multidimensional neuropsychological assessment (10 tests) ascertained performance in domains of memory, language, executive function/processing speed, and global cognition. For relative comparisons across the tests, raw cognitive test scores were standardized to z scores and averaged to yield domain scores. Following review of neuropsychological assessments, medical history, cerebral magnetic resonance imaging, and physical examinations, MCI was classified by a neurologist and neuropsychologist, and adjudicated by a third reviewer. Multivariable linear regression estimated the mean difference in domain-specific z scores among participants with and without OI. Logistic regression was used to quantify the prevalence odds of MCI in participants with vs. those without OI. Models were adjusted for age, sex, race, education, ARIC study center, hypertension, diabetes, smoking, and ApoE4. Race and sex were explored as effect modifiers. Results: The participants’ mean age was 76 years; 41% were male and 23% Black. The prevalence of olfactory impairment was 14%. Compared to participants with no OI, those with OI had a statistically significantly lower mean z score across all cognitive domains [memory: Beta= -0.37 (95% confidence interval [CI]: -0.45, -0.30); language: Beta= -0.39 (95% CI: -0.46, -0.33); executive function/processing speed: Beta= -0.24 (95% CI: -0.32, -0.17); global cognition: Beta= -0.34 (95% CI: -0.41, -0.26). Effect modification by race was observed in the domain of language. Blacks with OI had a greater mean difference in language z score compared to Blacks without OI (Beta= -0.57 (95% CI: -0.70, -0.44)). OI was associated with MCI in Whites, but not Blacks: white participants with OI had greater odds of MCI (Odds Ratio [OR] =1.76, 95% CI: 1.40, 2.21). Sex did not modify these associations. Conclusions: Compared to average cognitive aging (annual rate of decline of 0.04-0.05 standard deviation units/year) relatively large differences in standardized cognitive domain scores are observed between those with and without olfactory impairment among older adults. An impaired sense of smell may serve as a readily accessible early marker of neurodegeneration.

AbstractIntroductionWe tested the hypothesis that poor sense of smell is associated with lower cognitive function and higher mild cognitive impairment (MCI) prevalence.MethodsOlfaction, measured by the Sniffin' Sticks test, was categorized as olfactory impairment (OI) (score ≤6) or no OI (score >6). MCI was adjudicated based on review of a neuropsychological examination. Linear regression estimated the mean difference in cognitive factor scores, and log‐binomial regression quantified MCI prevalence among participants with versus without OI.ResultsParticipants with OI had lower mean factor scores (memory: −0.27 standard deviation [SD], 95% confidence interval [CI]: −0.35 to −0.19; language: −0.24 SD, 95% CI: −0.30 to −0.17; executive function/processing speed: −0.09 SD, 95% CI: −0.12 to −0.06; and general cognitive performance: −0.25 SD, 95% CI: −0.30 to −0.20). OI was also associated with MCI (n = 204; prevalence ratio = 1.56, 95% CI: 1.37, 1.78).DiscussionAn impaired sense of smell may serve as a readily accessible early marker of neurodegeneration and improve upon the prevailing delayed diagnoses and underascertainment of MCI/dementia.

AbstractRecent population studies suggest an intriguing inverse relationship between several types of cancer and neurodegenerative diseases, including Alzheimer's disease. Understanding the intersection of the underlying biology for these two distinct families of diseases with one another may offer novel approaches to identify new therapeutic approaches and possible opportunities to repurpose existing drug candidates. The Alzheimer's Association and the Alzheimer's Drug Discovery Foundation convened a one‐day workshop to delve into this discussion. Workshop participants outlined research focus areas, potential collaborations, and partnerships for future action.

Abstract Background: The etiology and natural history of Parkinson’s disease (PD) are not well understood. Some non-motor symptoms such as hyposmia, rapid eye movement sleep behavior disorder, and constipation may develop during the prodromal stage of PD and precede PD diagnosis by years. Objectives: We examined the promise and pitfalls of research on premotor symptoms of PD and developed priorities and strategies to understand their clinical and etiological implications. Methods: This review was based on a workshop, Parkinson’s Disease Premotor Symptom Symposium, held 7–8 June 2012 at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina. Discussion: Research on premotor symptoms of PD may offer an excellent opportunity to characterize high-risk populations and to better understand PD etiology. Such research may lead to evaluation of novel etiological hypotheses such as the possibility that environmental toxicants or viruses may initiate PD pathogenesis in the gastrointestinal tract or olfactory bulb. At present, our understanding of premotor symptoms of PD is in its infancy and faces many obstacles. These symptoms are often not specific to PD and have low positive predictive value for early PD diagnosis. Further, the pathological bases and biological mechanisms of these premotor symptoms and their relevance to PD pathogenesis are poorly understood. Conclusion: This is an emerging research area with important data gaps to be filled. Future research is needed to understand the prevalence of multiple premotor symptoms and their etiological relevance to PD. Animal experiments and mechanistic studies will further understanding of the biology of these premotor symptoms and test novel etiological hypothesis. Citation: Chen H, Burton EA, Ross GW, Huang X, Savica R, Abbott RD, Ascherio A, Caviness JN, Gao X, Gray KA, Hong JS, Kamel F, Jennings D, Kirshner A, Lawler C, Liu R, Miller GW, Nussbaum R, Peddada SD, Comstock Rick A, Ritz B, Siderowf AD, Tanner CM, Tröster AI, Zhang J. 2013. Research on the premotor symptoms of Parkinson’s Disease: clinical and etiological implications. Environ Health Perspect 121:1245–1252; http://dx.doi.org/10.1289/ehp.1306967

Abstract Background Parkinson’s disease (PD) is the second most common neurodegenerative disorder. People with PD, their families, scientists, health care providers, and the general public are increasingly interested in identifying environmental contributors to PD risk. Methods In June 2007, a multidisciplinary group of experts gathered in Sunnyvale, California, USA, to assess what is known about the contribution of environmental factors to PD. Results We describe the conclusions around which they came to consensus with respect to environmental contributors to PD risk. We conclude with a brief summary of research needs. Conclusions PD is a complex disorder, and multiple different pathogenic pathways and mechanisms can ultimately lead to PD. Within the individual there are many determinants of PD risk, and within populations, the causes of PD are heterogeneous. Although rare recognized genetic mutations are sufficient to cause PD, these account for &lt; 10% of PD in the U.S. population, and incomplete penetrance suggests that environmental factors may be involved. Indeed, interplay among environmental factors and genetic makeup likely influences the risk of developing PD. There is a need for further understanding of how risk factors interact, and studying PD is likely to increase understanding of other neurodegenerative disorders.