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Schematic of the olfactory system. Each olfactory sensory neuron expresses only one type of receptor. Neurons expressing the same receptor project into speci fi c glomeruli within the olfactory bulb and form synapses with mitral cells and tufted cells (not shown) in the glomeruli. The axons of mitral/tufted cells form the olfactory tract and project to many central olfactory structures including the olfactory tubercle, piriform cortices, amygdala, and lateral entorhinal cortex. Connections are extensive among these structures and other brain regions such as the orbitofrontal cortex, thalamus, hypothalamus, and hippocampus. The olfactory bulb also receives projections from secondary olfactory structures other than the olfactory tubercle. Directionality is denoted by arrows showing the projections among these brain structures.
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Hyposmia, identified as reduced sensitivity to odor, is a common non-motor symptom of Parkinson's disease (PD) that antedates the typical motor symptoms by several years. It occurs in ∼90% of early-stage cases of PD. In addition to the high prevalence, the occurrence of hyposmia may also predict a higher risk of PD. Investigations into hyposmia and...
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... 1817, James Parkinson first noted people in London exhibiting particular symptoms including involuntary tremulous motion, lessened muscular power, a propensity to bend the trunk forward, and a running pace. He found that individuals with this disease, later called Parkinson’s disease (PD), had difficulty planning and controlling movements [1] . Today, 1–2% of the population >65 years old suffer from this disease and the rate increases to 3–5% at 85 years and older [2] . James Parkinson in this thesis stated “the senses and intellects being uninjured” [1] , but in 1975 Ansari and Johnson first reported olfactory dysfunction in PD patients [3] and today, hyposmia is widely accepted as a major symptom. In fact, it is hypothesized that this olfactory dysfunction is not simply a benign symptom, but rather a potential culprit behind PD [4] . This article therefore discusses the current research in this area and explores the relationship between hyposmia and PD. Olfactory information-processing is a complicated multi- step process. There are many places in the olfactory system where PD-related pathology could occur; therefore, we fi rst overview the anatomy of this system (Fig. 1). First, odorant molecules are directed with the air into the nasal cavity and contact the olfactory epithelium. This epithelium is a sheet of cells that lines the dorsal surface of the nasal cavity. The epithelium contains four main cell-types: bipolar olfactory receptor cells, basal cells, supporting cells, and microvillus cells [5] , of which the olfactory receptor cells are the most important because they detect odorant molecules. These receptor cells are abundant in the epithelium (~ 6 000 000 per individual), occurring at 3–5 μ m intervals across the surface [5] . Each receptor cell sends 10–30 cilia towards the epithelial surface and a long unmyelinated axon through the cribriform plate to the olfactory bulb [5] . Once odorants bind to their receptors, they activate GTP- binding proteins, which in turn trigger the synthesis of the second messenger 3',5'-cyclic monophosphate (cAMP). cAMP opens a cyclic nucleotide-gated channel, resulting in an in fl ux of Na + and Ca 2+ ions and depolarization of the receptor cell [6] . Each receptor neuron expresses only one kind of receptor among approximately a thousand receptor proteins. Sensory neurons expressing the same ...
Similar publications
Introduction: Parkinson’s disease (PD) often first presents with asymmetric motor symptoms. A number of studies have now established that sensory deficits can also be similarly asymmetric. It is well established that PD is associated with marked olfactory dysfunction, but whether this too present asymmetrically is a currently contentious question....
Citations
... The precise cause of olfactory dysfunction in PD is not fully understood but could be linked to neuropathological alterations within the olfactory system, spanning from the olfactory bulb to olfaction-related cortical structures. [1][2][3][24][25][26][27][28] On the other hand, the observation that the peripheral olfactory system, specifically the olfactory threshold, is primarily affected in DIP in this study aligns with the understanding that the olfactory threshold is typically the first aspect of olfactory function to be affected, followed by discrimination and then identification in the normal aging process. 18 This can explain the results showing an impaired odor threshold in both groups without significant differences but significantly more diminished discrimination in the PD group than in the DIP group, regardless of age. ...
Objective:
Drug-induced Parkinsonism (DIP) stands as a frequently encountered diagnostic possibility when considering Parkinson's disease (PD). While olfactory dysfunction is a common clinical feature in PD, the comparison of olfactory function between two conditions remains insufficient. This study aimed to compare the olfactory function, including threshold, discrimination, and identification (TDI) profiles between PD and DIP.
Methods:
Consecutive patients with drug-naïve PD (n=78) or DIP (n=31) confirmed through dopamine transporter image were enrolled in this study. The YSK olfactory function (YOF) test composed of TDI domains culturally familiar odorants to Koreans, was administered to all patients.
Results:
In the study population, the patients with DIP were significantly older than the patients with PD. Over 70% of patients in each group had hyposmia or anosmia, and there was no significant difference in the occurrence of olfactory dysfunction between the two groups. In addition, there were no differences in the total YOF score and threshold score between the two groups. Meanwhile, the PD group had a significantly lower discrimination and identification score compared to the DIP group, after adjusting for age, sex, the existence of diabetes, disease duration, and cognitive function.
Conclusions:
This study demonstrated that detailed olfactory profiles are different in PD and DIP, even though olfactory dysfunction can be observed in both conditions.
... It can be divided into the head, body, and tail [84]. The hippocampus receives input from the piriform cortex [85], but the primary source of information comes from the entorhinal cortex via the perforant pathway, which reaches the dentate gyrus. Then, this structure forms a synapse with the CA3 region through the mossy fibers, and from there, forms a synapse with the CA1 region through the Schaffer collateral pathway; it finally sends efferent projections to the entorhinal cortex, completing the classical trisynaptic circuit of the hippocampus [86]. ...
Parkinson's disease (PD) is known for its motor alterations, but the importance of non-motor symptoms (NMSs), such as olfactory dysfunction (OD), is increasingly recognized. OD may manifest during the prodromal period of the disease, even before motor symptoms appear. Therefore, it is suggested that this symptom could be considered a marker of PD. This article briefly describes PD, the evolution of the knowledge about OD in PD, the prevalence of this NMS and its role in diagnosis and as a marker of PD progression, the assessment of olfaction in patients with PD, the role of α-synuclein and its aggregates in the pathophysiology of PD, and then describes some functional, morphological, and histological alterations observed in different structures related to the olfactory system, such as the olfactory epithelium, olfactory bulb, anterior olfactory nucleus, olfactory tract, piriform cortex, hippocampus, orbitofrontal cortex, and amygdala. In addition, considering the growing evidence that suggests that the cerebellum is also involved in the olfactory system, it has also been included in this work. Comprehending the existing functional and neuroanatomical alterations in PD could be relevant for a better understanding of the mechanisms behind OD in patients with this neurodegenerative disorder.
... Thus, ODs appear with a greater occurrence than the main motor symptom, i.e. resting tremor (around 70 to 80%) [11], although a majority of patients are unaware of their olfactory loss [12,13]. ODs are clinically significant in the early stage of PD [14,15] and have been reported for a long time to suggest idiopathic PD [16][17][18][19][20], to serve as a diagnostic marker [21][22][23], and to distinguish PD from Progressive Supranuclear Palsy and essential tremor [24,25]. Within the spectrum of parkinsonism, ODs are not specific to PD, but have also been reported in multiple system atrophy (MSA) patients, although ODs appear to differentiate between vascular parkinsonism and PD and are absent in parkin disease [26,27]. ...
Deep brain stimulation (DBS) is a surgical therapy typically applied in Parkinson's disease (PD). The efficacity of DBS on the control of motor symptoms in PD is well grounded while the efficacity on non-motor symptoms is more controversial, especially on olfactory disorders (ODs). The present review shows that DBS does not improve hyposmia but can affect positively identification/discrimination scores in PD. The functional hypotheses suggest complex mechanisms in terms of cerebral connectivity and neurogenesis process which could act indirectly on the olfactory bulb and olfactory pathways related to specific cognitive olfactory tasks. The functional hypotheses also suggest complex mechanisms of cholinergic neurotransmitter interactions involved in these pathways. Finally, the impact of DBS on general cognitive functions in PD could also be beneficial to identification/discrimination tasks in PD.
... It can also be related to hyposmia, which is a decrease in the capability to sense a smell. Hyposmia is also considered to be one of the earliest non-motor symptoms of PD [60]. ...
Objectives:
This systematic review analyzed the prevalence of malnutrition in patients with Parkinson's Disease.
Study design:
a systematic review.
Method:
Four databases-Cochrane, PubMed, Embase and Web of Science-were searched from October 2021 to June 2022 by two independent researchers. The inclusion criteria were as follows: patients above 18 years old with confirmed Parkinson's Disease, performed screening nutritional assessment, cohort studies, case-control studies, and cross-sectional studies. Patients without Parkinson's Disease and with other parkinsonian syndromes were excluded.
Results:
49 studies were included in this systematic review. Patients ranged in age from 20 to 96 years. There were 5613 subjects included. According to Mini Nutritional Assessment, 23.9% (n = 634) participants were at risk of malnutrition and 11.1% (n = 294) were malnourished. According to BMI score, most patients were either obese or overweight.
Conclusions:
the prevalence of malnutrition or risk of malnutrition in the study group was significant. Therefore, more specific and detailed studies on the prevalence of malnutrition in patients with Parkinson's Disease are needed.
... Furthermore, the olfactory test has been suggested as a useful tool for screening for PD, but it can be time consuming in the clinical period (Titova, Chaudhuri, 2018). In addition to its prevalence, olfactory dysfunctions are also predictors of the development of PD, being reiterated by cohort and longitudinal studies (Xiao et al., 2014). Several large-scale longitudinal studies are currently underway, such as the PARS (Parkinson Associated Risk Study) and TREND (Tübinger Assessment of Risk Factors for the Early Detection of Neurodegeneration) (Xiao et al., 2014). ...
... In addition to its prevalence, olfactory dysfunctions are also predictors of the development of PD, being reiterated by cohort and longitudinal studies (Xiao et al., 2014). Several large-scale longitudinal studies are currently underway, such as the PARS (Parkinson Associated Risk Study) and TREND (Tübinger Assessment of Risk Factors for the Early Detection of Neurodegeneration) (Xiao et al., 2014). These dysfunctions are also described as factors that imply cognitive impacts (Morley et al., 2011), which tend to be greater in older people with PD who have hyposmia than in people who do not (De Rui et al., 2020). ...
Parkinson's Disease (PD) is a neurodegenerative disorder that affects dopaminergic neurons in the mesencephalic substantia nigra, causing a progressive clinical course characterized by pre-motor, non-motor and motor symptoms, which negatively impact the quality of life of patients and cause high health care costs. Therefore, the present study aims to discuss the clinical manifestations of PD and to make a correlation with the gut-brain (GB) axis, approaching epidemiology and therapeutic perspectives, to better understand its clinical progression and identify symptoms early. A literature review was performed regarding the association between clinical progression, the gut-brain axis, epidemiology, and therapeutic perspectives, in addition to detailing pre-motor, non-motor symptoms (neuropsychiatric, cognitive, autonomic, sleep disorders, sensory abnormalities) and cardinal motor symptoms. Therefore, this article addresses a topic of extreme relevance, since the previously mentioned clinical manifestations (pre-motor and non-motor) can often act as prodromal markers for the early diagnosis of PD and may precede it by up to 20 years.
... Typically, in the prodromal PD phase, the spread of protein aggregates resulting in the appearance of motor symptomatology manifests only after extensive pathology (3). Accordingly, non-motor symptoms have been extensively reported among patients later diagnosed with PD (76)(77)(78), appearing long before the characteristic motor impairments (79), thus pointing to early biomarker potential of non-motor phenotypes. While prodromal symptoms in patients with PD are most commonly autonomic (constipation, loss of sense of smell, etc …) and sleep disturbances, these symptoms are difficult to examine in mice. ...
There is significant evidence suggesting aggregated misfolded alpha-synuclein, a major component of Lewy bodies, propagates in a prion-like manner contributing to disease progression in Parkinson’s disease (PD) and other synucleinopathies. Animal models are essential for understanding and developing treatments for these diseases. However, despite modelling human pathology, most endpoints studied in mice do not translate to humans. Furthermore, the progression by which alpha-synuclein misfolding affects human-relevant measures such as brain volume and underlying subtle, high-level cognitive deficits is poorly understood. Here we used a mouse model of synucleinopathy; hemizygous M83 human A53T alpha-synuclein transgenic mice inoculated with recombinant human alpha-synuclein preformed fibrils (PFF) injected in the right striatum to initiate alpha-synuclein misfolding and aggregation. We examined alpha-synuclein-induced atrophy at 90 days post-injection using ex vivo magnetic resonance imaging as well as high-level cognition and motor function, as biomarkers of alpha-synuclein toxicity. We observed widespread atrophy in bilateral regions that project to or receive input from the injection site, highlighting a network of regions that are consistent with structural changes observed in humans with PD. Moreover, we detected early deficits in reversal learning with touchscreen testing in PFF-injected mice prior to motor dysfunction, consistent with the pathology observed in cortical-striatal and thalamic loops. We show, using translational approaches in mice, that progression of prion-like spreading of alpha-synuclein causes selective atrophy via connected brain regions leading to high-level cognitive deficits. We propose that precise imaging and cognitive biomarkers can provide a more direct and human-relevant measurement of alpha-synuclein-induced toxicity in pre-clinical testing.
Significance Statement
The work described in this manuscript showcases the utility of state-of-the-art methodologies (magnetic resonance imaging and touchscreen behavioural tasks) to examine endophenotypes, both in terms of symptomatology and neuroanatomy, of alpha-synuclein propagation in a mouse model of synucleinopathy. Our work further validates the M83-Hu-PFF mouse model of synucleinopathy-associated pathogenesis of neurodegenerative diseases while highlighting precise imaging and cognitive biomarkers of protein misfolding toxicity. Specifically, we identified rapid and translational biomarkers that can serve as a proxy for the direct examination of cellular levels for pathology. We anticipate that these biomarkers can measure progression of toxicity, specifically in the early phases, and may be more reliable than end stage pathology and more useful as endpoints in the examination of novel therapeutics.
... Olfactory deficits are common in an array of neurological and neurodegenerative conditions such as cerebrovascular accidents, traumatic brain injuries and dementias (e. g., Aliani et al., 2013). Reduced sensibility to odor -hyposmia -is a major symptom of Parkinson's Disease (PD) present in approximately 90 percent of early-staged cases (Xiao, Chen, & Le, 2014). The gradual loss of smell is considered a predictor of the development of PD. ...
... The observation that olfactory deficits manifest themselves prior to other symptoms of PD led to the hypothesis that the initial causative event for the development of the disorder takes place in the rhinencephalon -olfactory region -before the basal ganglia becomes affected (Hawkes, Shephard, & Daniel, 1999). Hyposmia and anosmia are studied as potential biomarkers for different brain-based disorders; examining olfactory symptoms in neurological conditions could help clarify their underlying pathological mechanisms (Xiao et al., 2014). ...
... The empirical body of literature has linked olfactory dysfunctions to a widerange of health conditions. Those include, but are not limited to, neurological and neurodegenerative illnesses, such as traumatic brain injuries, cerebrovascular accidents and Alzheimer's disease, Parkinson's Disease, psychological disorders, including anxiety, depression, and psychotic conditions, and even the current pandemic of SARS-CoV2 (e. g., Hornuss et al., 2020;Rottstaedt et al., 2018;Sun et al., 2012;Xiao et al., 2014). Assessing abnormalities in olfaction is, thus, crucial as it may help diagnose numerous conditions that affect the human brain. ...
Olfactory deficits are common among nonclinical and clinical patients, particularly in those with neuropsychological conditions. They are, however, often not diagnosed because standard assessments focus on superior cognitive domains and do not examine the senses. Olfactory function greatly impacts mental health and quality of life. It is also associated with the likelihood of developing neurological or psychological conditions and impacts the prognostic and rehabilitative outcomes of patients, particularly in regards to cognitive health. The purpose of this article is to (a) provide an overview of the olfactory sense and its unique characteristics, (b) discuss the scientific literature around olfaction and related neurological and psychological conditions, (c) present common olfactory assessment techniques, and (d) argue for the inclusion of olfactory measures to standard neuropsychological examinations. An olfactory measurement tool is currently being developed that is suitable to supplement neuropsychological examinations.
... Hyposmia occurs in~90% of early-stage cases of PD [41]. The shorter version of The University of Pennsylvania Smell Identification Test (UPSIT) smell test was used to evaluate hyposmia using twelve cards, each with a different smell (Brief Smell Identification Test™ (B-SIT ® )). ...
Carriers of GBA1 gene variants have a significant risk of developing Parkinson’s disease (PD). A cohort study of GBA carriers between 40–75 years of age was initiated to study the presence of prodromal PD features. Participants underwent non-invasive tests to assess different domains of PD. Ninety-eight unrelated GBA carriers were enrolled (43 males) at a median age (range) of 51 (40–74) years; 71 carried the N370S variant (c.1226A > G) and 25 had a positive family history of PD. The Montreal Cognitive Assessment (MoCA) was the most frequently abnormal (23.7%, 95% CI 15.7–33.4%), followed by the ultrasound hyperechogenicity (22%, 95% CI 14–32%), Unified Parkinson’s Disease Rating Scale part III (UPDRS-III) (17.2%, 95% CI 10.2–26.4%), smell assessment (12.4%, 95% CI 6.6–20.6%) and abnormalities in sleep questionnaires (11%, 95% CI 5.7–19.4%). Significant correlations were found between tests from different domains. To define the risk for PD, we assessed the bottom 10th percentile of each prodromal test, defining this level as “abnormal”. Then we calculated the percentage of “abnormal” tests for each subject; the median (range) was 4.55 (0–43.5%). Twenty-two subjects had more than 15% “abnormal” tests. The limitations of the study included ascertainment bias of individuals with GBA-related PD in relatives, some incomplete data due to technical issues, and a lack of well-characterized normal value ranges in some tests. We plan to enroll additional participants and conduct longitudinal follow-up assessments to build a model for identifying individuals at risk for PD and investigate interventions aiming to delay the onset or perhaps to prevent full-blown PD.
... Reversetranscription polymerase chain reaction (RT-PCR), in situ hybridization and immunohistochemical staining techniques have, indeed, revealed an increased SARS-CoV-2 viral load in the nasal epithelium (Meinhardt et al., 2021). Impaired sense of smell is a highly prevalent non-motor symptom in PD as well, appearing in approximately 90% of PwP in the early or premotor prodromal stage, occasionally preceding the emergence of motor symptoms by years (Haehner, Hummel, & Reichmann, 2011;Xiao, Chen, & Le, 2014). Hyposmic PwP have been found to exhibit worse motor and cognitive progression, lower QoL scores and requiring higher levodopa equivalent doses (LED) compared to normosmic ones (Gjerde et al., 2018;He et al., 2020). ...
The Coronavirus Disease 2019 (Covid-19) pandemic has profoundly affected the quality of life (QoL) and health of the general population globally over the past 2 years, with a clear impact on people with Parkinson's Disease (PwP, PD). Non-motor symptoms have been widely acknowledged to hold a vital part in the clinical spectrum of PD, and, although often underrecognized, they significantly contribute to patients' and their caregivers' QoL. Up to now, there have been numerous reports of newly emerging or acutely deteriorating non-motor symptoms in PwP who had been infected by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), while some of these symptoms, like fatigue, pain, depression, anxiety and cognitive impairment, have also been identified as part of the long-COVID syndrome due to their persistent nature. The subjacent mechanisms, mediating the appearance or progression of non-motor symptoms in the context of Covid-19, although probably multifactorial in origin, remain largely unknown. Such mechanisms might be, at least partly, related solely to the viral infection per se or the lifestyle changes imposed during the pandemic, as many of the non-motor symptoms seem to be prevalent even among Covid-19 patients without PD. Here, we summarize the available evidence and implications of Covid-19 in non-motor PD symptoms in the acute and chronic, if applicable, phase of the infection, with a special reference on studies of PwP.
... Clinically, before the onset of motor symptoms, PD will involve the pre-olfactory nucleus and the olfactory bulb and cause olfactory disorders, and hyposmia is a common clinical manifestation in the early stage of PD (Ansari and Johnson, 1975). The reported prevalence of hyposmia in early Parkinson's disease is up to 90%, making it a potential biomarker of the disease (Xiao et al., 2014), and the hyposmia gradually worsens as the disease progresses after entering the motor-symptom stage (Schapira et al., 2017). It has been accepted as one of the supportive diagnoses of Parkinson's disease (Postuma et al., 2015) and is considered to be a reliable disease marker (Sui et al., 2019). ...
Before the onset of motor symptoms, Parkinson’s disease (PD) involves dysfunction of the anterior olfactory nucleus and olfactory bulb, causing olfactory disturbance, commonly resulting in hyposmia in the early stages of PD. Accumulating evidence has shown that blood oxygen level dependent (BOLD) signals in white matter are altered by olfactory disorders and related stimuli, and the signal changes in brain white matter pathways show a certain degree of specificity, which can reflect changes of early olfactory dysfunction in Parkinson’s disease. In this study, we apply the functional covariance connectivity (FCC) method to decode FCC of gray and white matter in olfactory-related brain regions in Parkinson’s disease. Our results show that the dorsolateral prefrontal, anterior entorhinal cortex and fronto-orbital cortices in the gray matter have abnormal connectivity with the posterior corona radiata and superior corona radiata in white matter in patients with Parkinson’s hyposmia. The functional covariance connection strength (FCS) of the right dorsolateral prefrontal cortex and white matter, and the covariance connection strength of the left superior corona radiata and gray matter function have potential diagnostic value. These results demonstrate that alterations in FCC of gray and white matter in olfactory-related brain regions can reflect the change of olfactory function in the early stages of Parkinson’s disease, indicating that it could be a potential neuroimaging marker for early diagnosis.
