Objective
To update evidence‐based medicine recommendations for treating nonmotor symptoms in Parkinson's disease (PD).

https://onlinelibrary.wiley.com/doi/pdf/10.1002/mds.27602

Update on treatments for nonmotor symptoms of Parkinson's disease—an evidence-based medicine review

Neurodegenerative diseases are among the leading causes of disability and death worldwide. The disease-related socioeconomic burden is expected to increase with the steadily increasing life expectancy. In spite of decades of clinical and basic research, most strategies designed to manage degenerative brain diseases are palliative. This is not surprising as neurodegeneration progresses "silently" for decades before symptoms are noticed. Importantly, conceptual models with heuristic value used to study neurodegeneration have been constructed retrospectively, based on signs and symptoms already present in affected patients; a circumstance that may confound causes and consequences. Hence, innovative, paradigm-shifting views of the etiology of these diseases are necessary to enable their timely prevention and treatment. Here, we outline four alternative views, not mutually exclusive, on different etiological paths toward neurodegeneration. First, we propose neurodegeneration as being a secondary outcome of a primary cardiovascular cause with vascular pathology disrupting the vital homeostatic interactions between the vasculature and the brain, resulting in cognitive impairment, dementia, and cerebrovascular events such as stroke. Second, we suggest that the persistence of senescent cells in neuronal circuits may favor, together with systemic metabolic diseases, neurodegeneration to occur. Third, we argue that neurodegeneration may start in response to altered body and brain trophic interactions established via the hardwire that connects peripheral targets with central neuronal structures or by means of extracellular vesicle (EV)-mediated communication. Lastly, we elaborate on how lifespan body dysbiosis may be linked to the origin of neurodegeneration. We highlight the existence of bacterial products that modulate the gut-brain axis causing neuroinflammation and neuronal dysfunction. As a concluding section, we end by recommending research avenues to investigate these etiological paths in the future. We think that this requires an integrated, interdisciplinary conceptual research approach based on the investigation of the multimodal aspects of physiology and pathophysiology. It involves utilizing proper conceptual models, experimental animal units, and identifying currently unused opportunities derived from human data. Overall, the proposed etiological paths and experimental recommendations will be important guidelines for future cross-discipline research to overcome the translational roadblock and to develop causative treatments for neurodegenerative diseases.

/pdf/re-thinking-the-etiological-framework-of-neurodegeneration-2y0475p6zk.pdf

Re-thinking the Etiological Framework of Neurodegeneration.

Human Olfaction at the Intersection of Language, Culture, and Biology

Olfaction is a sense involved in a complex set of tasks, influencing eating behavior, increasing awareness of environmental hazards and affecting social communication. Surprisingly, smell disorders are very frequent, especially in the elderly population. Several recent studies conducted mostly in older subjects have demonstrated a strong association between olfactory impairment and overall mortality risk, with anosmia being even more predictive of 5 years mortality risk than cardiovascular disease. Presently, the underlying pathophysiology linking olfactory impairment to mortality remains unknown and only putative mechanisms are suggested. This review aims to examine the link between olfactory impairment and mortality and to discuss existing ideas on underlying existing mechanisms including, (1) the effect of olfactory loss on nutrition, life-threatening situations and social interactions, (2) associated neurodegenerative diseases, (3) accelerated brain aging, and (4) reflection of general health status being reflected in olfactory function.

/pdf/mechanisms-linking-olfactory-impairment-and-risk-of-20u5lx0mfn.pdf

Mechanisms Linking Olfactory Impairment and Risk of Mortality

The loss of the senses of smell (anosmia) and taste (ageusia) are rather common disorders, affecting up to 20% of the adult population. Yet, this condition has not received the attention it deserves, most probably because per se such a disorder is not life threatening. However, loss of olfactory function significantly reduces the quality of life of the affected patients, leading to dislike in food and insufficient, exaggerated or unbalanced food intake, unintentional exposure to toxins such as household gas, social isolation, depression, and an overall insecurity. Not only is olfactory dysfunction rather prevalent in the healthy population, it is, in many instances, also a correlate or an early indicator of a panoply of diseases. Importantly, olfactory dysfunction is linked to the two most prominent neurodegenerative disorders, Parkinson's disease and Alzheimer's disease. Anosmia and hyposmia (reduced sense of smell) affect a majority of patients years before the onset of cognitive or motor symptoms, establishing olfactory dysfunction as early biomarker that can enable earlier diagnosis and preventative treatments. In the current health crisis caused by SARS-CoV2, anosmia and dysgeusia as early-onset symptoms in virus-positive patients may prove to be highly relevant and crucial for pre-symptomatic Covid-19 detection from a public health perspective, preceding by days the more classical respiratory tract symptoms such as cough, tightness of the chest or fever. Thus, the olfactory system seems to be at the frontline of pathologic assault, be it through pathogens or insults that can lead to or at least associate with neurodegeneration. The aim of this review is to assemble current knowledge from different medical fields that all share a common denominator, olfactory/gustatory dysfunction, and to distill overarching etiologies and disease progression mechanisms.

/pdf/loss-of-olfactory-function-early-indicator-for-covid-19-2cmwv80a9g.pdf

Loss of Olfactory Function-Early Indicator for Covid-19, Other Viral Infections and Neurodegenerative Disorders.

The sense of smell is today one of the focuses of interest in aging and neurodegenerative disease research. In several neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s disease, the olfactory dysfunction is one of the initial symptoms appearing years before motor symptoms and cognitive decline, being considered a clinical marker of these diseases’ early stages and a marker of disease progression and cognitive decline. Overall and under the umbrella of precision medicine, attention to olfactory function may help to improve chances of success for neuroprotective and disease-modifying therapeutic strategies. The use of olfaction, as clinical marker for neurodegenerative diseases is helpful in the characterization of prodromal stages of these diseases, early diagnostic strategies, differential diagnosis, and potentially prediction of treatment success. Understanding the mechanisms underlying olfactory dysfunction is central to determine its association with neurodegenerative disorders. Several anatomical systems and environmental factors may underlie or contribute to olfactory loss associated with neurological diseases, although the direct biological link to each disorder remains unclear and, thus, requires further investigation. In this review, we describe the neurobiology of olfaction, and the most common olfactory function measurements in neurodegenerative diseases. We also highlight the evidence for the presence of olfactory dysfunction in several neurodegenerative diseases, its value as a clinical marker for early stages of the diseases when combined with other clinical, biological, and neuroimage markers, and its role as a useful symptom for the differential diagnosis and follow-up of disease. The neuropathological correlations and the changes in neurotransmitter systems related with olfactory dysfunction in the neurodegenerative diseases are also described.

Dolores Vilas

Papers

Olfactory Dysfunction in Neurodegenerative Diseases.