Olfactory dysfunction in the pathophysiological continuum of dementia

Abstract

A B S T R A C TSensory capacities like smell, taste, hearing, vision decline with aging, but increasing evidence show that sensory dysfunctions are one of the early signs diagnosing the conversion from physiological to pathological brain state. Smell loss represents the best characterized sense in clinical practice and is considered as one of the first preclinical signs of Alzheimer's and Parkinson's disease, occurring a decade or more before the onset of cognitive and motor symptoms. Despite the numerous scientific reports and the adoption in clinical practice, the etiology of sensory damage as prodromal of dementia remains largely unexplored and more studies are needed to resolve the mechanisms underlying sensory network dysfunction. Although both cognitive and sensory domains are progressively affected, loss of sensory experience in early stages plays a major role in reducing the autonomy of demented people in their daily tasks or even possibly contributing to their cognitive decline. Interestingly, the chemosensory circuitry is devoid of a blood brain barrier, representing a vulnerable port of entry for neurotoxic species that can spread to the brain. Furthermore, the exposure of the olfactory system to the external environment make it more susceptible to mechanical injury and trauma, which can cause degenerative neuroinflammation. In this review, we will summarize several findings about chemosensory impairment signing the conversion from healthy to pathological brain aging and we will try to connect those observations to the promising research linking environmental influences to sporadic dementia. The scientific body of knowledge will support the use of chemosensory diagnostics in the presymptomatic stages of AD and other biomarkers with the scope of finding treatment strategies before the onset of the disease. ⁎

Smell, an Underrated Early Biomarker for Brain Aging

“…Olfactory performance reaches its peak at the age of 40 years (Buschhüter et al, 2008) and then progressively declines with aging (Eibenstein et al, 2005;Doty and Kamath, 2014;Palmquist et al, 2020;Parvand and Rankin, 2020;Van Regemorter et al, 2020). In addition, in different neurological pathologies, like Parkinson's and Alzheimer's disease, dysosmia is exacerbated compared to the physiological decrease and occurs prior to motor and cognitive disabilities (Doty, 2012;Masala et al, 2018;Bathini et al, 2019;Cecchini et al, 2019;Dintica et al, 2019;Murphy, 2019). Many studies sustain that the alteration of the olfactory system may be used as an early predictor for detecting AD because several brain olfactory regions are impaired in the asymptomatic phase of this disorder due to the deposition of pathological hallmarks (Braak and Braak, 1991).…”

Functional Alterations in the Olfactory Neuronal Circuit Occur before Hippocampal Plasticity Deficits in the P301S Mouse Model of Tauopathy: Implications for Early Diagnosis and Translational Research in Alzheimer’s Disease

“…Olfactory dysfunction, a prodromal symptom of AD, is often an antecedent to classical cognitive impairments [9,10]. Gamma oscillations in the frequency range of 40-100 Hz, have extensively been studied in the OB and are the result of a negative feedback loop between excitatory mitral cells and inhibitory granule cells [44].…”

“…Cognitive deficits, which are the main clinical endpoint indices are typically diagnosed late in the disease progression at a time when irreversible processes have already occurred. Sensory processes such as smelling, hearing, and vision are naturally declining to some extent in aged humans but have been shown to be prodromal of dementia [9,10]. Worsening of olfaction impairments are subsequently predictive of MCI developments and may predict the progression to AD [80][81][82][83].…”

“…The preferential localization of proteinopathies in the olfactory, cortex, and hippocampal structures correlates well with primary cognitive and memory disturbances [ 8 ]. In recent years there has been a rising interest in olfaction as a potential early functional biomarker in AD [ 9 , 10 ]. Impairments in olfactory processing are amongst the very first clinical signs that occur in almost 100% of AD cases [ 11 ], with evidence that tau (NTF) pathology in the OB may be more important than amyloid pathology underlying the early olfactory deficit in AD, clearly preceding cognitive impairments [ 12 , 13 , 14 , 15 ].…”

Perspectives on the Intracellular Bacterium Chlamydia pneumoniae in Late-Onset Dementia

“…We are not suggesting here that any single agent is responsible solely for non-genetic triggering or causation in late-onset dementia; however, a focus on underlying infections in the olfactory system is of real importance. The importance of infections and other environmental insults with relevance to olfaction is well-reviewed in a recent article on olfactory dysfunction in the pathophysiological continuum of dementia [15]. In this regard, our discovery of Cpn in the late-onset brain is relevant, since this is a ubiquitous intracellular respiratory pathogen which has been shown to infect the olfactory regions of the brain [2].…”