Hyposmia in neurodegenerative disorders …

Douglas J Lanska MD MS MSPH

Neurobehavioral & Cognitive Disorders

Updated 04.30.2024
Released 04.21.2013
Expires For CME 04.30.2027

Hyposmia in neurodegenerative disorders

Author: Douglas J Lanska MD MS MSPH

See Contributor Disclosures

Hyposmia in neurodegenerative disorders

In This Article

Quick Link

Introduction

Overview

In this article, the author explains the clinical presentation, pathophysiology, diagnostic workup, and management of hyposmia in neurodegenerative disorders. Olfactory deficits involving odor detection, identification, and discrimination are very common early in the course of Parkinson disease and dementia with Lewy bodies. Odor identification is also impaired in patients with REM sleep behavior disorder, a common and very early feature of Lewy body alpha-synucleinopathies. In patients with Parkinson disease or dementia with Lewy bodies, olfactory threshold and odor identification do not improve with levodopa therapy or with other pharmacologic manipulation of dopaminergic or cholinergic status.

Key points

	• Olfactory deficits involving odor detection, identification, and discrimination are very common early in the course of Parkinson disease and dementia with Lewy bodies.
	• Odor identification is also impaired in patients with REM sleep behavior disorder, a common and very early feature of Lewy body alpha-synucleinopathies.
	• Less commonly, some degree of olfactory loss has also been reported in various other dementing disorders, including Alzheimer disease and frontotemporal dementia.
	• In patients with Parkinson disease or dementia with Lewy bodies, olfactory threshold and odor identification do not improve with levodopa therapy or with other pharmacologic manipulation of dopaminergic or cholinergic status.

Clinical manifestations

Presentation and course

	• Olfactory deficits involving odor detection, identification, and discrimination are very common early in the course of Parkinson disease.
	• The decline of cognitive function in early Parkinson disease is more rapid in patients with hyposmia at diagnosis than in those with normosmia.
	• Olfaction is significantly reduced in some genetic forms of Parkinson disease, but when present, the degree of impairment is usually less than that in Parkinson disease.
	• Patients with Parkinson disease scored lower than age- and gender-matched controls on smell detection, definition, recognition, and forced choice (discrimination).
	• In dementia with Lewy bodies, olfactory dysfunction is nearly universal, develops early (ie, before any movement or cognitive disorder), and is often severe.
	• Odor identification is also impaired in patients with REM sleep behavior disorder, a common and very early feature of Lewy body alpha-synucleinopathies.
	• Although hyposmia is a frequent, early, and often severe abnormality in Parkinson disease and dementia with Lewy bodies, this is not so in other forms of parkinsonism, including multiple system atrophy, vascular parkinsonism, progressive supranuclear palsy, or corticobasal degeneration, nor is hyposmia a feature of essential tremor.
	• Some degree of olfactory loss has also been reported in various other dementing disorders, including Alzheimer disease and frontotemporal dementia.

Olfactory dysfunction is a clinical marker for early stages of neurodegenerative diseases (34). In addition, cerebral neurodegenerative and microvascular lesions are common neuropathologies linking anosmia with mild cognitive impairment in older adults (21).

Idiopathic Parkinson disease. Olfactory deficits involving odor detection, identification, and discrimination are very common early in the course of Parkinson disease (53; 23; 07; 129; 112; 30; 12; 43; 83; 115; 29; 67; 63; 20). Occasionally, patients with Parkinson disease may develop pleasant olfactory hallucinations (phantosmias) (65). Impaired olfaction can predate the motor symptoms of Parkinson disease by at least 4 or 5 years (103; 60; 03; 35; 115). Nevertheless, olfactory defects in Parkinson disease don’t progress markedly with development of motor manifestations (23).

Hyposmia in Parkinson disease is associated with various motor and nonmotor symptoms like cognition, depression, anxiety, autonomic dysfunction, constipation, rapid eye movement sleep behavior disorder, and other sleep disturbances, and with the degree of nigrostriatal dopaminergic cell loss (117; 102). In multivariate regression models adjusting for age, sex, and disease duration, all motor and nonmotor symptoms of Parkinson disease were associated with olfactory function (as measured by UPSIT scores) (102). In addition, olfactory test scores were strongly associated with DaT binding in the putamen and caudate nuclei on DaT-SPECT scans (102).

In patients with Parkinson disease, olfactory deficits are associated with cognitive dysfunction, including memory impairment (02). The decline of cognitive function in early Parkinson disease is more rapid in patients with hyposmia at diagnosis than in those with normosmia (44). Olfactory impairment is also a significant predictor of postoperative delirium in patients with Parkinson disease (63). The presence of olfactory dysfunction in newly diagnosed patients with Parkinson disease increases the risk of dementia up to 10 years after Parkinson disease diagnosis regardless of baseline cognitive function, whereas normal olfaction (with normal cognition) at baseline predicts a benign cognitive course up to 10 years after diagnosis (20).

In patients with Parkinson disease, olfactory deficits are associated with autonomic defects (46). Anosmia in Parkinson disease is associated with autonomic failure, including baroreflex failure and noradrenergic denervation of the heart and other organs, independently of parkinsonism or striatal dopaminergic denervation (46).

Genetic forms of Parkinson disease. Olfaction is significantly reduced in some genetic forms of Parkinson disease, but when present, the degree of impairment is usually less than that in Parkinson disease (40; 06). Olfaction is significantly reduced among Parkin mutation heterozygotes with Parkinson disease but not among their heterozygous relatives without Parkinson disease (01). Subjects with LRRK2 G2019S mutations and Parkinson disease also have been reported to have impaired olfactory identification, although their olfactory impairment is much less than subjects with idiopathic Parkinson disease (75; 108; 118; 40; 58), and olfactory impairment seems to be limited to a specific subgroup of patients (107). Olfactory dysfunction in patients with LRRK2 mutation is positively correlated with reduced uptake of (123)I-meta-iodobenzylguanidine (MIBG) on cardiac scintigraphy, a measure of postganglionic sympathetic cardiac innervation (127). Hyposmia is less common in asymptomatic carriers of the LRRK2 G2019S mutation (118). Olfactory impairment among subjects with LRRK2 mutations and Parkinson disease has not been consistently identified in all studies; one study reported that subjects with LRRK2 mutation and Parkinson disease had a similar sense of smell to healthy LRRK2 mutation carriers and healthy family members without the mutation when adjusting for age (58). Glucocerebrosidase gene mutation-positive individuals also show deterioration in olfactory and cognitive assessment scores compared with controls, which is consistent with the prodrome of Parkinson disease (06).

Patients with Parkinson disease scored lower than age- and gender-matched controls on smell detection, definition, recognition, and forced choice (discrimination) (15). Compared with patients with acute respiratory infections, patients with Parkinson disease scored better on forced-choice testing, but no differences were found regarding other olfactory characteristics. Patients with traumatic brain injury scored significantly worse than patients with Parkinson disease on the olfaction domains.

Dementia with Lewy bodies. In dementia with Lewy bodies, like Parkinson disease, olfactory dysfunction is nearly universal, develops early (ie, before any movement or cognitive disorder), and is often severe (51; 04). Nevertheless, although olfactory disturbances have been considered a useful clinical marker of dementia with Lewy body disease (138), the addition of anosmia to the consensus diagnostic criteria for dementia with Lewy bodies did not significantly improve their overall performance (79; 87; 134). Severe hyposmia is nevertheless helpful in distinguishing neuropathologically confirmed dementia with Lewy bodies from Alzheimer disease (04). In patients with dementia with Lewy bodies, olfactory and trigeminal detection thresholds are significantly lower as compared to Parkinson disease dementia patients (37).

REM sleep behavior disorder. Odor identification is also impaired in patients with REM sleep behavior disorder, a common and very early feature of Lewy body alpha-synucleinopathies (122; 33; 82; 81; 98; 97; 57; 115; 73; 56; 71). Olfactory dysfunction also predicts early transition to a Lewy body disease in idiopathic REM sleep behavior disorder (73; 80) but cannot distinguish between Parkinson disease and dementia with Lewy bodies (80). Olfactory impairment is a sensitive and stable diagnostic biomarker of REM sleep behavior disorder and appears to be useful for identifying patients with idiopathic REM sleep behavior disorder at high risk for early conversion to Parkinson disease (71). Olfactory abnormalities are often measurable at least 5 years before disease onset and progress slowly in the preclinical stages but do not progress much, if at all, after onset (97; 57; 71).

Other movement disorders. Although hyposmia is a frequent, early, and often severe abnormality in Parkinson disease and dementia with Lewy bodies, this is not so in other forms of parkinsonism, including multiple system atrophy, vascular parkinsonism, progressive supranuclear palsy, or corticobasal degeneration, nor is hyposmia a feature of essential tremor (130; 61; 113; 92; 31).

Pathologically confirmed Parkinson disease had reduced olfaction compared with progressive supranuclear palsy or controls (114). Indeed, the presence of hyposmia in progressive supranuclear palsy suggests the presence of additional Lewy body pathology.

Most studies of olfaction in corticobasal degeneration have reported relatively mild deficits, but olfactory dysfunction can be moderate or severe in this disorder (92).

A mild olfactory loss develops later in the course of multiple system atrophy (61), but it is not clear that this is of clinical significance (64).

Olfactory assessment using the TDI global olfactory score (ie, comprised of the Threshold, Discrimination, and Identification subtests) from the Sniffin' Sticks test is a rapid, safe, and easily applicable biomarker that can differentiate tremor-dominant Parkinson disease from essential tremor in doubtful cases (31).

Other dementing disorders (eg, Alzheimer disease and frontotemporal dementia). Some degree of olfactory loss has also been reported in various other dementing disorders, including Alzheimer disease and frontotemporal dementia (26; 133; 136; 134; 39; 106; 67; 72; 18; 48; 128; 17; 19; 36; 74; 88; 93; 99; 141; 16). Olfactory impairment is more marked early in the course of the disease in patients with dementia with Lewy bodies than in those with either Alzheimer disease or frontotemporal dementia (134). Nevertheless, olfactory deficits have been reported in Alzheimer disease (26; 120; 77; 69; 106; 67; 18; 48; 128; 17; 19; 36; 88; 93; 99; 141), and these deficits may be detectable before the appearance of overt memory loss (69; 17), increase with severity of dementia (85; 111; 135; 128; 17), are associated with noncognitive neuropsychiatric symptoms (128), and correlate with density of neurofibrillary tangles in the entorhinal cortex and hippocampus (136) and with cortical Lewy body pathology (79). It remains unclear, though, whether Alzheimer disease is associated with clinically meaningful hyposmia in the absence of Lewy body pathology (79). Olfactory dysfunction, if apparent in Alzheimer disease, can sometimes help in the differential diagnosis with depression (120; 77). Frontotemporal dementia is also associated with relatively mild olfactory deficits, comparable to those seen in Alzheimer disease (78; 72; 74).

Familial ataxias. Mild hyposmia, less severe than that seen in Parkinson disease, has been observed in familial ataxias, but it has been suggested that this may be due to general cognitive deficits rather than specific olfactory problems (84). The ability of patients with spinocerebellar ataxia type 7 to discriminate and identify odors is significantly impaired, although their odor detection thresholds are normal, suggesting that olfactory perception is affected even when olfactory sensory capabilities are spared (42). Olfactory identification deficits have also been observed in FMR1 premutation carriers at risk for fragile X tremor/ataxia syndrome (59). The severity of olfactory impairment is comparable to that reported in hereditary ataxias (84) but less than that in Parkinson disease and Alzheimer disease (59). The frequency and severity of these olfactory defects are greater in cognitively impaired compared to cognitively intact carriers (59).

Motor neuron disease. According to some investigators, olfactory deficits may also occur with motor neuron disease (32; 51; 125; 95), but smell testing is not likely to be of clinical value in this condition. In any case, other investigators have not substantiated significant olfactory deficits in motor neuron disease (66).

Prognosis and complications

In some elderly patients, hyposmia may be an early ("preclinical") marker for the subsequent development of overt neurodegenerative disease. Among older persons without manifest cognitive impairment or parkinsonism, impairment of odor identification predicts subsequent cognitive decline, the development of both mild cognitive impairment and Parkinson disease, and the progression of amnestic mild cognitive impairment to Alzheimer disease (137; 103; 39; 25; 119; 101). Impaired olfaction can predate clinical Parkinson disease in men by at least 4 or 5 years and may be a useful screening tool to detect those at high risk for developing Parkinson disease in later life (103). The severity of olfactory impairment early in the course of Parkinson disease may also be a useful marker for the risk of neuropsychiatric complications (121). Impaired olfaction is also a putative predictor of the conversion of amnestic mild cognitive impairment to subsequent Alzheimer disease (39; 123).

In general, for patients with olfactory dysfunction, the prognosis depends primarily on etiology and the degree of residual function but also secondarily on gender, parosmia (distortion of the sense of smell), smoking habits, and age (38; 55). Male gender, initial presence of parosmia, smoking, and older age are negative prognostic factors (55).

Impaired olfaction adversely affects quality of life and the enjoyment of eating and contributes to hypogeusia, impaired appetite, weight loss, frailty, and depression in elderly patients (41). In addition, it may pose a safety risk, as affected individuals may not smell smoke or gas leaks and are less likely to recognize that food has spoiled.

A systematic review of neurodegenerative changes on MRI in patients with olfactory impairment and mild cognitive impairment or dementia found that hippocampal volume correlates with olfactory performance in individuals with cognitive impairment and that olfactory functional MRI may improve early detection of Alzheimer disease (142); however, the predictive utility of these imaging markers was limited in prospective studies.

In a cross-sectional and longitudinal study of olfaction among 364 initially cognitively normal community-dwelling older adults who had baseline olfaction data and subsequent cognitive assessments during an average 2.4-year follow-up period, poorer olfaction predicted incident mild cognitive impairment (126). Additionally, poorer olfaction was associated with overall and regional amyloid beta peptide (Aβ) in a subset who had PET amyloid imaging. Greater olfaction decline is associated with faster Aβ and tau accumulation in olfaction-related regions.

A cohort study from Shanghai, China, included 1811 participants aged 60 years or older who completed both an olfactory identification test and a cognitive assessment at baseline (2010–2011) (11). At the 10-year follow-up, olfactory impairment was associated with long-term mortality in older adults, and the association was even stronger in those with neurodegenerative diseases. Failure to identify coffee or a rose was associated with a higher mortality risk, and the association was mediated by neurodegenerative diseases.

A systematic review and meta-analysis also found that olfactory impairment is associated with all-cause mortality (91). Olfactory loss was associated with a significantly higher pooled hazard (hazard ratio: 1.52) of all-cause mortality.

Biological basis

	• Olfactory loss in Parkinson disease and dementia with Lewy bodies is not due to damage to the olfactory epithelium but instead results from central nervous system abnormalities.
	• Pathology of the olfactory bulb and tract occurs prior to motor signs of Parkinson disease.
	• The pathophysiology of hyposmia in Lewy body alpha-synucleinopathies may have multiple components, including those resulting from degenerative changes in the olfactory bulb and primary olfactory cortex as well as limbic dysfunction and, possibly, prefrontal dysfunction.
	• Impaired olfaction in Alzheimer disease may reflect neurodegeneration within basal telencephalic structures that mediate olfactory processing, including the anterior olfactory nucleus.

Etiology and pathogenesis

Olfactory loss in neurodegenerative disorders is thought to result from central nervous system abnormalities involving olfactory pathways.

Olfactory loss in Parkinson disease and dementia with Lewy bodies is not due to damage to the olfactory epithelium but instead results from central nervous system abnormalities (52; 139; 02). Patients with Parkinson disease and severe hyposmia show decreased gray matter volume in the bilateral cuneus, associative visual area, precuneus, and anterior temporal lobes as well as a widespread significant decrease in amygdala functional connectivity (143). The decrease in amygdala functional connectivity with the inferior parietal lobule, lingual gyrus, and fusiform gyrus was significantly correlated with both reduction of cognitive assessment scores and the severity of hyposmia (143).

In 1-methyl-4-phenyl-1, 2, 3, 6- tetrahydropyridine (MPTP)-induced Parkinson disease in mice, nicotine intervention significantly alleviated olfactory and motor dysfunction (49). These improvements were correlated with reduced apoptosis of olfactory sensory neurons via activation of the prok2R/Akt/FoxO3a signaling pathway.

Pathology of the olfactory bulb and tract occurs prior to motor signs of Parkinson disease (52). In synucleinopathies, olfactory dysfunction relates specifically to Lewy body pathology, and correlates with cardiac sympathetic denervation, independently of striatal dopamine deficiency or parkinsonism (45). Impaired olfaction in Parkinson disease is associated with the presence of Lewy bodies and neuronal loss in the olfactory bulb and tract, with a strong correlation between neuronal loss and disease duration (94). In Parkinson disease, the olfactory bulb contains numerous Lewy bodies, and severe neuronal loss is present in the anterior olfactory nucleus (64). Immunolabeling for alpha-synuclein in the olfactory bulb and tract occurs prior to clinical signs of parkinsonism in dementia with Lewy bodies (52). The presence of Lewy body alpha-synucleinopathy in the olfactory bulb accurately predicts the presence of Lewy body pathology in other brain regions (05). Cortical olfactory receptors also become dysregulated in Parkinson disease (43). In pathological models overexpressing alpha-synuclein, high expression of this protein in neurons is a critical risk factor for neurodegeneration (124). Progressive atrophy of central olfactory structures using voxel-based morphometry may be a potential indicator of Lewy body disease progression in isolated REM sleep behavior disorder (140).

A cross-sectional study of 541 participants in the Rhineland Study, a population-based cohort study in Bonn, Germany, found that olfactory bulb volume on MRI was independently associated with odor identification function and was a strong mediator of the age-dependent association between volumes of central olfactory structures and olfactory function (70). Consequently, neurodegeneration-associated olfactory dysfunction may primarily originate from the pathology of peripheral olfactory structures.

Environmental toxins may also play a role in the development of Parkinson disease and in the associated olfactory impairment. From epidemiological studies, chronic inhalation exposure to welding fumes containing metal mixtures is associated with, and may play a role in the etiology of, the development of Parkinson disease. In particular, nasal exposure to vanadium pentoxide adversely affects olfactory bulbs, resulting in neurobehavioral and neurochemical impairments (86). Vanadium is present in welding fumes, such as vanadium pentoxide, and vanadium is increasingly incorporated in the production of high-strength steel. Vanadium pentoxide induces dopaminergic neurotoxicity via protein kinase C delta-dependent oxidative signaling mechanisms in dopaminergic neuronal cells (86).

The pathophysiology of hyposmia in Lewy body alpha-synucleinopathies may have multiple components, including those resulting from degenerative changes in the olfactory bulb and primary olfactory cortex, as well as limbic dysfunction and possibly prefrontal dysfunction (53; 08; 09; 131; 02). Functional imaging indicates that reduced neuronal activity in the amygdala, hippocampus, and piriform cortex (uncus) contributes to olfactory dysfunction in Parkinson disease (131; 02). Hyposmia in Parkinson disease is more closely associated with cholinergic denervation of limbic archicortex (ie, hippocampus and amygdala) than with nigrostriatal dopaminergic denervation (09). However, because olfactory threshold and odor identification in Parkinson disease are not related to duration of disease, to current therapy with levodopa or anticholinergic drugs, or to “on” and “off” states, olfactory impairment in Parkinson disease likely involves mechanisms that are not due to dopaminergic or cholinergic denervation and that are not influenced by pharmacologic manipulation of dopaminergic or cholinergic status (100).

Impaired olfaction in Alzheimer disease may reflect neurodegeneration within basal telencephalic structures that mediate olfactory processing, including the anterior olfactory nucleus (106). Similarly, olfactory dysfunction in behavioral variant frontotemporal dementia has been attributed to disruption of association areas involved in olfactory processing, particularly those in the temporal lobe and amygdala (89). In a large, prospective, population-based study, odor identification impairment was associated with a decline in episodic memory but only in carriers of the ɛ4 allele of the apolipoprotein E gene (88). Other studies of olfaction in Alzheimer disease have implicated an early imbalance in splicing factors, the subsequent interruption of the cycling of neurotransmitters, alteration in toxic and protective mechanisms of beta-amyloid, and ultimately mitochondrial dysfunction in conjunction with a disturbance in neuron-neuron adhesion (144).

A mild olfactory loss develops later in multiple system atrophy (61) and is associated with characteristic glial cytoplasmic inclusions in the olfactory bulb and some degree of neuronal loss in the anterior olfactory nucleus (64).

A relatively mild olfactory impairment has also been reported in patients with normal pressure hydrocephalus, but odor identification test scores are unaffected by either extended lumbar drainage or implantation of a ventriculo-peritoneal shunt (93).

The relationship between sensory impairment and cognitive impairment is not unique to the olfactory system, but a similar relationship or comparable magnitude exists for hearing and visual impairments, which implies that sensory health per se may be a marker of brain health or, equivalently, that impairments of the special senses may be an indicator of brain aging or disease-related dysfunction (36). This does not obviate the strong associations between some forms of modality-specific dysfunction of the special senses and certain disease states.

Epidemiology

• Olfactory deficits are very common early in the course of Parkinson disease and are present in more than 90% of patients with early-stage Parkinson disease.

Factors associated with olfactory status and decline over 5 years were examined in the Atherosclerosis Risk in Communities (ARIC) Neurocognitive Study, which included 6053 participants with a mean age of 76 years (116). Older age, male sex, lower education, Black race, APOE ε4 alleles, and diabetes were associated with more odor identification errors and higher anosmia prevalence, whereas greater physical activity and hypertension were associated with better olfaction. Age, male sex, lower education, Black race, APOE ε4 allele, and vitamin B12 levels were associated with incident anosmia over 5 years.

Olfactory deficits are very common early in Parkinson disease and are present in more than 90% of patients with early-stage Parkinson disease (53; 23; 07; 112; 30; 50). Using standardized olfactory assessment tools (ie, University of Pennsylvania Smell Identification Test), olfactory deficits are nearly universal in patients with Parkinson disease who have confirmed evidence of nigrostriatal denervation by PET imaging (50). Idiopathic olfactory dysfunction in first-degree relatives of Parkinson disease patients is also associated with an increased risk of developing Parkinson disease within 2 to 5 years (96). Olfactory deficits are nearly universal in the early stages of dementia with Lewy bodies (51).

Prodromal Parkinson disease is infrequent among patients with idiopathic hyposmia (76).

Hyposmia is associated with dysautonomia in Parkinson disease and is selectively associated with cardiac sympathetic burden (105).

Olfactory deficits are less common and less severe in Alzheimer disease and other neurodegenerative disorders (132), though some studies still report a high prevalence of olfactory dysfunction in Alzheimer disease, approaching 90% in some studies (144).

Nevertheless, olfactory dysfunction is associated with an increased risk of dementia, especially in those with severe olfactory impairment in combination with a genetic risk of Alzheimer disease (68). In a population-based study of 2473 dementia-free persons with a mean age of 70 years, the Sniffin sticks odor identification task was used to identify those with mild (hyposmia) and severe (anosmia) olfactory dysfunction (68). Olfactory dysfunction was significantly associated with a 2.0-fold increased hazard of dementia, with the strongest association for anosmia (2.9). Results were consistent across age and sex subgroups and after adjusting for potential confounders. APOE ε4 carriers with anosmia had the highest hazard of dementia (ε4: 7.0; ε4/ε4: 19.8).

Differential diagnosis

Disorders of olfaction in the elderly can be conveniently divided into conductive, sensorineural, and central disorders, where (1) conductive disorders involve transmission of the sensory stimuli to the sensory receptors (usually, but not always, by impeding transmission), (2) sensorineural disorders involve dysfunction of the sensory receptors or conduction of signals from the sensory receptors to the brain, and (3) central disorders involve dysfunction of processing of sensory information within the central nervous system, and particularly within the brainstem and cerebrum.

Conductive hyposmia (depending on the author or circumstance, “conductive” is sometimes stated conversely as “obstructive”) occurs if there are impediments to conveyance of odorants to the olfactory neuroepithelium (eg, upper respiratory infection, chronic rhinosinusitis, nasal polyposis). Sensorineural disorders involve the receptors themselves (“sensory”) or the afferent neural pathways involving the respective cranial nerves, tracts, or central processing centers of the brain (collectively “neural”). In addition to presbyosmia (age-related olfactory dysfunction), other common causes of sensorineural hyposmia in the elderly include tobacco smoking, drug toxicity, head injury, hypothyroidism, and post-viral disorders (following an influenza-like infection). Common causes of central hyposmia in the elderly include Parkinson disease and dementia with Lewy bodies, but other neurodegenerative disorders (eg, Alzheimer disease) may also cause olfactory impairment.

Markedly reduced olfaction in a parkinsonian patient is supportive of Parkinson disease or dementia with Lewy bodies (130), whereas normal smell identification is rare with these conditions and should prompt review of the diagnosis (unless possibly if the patient is female with tremor-dominant disease) (51). Nevertheless, adding anosmia to the consensus criteria for dementia with Lewy bodies did not significantly improve their overall performance (79; 87; 134).

Preserved or mildly impaired olfactory function in a parkinsonian patient is more likely to be related to atypical parkinsonism, such as vascular parkinsonism, multiple system atrophy, progressive supranuclear palsy, or corticobasal degeneration (62; 51). Although hyposmia is a frequent and early abnormality in Parkinson disease and dementia with Lewy bodies, this is not so in other forms of parkinsonism (ie, without Lewy bodies), nor is hyposmia a feature of essential tremor (130; 61; 113; 92). However, these heuristic clinical rules are not absolute because occasional patients with corticobasal degeneration have moderate or severe olfactory impairment (92).

Diagnostic workup

	• Elderly patients with hyposmia should undergo a focused history and examination that particularly addresses the sense of smell, the nasal passages, and the nervous system, with attention to recognizing disorders of movement and cognition.
	• Office smell testing can include well-standardized, commercially available tests (eg, University of Pennsylvania Smell Identification Test or UPSIT) or crude approaches utilizing identification of a few readily available odorants (eg, oil of Wintergreen, oil of cloves).
	• A history of head trauma, past and current tobacco smoking, and medications should be reviewed for potential contributing causes to olfactory dysfunction.
	• Thyroid dysfunction should be excluded.
	• Patients with neurologic signs or symptoms need further evaluation to exclude neurodegenerative disorders and, rarely, structural lesions of the cribriform plate or basal forebrain.
	• Neuroimaging is recommended in patients with dementia and in those with asymmetric or unilateral hyposmia not attributable to conductive hyposmia.

Even if disease-modifying therapies were available for neurodegenerative disease, smell tests alone do not have a high enough predictive power to be used in a screening program for neurodegenerative disease (47). However, they could serve as a component of a short test battery or as part of a stepwise process that could be used to more accurately identify early neurodegeneration in large populations.

Elderly patients with hyposmia should undergo a focused history and examination that particularly addresses the sense of smell, the nasal passages, and the nervous system, with attention to recognizing disorders of movement and cognition. Office testing of smell can include well-standardized, commercially available tests (eg, University of Pennsylvania Smell Identification Test or UPSIT) or crude approaches utilizing identification of a few readily available odorants (eg, oil of Wintergreen, oil of cloves) (27; 28; 22; 24; 90). More complicated odor identification and detection tests are also available but are rarely practical outside of specialized diagnostic laboratories (22). The UPSIT is a forced-choice olfactory discrimination test utilizing micro-encapsulated odorants in standardized “scratch 'n sniff” booklets. UPSIT scores are standardized by gender and age and can be used to identify degrees of hyposmia and some malingerers. UPSIT may be sensitive to decline in dementia and is largely unaffected by premorbid cognitive functioning, making it particularly useful in the evaluation of olfaction in patients with cognitive dysfunction (109). Irritant substances, such as ammonia, are sometimes employed when psychogenic or malingered anosmia is a consideration because such substances are perceived via trigeminal afferent pathways rather than through the olfactory system.

A history of head trauma, past and current tobacco smoking, and medications should be reviewed for potential contributing causes to olfactory dysfunction. Thyroid dysfunction should be excluded with thyroid-stimulating hormone (TSH) and free T4 assays. Patients with evidence of a conductive olfactory disturbance may warrant CT imaging of the paranasal sinuses or otolaryngological referral. Patients with neurologic signs or symptoms need further evaluation to exclude neurodegenerative disorders and, rarely, structural lesions of the cribriform plate or basal forebrain. Neuroimaging is recommended in patients with dementia and in those with asymmetric or unilateral hyposmia not attributable to conductive hyposmia. Patients without conductive hyposmia and without evidence of neurologic signs or symptoms most likely have presbyosmia, although early neurologic disease is possible. Periodic re-examination may help identify cases of early neurodegenerative disease (eg, Alzheimer disease, Parkinson disease, dementia with Lewy bodies).

Management

	• There is no established treatment for hyposmia associated with neurodegenerative diseases, and, in general, sensorineural and central causes of hyposmia are seldom correctable.
	• In patients with Parkinson disease or dementia with Lewy bodies, olfactory threshold and odor identification do not improve with levodopa therapy or with other pharmacologic manipulation of dopaminergic or cholinergic status.
	• There is no evidence that acetylcholinesterase inhibitors or memantine help alleviate the olfactory disturbances in Alzheimer disease.

There is no established treatment for hyposmia associated with neurodegenerative diseases, and, in general, sensorineural and central causes of hyposmia are seldom correctable.

In patients with Parkinson disease or dementia with Lewy bodies, olfactory threshold and odor identification do not improve with levodopa therapy or with other pharmacologic manipulation of dopaminergic or cholinergic status (100; 54; 104). The lack of efficacy of dopaminergic therapies to correct olfactory disturbances in Parkinson disease is, at least in part, because dopamine inhibits olfactory transmission in the olfactory glomeruli (54). Deep brain stimulation does not improve olfactory function (10).

There is no evidence that acetylcholinesterase inhibitors or memantine help alleviate the olfactory disturbances in Alzheimer disease.

In general, conductive loss of olfaction is more likely to be remediable (ie, to result in significantly improved function) than is a sensorineural or central loss (110). Concomitant sinonasal disease should be treated when present. Smokers should be advised to quit smoking, and further counseling and pharmacologic management should be employed as necessary to facilitate cessation. Patients should be counseled regarding safety issues and the use of proper monitoring devices for smoke and natural gas; this is particularly important for those who are living alone. In addition, the effects of hyposmia on gustation and appetite should be assessed, and, if necessary, a dietary consult should be obtained. In some cases, dietary supplements or flavor enhancers may prove beneficial.

Multiple studies and reports of olfactory training have made unsupported claims about purported benefits in individuals with dementia. Most have been poorly designed and have not separated the effects of increased activity and engagement in the study groups from supposed benefits of improving depression and attention in subjects (13). In subjects with mild cognitive impairment, olfactory training twice a day for 4 months had no significant effect on olfaction and cognitive function (14).

References

01: Alcalay RN, Siderowf A, Ottman R, et al. Olfaction in Parkin heterozygotes and compound heterozygotes: the CORE-PD study. Neurology 2011;76(4):319-26. PMID 21205674
02: Baba T, Takeda A, Kikuchi A, et al. Association of olfactory dysfunction and brain. Metabolism in Parkinson’s disease. Mov Disord 2011;26(4):621-8. PMID 21284041
03: Bassetti CL. Nonmotor disturbances in Parkinson's disease. Neurodegener Dis 2011;8(3):95-108. PMID 21196687
04: Beach TG, Adler CH, Zhang N, et al. Severe hyposmia distinguishes neuropathologically confirmed dementia with Lewy bodies from Alzheimer's disease dementia. PLoS One 2020;15(4):e0231720. PMID 32320406
05: Beach TG, White CL 3rd, Hladik CL, et al. Olfactory bulb alpha-synucleinopathy has high specificity and sensitivity for Lewy body disorders. Acta Neuropathol 2009;117(2):169-74. PMID 18982334
06: Beavan M, McNeill A, Proukakis C, Hughes DA, Mehta A, Schapira AH. Evolution of prodromal clinical markers of Parkinson disease in a GBA mutation-positive cohort. JAMA Neurol 2015;72(2):201-8. PMID 25506732
07: Boesveldt S, Verbaan D, Knol DL, et al. A comparative study of odor identification and odor discrimination deficits in Parkinson's disease. Mov Disord 2008;23(14):1984-90. PMID 18759360
08: Bohnen NI, Gedela S, Herath P, Constantine GM, Moore RY. Selective hyposmia in Parkinson disease: association with hippocampal dopamine activity. Neurosci Lett 2008;447(1):12-6. PMID 18838108
09: Bohnen NI, Müller ML, Kotagal V, et al. Olfactory dysfunction, central cholinergic integrity and cognitive impairment in Parkinson's disease. Brain 2010;133(Pt 6):1747-54. PMID 20413575
10: Breen DP, Low HL, Misbahuddin A. The impact of deep brain stimulation on sleep and olfactory function in Parkinson's disease. Open Neurol J 2015;9:70-2. PMID 26535069
11: Cao Y, Xiao Z, Wu W, Zhao Q, Ding D. Is olfactory impairment associated with 10-year mortality mediating by neurodegenerative diseases in older adults? The four-way decomposition analysis. Front Public Health 2021;9:771584. PMID 34900915
12: Casjens S, Eckert A, Woitalla D, et al. Diagnostic value of the impairment of olfaction in Parkinson's disease. PLoS One 2013;8(5):e64735. PMID 23696904
13: Cha H, Kim S, Kim H, Kim G, Kwon KY. Effect of intensive olfactory training for cognitive function in patients with dementia. Geriatr Gerontol Int 2022;22(1):5-11. PMID 34749425
14: Chen B, Espin M, Haussmann R, et al. The effect of olfactory training on olfaction, cognition, and brain function in patients with mild cognitive impairment. J Alzheimers Dis 2022;85(2):745-54. PMID 34864678
15: Crespo Cuevas AM, Ispierto L, Vilas D, Planas A, et al. Distinctive olfactory pattern in Parkinson's disease and non-neurodegenerative causes of hyposmia. Neurodegener Dis 2018;18(2-3):143-9. PMID 29940577
16: Dan X, Wechter N, Gray S, Mohanty JG, Croteau DL, Bohr VA. Olfactory dysfunction in aging and neurodegenerative diseases. Ageing Res Rev 2021;70:101416. PMID 34325072
17: Devanand DP. Olfactory identification deficits, cognitive decline, and dementia in older adults. Am J Geriatr Psychiatry 2016;24(12):1151-7. PMID 27745824
18: Devanand DP, Lee S, Manly J, et al. Olfactory deficits predict cognitive decline and Alzheimer dementia in an urban community. Neurology 2015;84(2):182-9. PMID 25471394
19: Dhilla Albers A, Asafu-Adjei J, Delaney MK, et al. Episodic memory of odors stratifies Alzheimer biomarkers in normal elderly. Ann Neurol 2016;80(6):846-57. PMID 27696605
20: Domellöf ME, Lundin KF, Edström M, Forsgren L. Olfactory dysfunction and dementia in newly diagnosed patients with Parkinson's disease. Parkinsonism Relat Disord 2017;38:41-7. PMID 28242255
21: Dong Y, Li Y, Liu K, et al. Anosmia, mild cognitive impairment, and biomarkers of brain aging in older adults. Alzheimers Dement 2023;19(2):589-601. PMID 36341691
22: Doty RL. Office procedures for quantitative assessment of olfactory function. Am J Rhinol 2007a;21(4):460-73. PMID 17882917
23: Doty RL. Olfaction in Parkinson's disease. Parkinsonism Relat Disord 2007b;13 Suppl 3:S225-8. PMID 18267240
24: Doty RL. The Smell Identification Test Administration Manual. Haddon Heights, NJ: Sensonics, 2008.
25: Doty RL. Olfaction in Parkinson's disease and related disorders. Neurobiol Dis 2012;46(3):527-52. PMID 22192366
26: Doty RL, Reyes PF, Gregor T. Presence of both odor identification and detection deficits in Alzheimer's disease. Brain Res Bull 1987;18(5):597-600. PMID 3607528
27: Doty RL, Shaman P, Dann M. Development of the University of Pennsylvania Smell Identification Test: a standardized microencapsulated test of olfactory function. Physiol Behav 1984a;32(3):489-502. PMID 6463130
28: Doty RL, Shaman P, Kimmelman CP, Dann MS. University of Pennsylvania Smell Identification Test: a rapid quantitative olfactory function test for the clinic. Laryngoscope 1984b;94(2 Pt 1):176-8. PMID 6694486
29: Driver-Dunckley E, Adler CH, Hentz JG, et al. Olfactory dysfunction in incidental Lewy body disease and Parkinson's disease. Parkinsonism Relat Disord 2014;20(11):1260-2. PMID 25172126
30: Duda JE. Olfactory system pathology as a model of Lewy neurodegenerative disease. J Neurol Sci 2010;289(1-2):49-54. PMID 19783257
31: Elhassanien MEM, Bahnasy WS, El-Heneedy YAE, et al. Olfactory dysfunction in essential tremor versus tremor dominant Parkinson disease. Clin Neurol Neurosurg 2021;200:106352. PMID 33168334
32: Elian M. Olfactory impairment in motor neuron disease: a pilot study. J Neurol Neurosurg Pysychiatry 1991;54(10):927-8. PMID 1744650
33: Fantini ML, Postuma RB, Montplaisir J, Ferini-Strambi L. Olfactory deficit in idiopathic rapid eye movements sleep behavior disorder. Brain Res Bull 2006;70(4-6):386-90. PMID 17027774
34: Fatuzzo I, Niccolini GF, Zoccali F, et al. Neurons, nose, and neurodegenerative diseases: olfactory function and cognitive impairment. Int J Mol Sci 2023;24(3):2117. PMID 36768440
35: Ferrer I, López-Gonzalez I, Carmona M, Dalfó E, Pujol A, Martínez A. Neurochemistry and the non-motor aspects of PD. Neurobiol Dis 2012;46(3):508-26. PMID 22737710
36: Fischer ME, Cruickshanks KJ, Schubert CR, et al. Age-related sensory impairments and risk of cognitive impairment. J Am Geriatr Soc 2016;64(10):1981-7. PMID 27611845
37: Foguem C, Lemdani M, Huart C. Nasal chemosensory tests: biomarker between dementia with Lewy bodies and Parkinson disease dementia. Rhinology 2020;58(6):605-9. PMID 32830809
38: Frye RE, Schwartz BS, Doty RL. Dose-related effects of cigarette smoking on olfactory function. JAMA 1990;263(9):1233-6. PMID 2304239
39: Fusetti M, Fioretti AB, Silvagni F, et al. Smell and preclinical Alzheimer disease: study of 29 patients with amnesic mild cognitive impairment. J Otolaryngol Head Neck Surg 2010;39(2):175-81. PMID 20211105
40: Gaig C, Vilas D, Infante J, et al. Nonmotor symptoms in LRRK2 G2019S associated Parkinson's disease. PLoS One 2014;9(10):e108982. PMID 25330404
41: Gaines AD. Anosmia and hyposmia. Allergy Asthma Proc 2010;31(3):185-9. PMID 20615320
42: Galvez V, Diaz R, Hernandez-Castillo CR, Campos-Romo A, Fernandez-Ruiz J. Olfactory performance in spinocerebellar ataxia type 7 patients. Parkinsonism Relat Disord 2014;20(5):499-502. PMID 24629799
43: Garcia-Esparcia P, Schlüter A, Carmona M, et al. Functional genomics reveals dysregulation of cortical olfactory receptors in Parkinson disease: novel putative chemoreceptors in the human brain. J Neuropathol Exp Neurol 2013;72(6):524-39. PMID 23656994
44: Gjerde KV, Müller B, Skeie GO, Assmus J, Alves G, Tysnes OB. Hyposmia in a simple smell test is associated with accelerated cognitive decline in early Parkinson's disease. Acta Neurol Scand 2018;138(6):508-14. PMID 30058142
45: Goldstein DS, Sewell L. Olfactory dysfunction in pure autonomic failure: Implications for the pathogenesis of Lewy body diseases. Parkinsonism Relat Disord 2009;15(7):516-20. PMID 19201246
46: Goldstein DS, Sewell L, Holmes C. Association of anosmia with autonomic failure in Parkinson disease. Neurology 2010;74(3):245-51. PMID 20083801
47: Goodwin GR, Bestwick JP, Noyce AJ. The potential utility of smell testing to screen for neurodegenerative disorders. Expert Rev Mol Diagn 2022;22(2):139-48. PMID 35129037
48: Growdon ME, Schultz AP, Dagley AS, et al. Odor identification and Alzheimer disease biomarkers in clinically normal elderly. Neurology 2015;84(21):2153-60. PMID 25934852
49: Guo Q, Wang Y, Yu L, et al. Nicotine restores olfactory function by activation of prok2R/Akt/FoxO3a axis in Parkinson's disease. J Transl Med 2024;22(1):350. PMID 38609979
50: Haugen J, Müller ML, Kotagal V, et al. Prevalence of impaired odor identification in Parkinson disease with imaging evidence of nigrostriatal denervation. J Neural Transm (Vienna) 2016;123(4):421-4. PMID 26911386
51: Hawkes C. Olfaction in neurodegenerative disorder. Adv Otorhinolaryngol 2006;63:133-51. PMID 16733338
52: Hubbard PS, Esiri MM, Reading M, McShane R, Nagy Z. Alpha-synuclein pathology in the olfactory pathways of dementia patients. J Anat 2007;211(1):117-24. PMID 17553102
53: Hudry J, Thobois S, Broussolle E, Adeleine P, Royet JP. Evidence for deficiencies in perceptual and semantic olfactory processes in Parkinson's disease. Chem Senses 2003;28(6):537-43. PMID 12907591
54: Huisman E, Uylings HB, Hoogland PV. A 100% increase of dopaminergic cells in the olfactory bulb may explain hyposmia in Parkinson's disease. Mov Disord 2004;19(6):687-92. PMID 15197709
55: Hummel T, Lotsch J. Prognostic factors of olfactory dysfunction. Arch Otolaryngol Head Neck Surg 2010;136(4):347-51. PMID 20403850
56: Iijima M, Okuma Y, Suzuki K, et al. Associations between probable REM sleep behavior disorder, olfactory disturbance, and clinical symptoms in Parkinson's disease: a multicenter cross-sectional study. PLoS One 2021;16(2):e0247443. PMID 33606814
57: Iranzo A, Serradell M, Vilaseca I, et al. Longitudinal assessment of olfactory function in idiopathic REM sleep behavior disorder. Parkinsonism Relat Disord 2013;19(6):600-4. PMID 23529022
58: Johansen KK, Warø BJ, Aasly JO. Olfactory dysfunction in sporadic Parkinson's disease and LRRK2 carriers. Acta Neurol Scand 2014;129(5):300-6. PMID 23937295
59: Juncos JL, Lazarus JT, Rohr J, et al. Olfactory dysfunction in fragile X tremor ataxia syndrome. Mov Disord 2012;27(12):1556-9. PMID 23079771
60: Karpa MJ, Gopinath B, Rochtchina E, et al. Prevalence and neurodegenerative or other associations with olfactory impairment in an older community. J Aging Health 2010;22(2):154-68. PMID 20133956
61: Katzenschlager R, Lees AJ. Olfaction and Parkinson's syndromes: its role in differential diagnosis. Curr Opin Neurol 2004;17(4):417-23. PMID 15247536
62: Katzenschlager R, Zijlmans J, Evans A, Watt H, Lees AJ. Olfactory function distinguishes vascular parkinsonism from Parkinson’s disease. J Neurol Neurosurg Psychiatry 2004;75(12):1749-52. PMID 15548497
63: Kim MS, Yoon JH, Kim HJ, Yong SW, Hong JM. Olfactory dysfunction is related to postoperative delirium in Parkinson's disease. J Neural Transm (Vienna) 2016;123(6):589-94. PMID 27098668
64: Kovacs T, Papp MI, Cairns NJ, Khan MN, Lantos PL. Olfactory bulb in multiple system atrophy. Mov Disord 2003;18(8):938-42. PMID 12889086
65: Landis BS, Burkhard PR. Phantosmias and Parkinson disease. Arch Neurol 2008;65(9):1237-9. PMID 18779429
66: Lang CJ, Schwandner K, Hecht M. Do patients with motor neuron disease suffer from disorders of taste or smell. Amyotroph Lateral Scler 2011;12(5):368-71. PMID 21554187
67: Lanska DJ. Disorders of the special senses in the elderly. In: Nair A, Sabbagh M, editors. Geriatric neurology. Chichester, West Sussex, UK: John Wiley & Sons, 2014: 396-459.
68: Laukka EJ, Ekström I, Larsson M, Grande G, Fratiglioni L, Rizzuto D. Markers of olfactory dysfunction and progression to dementia: a 12-year population-based study. Alzheimers Dement 2023;19(7):3019-27. PMID 36689643
69: Li W, Howard JD, Gottfried JA. Disruption of odour quality coding in piriform cortex mediates olfactory deficits in Alzheimer's disease. Brain 2010;133(9):2714-26. PMID 20724290
70: Lu R, Aziz NA, Reuter M, Stöcker T, Breteler MMB. Evaluation of the neuroanatomical basis of olfactory dysfunction in the general population. JAMA Otolaryngol Head Neck Surg 2021;147(10):855-63. PMID 34436517
71: Lyu Z, Zheng S, Zhang X, et al. Olfactory impairment as an early marker of Parkinson's disease in REM sleep behaviour disorder: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2021;92(3):271-81. PMID 33436502
72: Magerova H, Vyhnalek M, Laczo J, et al. Odor identification in frontotemporal lobar degeneration subtypes. Am J Alzheimers Dis Other Demen 2014;29(8):762-8. PMID 24939002
73: Mahlknecht P, Iranzo A, Högl B, et al. Olfactory dysfunction predicts early transition to a Lewy body disease in idiopathic RBD. Neurology 2015;84(7):654-8. PMID 25609758
74: Markopoulou K, Chase BA, Robowski P, et al. Assessment of olfactory function in MAPT-associated neurodegenerative disease reveals odor-identification irreproducibility as a non-disease-specific, general characteristic of olfactory dysfunction. PLoS One 2016;11(11):e0165112. PMID 27855167
75: Marras C, Schüle B, Munhoz RP, et al. Phenotype in parkinsonian and nonparkinsonian LRRK2 G2019S mutation carriers. Neurology 2011;77(4):325-33. PMID 21753163
76: Marrero-Gonzalez P, Iranzo A, Bedoya D, et al. Prodromal Parkinson disease in patients with idiopathic hyposmia. J Neurol 2020;267(12):3673-82. PMID 32676768
77: McCaffrey RJ, Duff K, Solomon GS. Olfactory dysfunction discriminates probable Alzheimer’s dementia from major depression: a cross-validation and extension. J Neuropsychiatry Clin Neurosci 2000;12(1):29-33. PMID 10678509
78: McLaughlin NC, Westervelt HJ. Odor identification deficits in frontotemporal dementia: a preliminary study. Arch Clin Neuropsychol 2008;23(1):119-23. PMID 17875380
79: McShane RH, Nagy Z, Esiri MM, et al. Anosmia in dementia is associated with Lewy bodies rather than Alzheimer's pathology. J Neurol Neurosurg Psychiatry 2001;70(6):739-43. PMID 11385006
80: Miyamoto T, Miyamoto M. Odor identification predicts the transition of patients with isolated RBD: a retrospective study. Ann Clin Transl Neurol 2022;9(8):1177-85. PMID 35767550
81: Miyamoto T, Miyamoto M, Iwanami M, et al. Olfactory dysfunction in idiopathic REM sleep behavior disorder. Sleep Med 2010;11(5):458-61. PMID 20378403
82: Miyamoto T, Miyamoto M, Iwanami M, Suzuki K, Inoue Y, Hirata K. Odor identification test as an indicator of idiopathic REM sleep behavior disorder. Mov Disord 2009;24(2):268-73. PMID 18972547
83: Mollenhauer B, Trautmann E, Sixel-Döring F, et al. Nonmotor and diagnostic findings in subjects with de novo Parkinson disease of the DeNoPa cohort. Neurology 2013;81(14):1226-34. PMID 23997153
84: Moscovich M, Munhoz RP, Teive HA, et al. Olfactory impairment in familial ataxias. J Neurol Neurosurg Psychiatry 2012;83(10):970-4. PMID 22791905
85: Murphy C, Gilmore MM, Seery CS, Salmon DP, Lasker BR. Olfactory thresholds are associated with degree of dementia in Alzheimer's disease. Neurobiol Aging 1990;11(4):465-9. PMID 2381506
86: Ngwa HA, Kanthasamy A, Jin H, Anantharam V, Kanthasamy AG. Vanadium exposure induces olfactory dysfunction in an animal model of metal neurotoxicity. Neurotoxicology 2014;43:73-81. PMID 24362016
87: Olichney JM, Murphy C, Hofstetter CR, et al. Anosmia is very common in the Lewy body variant of Alzheimer's disease. J Neurol Neurosurg Psychiatry 2005;76(10):1342-7. PMID 16170073
88: Olofsson JK, Josefsson M, Ekström I, et al. Long-term episodic memory decline is associated with olfactory deficits only in carriers of ApoE-є4. Neuropsychologia 2016;85:1-9. PMID 26956928
89: Orasji SS, Mulder JL, de Bruijn SF, Wirtz PW. Olfactory dysfunction in behavioral variant frontotemporal dementia. Clin Neurol Neurosurg 2016;141:106-10. PMID 26773700
90: Ottaviano G, Frasson G, Nardello E, Martini A. Olfaction deterioration in cognitive disorders in the elderly. Aging Clin Exp Res 2016;28(1):37-45. PMID 26003671
91: Pang NY, Song HJJMD, Tan BKJ, et al. Association of olfactory impairment with all-cause mortality: a systematic review and meta-analysis. JAMA Otolaryngol Head Neck Surg 2022;148(5):436-45. PMID 35389456
92: Pardini M, Huey ED, Cavanagh AL, Grafman J. Olfactory function in corticobasal syndrome and frontotemporal dementia. Arch Neurol 2009;66(1):92-6. PMID 19139305
93: Passler JS, Doty RL, Dolske MC, St Louis PG, Basignani C, Pepe JW, Bushnev S. Olfactory ability in normal pressure hydrocephalus as compared to Alzheimer's disease and healthy controls. J Neurol Sci 2017;372:217-9. PMID 28017216
94: Pearce RK, Hawkes CH, Daniel SE. The anterior olfactory nucleus in Parkinson's disease. Mov Disord 1995;10(3):283-7. PMID 7651444
95: Pilotto A, Rossi F, Rinaldi F, et al. Exploring olfactory function and its relation with behavioral and cognitive impairment in amyotrophic lateral sclerosis patients: a cross-sectional study. Neurodegener Dis 2016;16(5-6):411-6. PMID 27497596
96: Ponsen MM, Stoffers D, Wolters ECh, Booij J, Berendse HW. Olfactory testing combined with dopamine transporter imaging as a method to detect prodromal Parkinson's disease. J Neurol Neurosurg Psychiatry 2010;81(4):396-9. PMID 19965851
97: Postuma RB, Gagnon JF, Vendette M, Desjardins C, Montplaisir JY. Olfaction and color vision identify impending neurodegeneration in rapid eye movement sleep behavior disorder. Ann Neurol 2011;69(5):811-8. PMID 21246603
98: Postuma RB, Gagnon JF, Vendette M, Montplaisir JY. Idiopathic REM sleep behavior disorder in the transition to degenerative disease. Mov Disord 2009;24(15):2225-32. PMID 19768814
99: Quarmley M, Moberg PJ, Mechanic-Hamilton D, et al. Odor identification screening improves diagnostic classification in incipient Alzheimer's disease. J Alzheimers Dis 2017;55(4):1497-507. PMID 27886011
100: Quinn NP, Rossor MN, Marsden CD. Olfactory threshold in Parkinson's disease. J Neurol Neurosurg Psychiatry 1987;50(1):88-9. PMID 3819760
101: Roberts RO, Christianson TJ, Kremers WK, et al. Association between olfactory dysfunction and amnestic mild cognitive impairment and Alzheimer disease dementia. JAMA Neurol 2016;73(1):93-101. PMID 26569387
102: Roos DS, Twisk JWR, Raijmakers PGHM, Doty RL, Berendse HW. Hyposmia as a marker of (non-) motor disease severity in Parkinson's disease. J Neural Transm (Vienna) 2019;126(11):1471-8. PMID 31515655
103: Ross GW, Petrovitch H, Abbott RD, et al. Association of olfactory dysfunction with risk for future Parkinson's disease. Ann Neurol 2008;63(2):167-73. PMID 18067173
104: Rosser N, Berger K, Vomhof P, Knecht S, Breitenstein C, Flöel A. Lack of improvement in odor identification by levodopa in humans. Physiol Behav 2008;93(4-5):1024-9. PMID 18294663
105: Ryu DW, Yoo SW, Choi KE, Oh YS, Kim JS. Correlation of olfactory function factors with cardiac sympathetic denervation in Parkinson's disease. J Neurol 2024;271(3):1397-407. PMID 37940708
106: Saiz-Sanchez D, Ubeda-Bañon I, De la Rosa-Prieto C, et al. Somatostatin, tau, and beta-amyloid within the anterior olfactory nucleus in Alzheimer disease. Exp Neurol 2010;223(2):347-50. PMID 19559700
107: Saunders-Pullman R, Ortega RA, Wang C, et al. Association of olfactory performance with motor decline and age at onset in people with Parkinson disease and the LRRK2G2019S variant. Neurology 2022;99(8):e814-23. PMID 35995594
108: Saunders-Pullman R, Stanley K, Wang C, et al. Olfactory dysfunction in LRRK2 G2019S mutation carriers. Neurology 2011;77(4):319-24. PMID 21753159
109: Schmitt AL, Livingston RB, Reese EM, Davis KM. The relationship between the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and olfaction in patients referred for a dementia evaluation. Appl Neuropsychol 2010;17(3):163-71. PMID 20799106
110: Seiden AM, Duncan HJ, Smith DV. Office management of taste and smell disorders. Otolaryngol Clin North Am 1992;25(4):817-35. PMID 1470441
111: Serby M, Larson P, Kalkstein D. The nature and course of olfactory deficits in Alzheimer's disease. Am J Psychiatry 1991;148(3):357-60. PMID 1992839
112: Shah M, Deeb J, Fernando M, et al. Abnormality of taste and smell in Parkinson's disease. Parkinsonism Relat Disord 2009;15(3):232-7. PMID 18606556
113: Shah M, Muhammed N, Findley LJ, Hawkes CH. Olfactory tests in the diagnosis of essential tremor. Parkinsonism Relat Disord 2008;14(7):563-8. PMID 18321760
114: Shill HA, Zhang N, Driver-Dunckley E, Mehta S, Adler CH, Beach TG. Olfaction in neuropathologically defined progressive supranuclear palsy. Mov Disord 2021;36(7):1700-4. PMID 33755262
115: Shin HY, Joo EY, Kim ST, Dhong HJ, Cho JW. Comparison study of olfactory function and substantia nigra hyperechogenicity in idiopathic REM sleep behavior disorder, Parkinson's disease and normal control. Neurol Sci 2013;34(6):935-40. PMID 22843227
116: Shrestha S, Zhu X, Kamath V, et al. Factors associated with poor olfaction and olfactory decline in older adults in the ARIC Neurocognitive Study. Nutrients 2023;15(16):3641. PMID 37630831
117: Siderowf A, Jennings D, Eberly S, et al. Impaired olfaction and other prodromal features in the Parkinson At-Risk Syndrome Study. Mov Disord 2012;27(3):406-12. PMID 22237833
118: Sierra M, Sánchez-Juan P, Martínez-Rodríguez MI, et al. Olfaction and imaging biomarkers in premotor LRRK2 G2019S-associated Parkinson disease. Neurology 2013;80(7):621-6. PMID 23325906
119: Sohrabi HR, Bates KA, Weinborn MG, et al. Olfactory discrimination predicts cognitive decline among community-dwelling older adults. Transl Psychiatry 2012;2:e118. PMID 22832962
120: Solomon GS, Petrie WM, Hart JR, Brackin HB Jr. Olfactory dysfunction discriminates Alzheimer’s dementia from major depression. J Neuropsychiatry Clin Neurosci 1998;10(1):64-7. PMID 9547468
121: Stephenson R, Houghton D, Sundarararjan S, et al. Odor identification deficits are associated with increased risk of neuropsychiatric complications in patients with Parkinson's disease. Mov Disord 2010;25(13):2099-104. PMID 20669288
122: Stiasny-Kolster K, Doerr Y, Möller JC, et al. Combination of 'idiopathic' REM sleep behaviour disorder and olfactory dysfunction as possible indicator for alpha-synucleinopathy demonstrated by dopamine transporter FP-CIT-SPECT. Brain 2005;128(Pt 1):126-37. PMID 15548552
123: Sun GH, Raji CA, Maceachern MP, Burke JF. Olfactory identification testing as a predictor of the development of Alzheimer's dementia: a systematic review. Laryngoscope 2012;122(7):1455-62. PMID 22552846
124: Taguchi K, Watanabe Y, Tsujimura A, Tanaka M. Expression of α-synuclein is regulated in a neuronal cell type-dependent manner. Anat Sci Int 2019;94(1):11-22. PMID 30362073
125: Takeda T, Iijima M, Uchihara T, et al. TDP-43 pathology progression along the olfactory pathway as a possible substrate for olfactory impairment in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 2015;74(6):547-56. PMID 25933387
126: Tian Q, Bilgel M, Moghekar AR, Ferrucci L, Resnick SM. Olfaction, cognitive impairment, and PET biomarkers in community-dwelling older adults. J Alzheimers Dis 2022;86(3):1275-85. PMID 35180111
127: Valldeoriola F, Gaig C, Muxí A, et al. 123I-MIBG cardiac uptake and smell identification in parkinsonian patients with LRRK2 mutations. J Neurol 2011;258(6):1126-32. PMID 21221623
128: Velayudhan L. Smell identification function and Alzheimer's disease: a selective review. Curr Opin Psychiatry 2015;28(2):173-9. PMID 5594420
129: Verbaan D, Boesveldt S, van Rooden SM, et al. Is olfactory impairment in Parkinson disease related to phenotypic or genotypic characteristics. Neurology 2008;71(23):1877-82. PMID 19047559
130: Wenning GK, Shephard B, Hawkes C, Petruckevitch A, Lees A, Quinn N. Olfactory function in atypical parkinsonian syndromes. Acta Neurol Scand 1995;91(4):247-50. PMID 7625148
131: Westermann B, Wattendorf E, Schwerdtfeger U, et al. Functional imaging of the cerebral olfactory system in patients with Parkinson's disease. J Neurol Neurosurg Psychiatry 2008;79(1):19-24. PMID 17519323
132: Westervelt HJ, Bruce JM, Faust MA. Distinguishing Alzheimer's disease and dementia with Lewy bodies using cognitive and olfactory measures. Neuropsychology 2016;30(3):304-11. PMID 26280301
133: Westervelt HJ, Carvalho J, Duff K. Presentation of Alzheimer's disease in patients with and without olfactory deficits. Arch Clin Neuropsychol 2007;22(1):117-22. PMID 17156971
134: Williams SS, Williams J, Combrinck M, Christie S, Smith AD, McShane R. Olfactory impairment is more marked in patients with mild dementia with Lewy bodies than those with mild Alzheimer disease. J Neurol Neurosurg Psychiatry 2009;80(6):667-70. PMID 19448090
135: Wilson RS, Arnold SE, Schneider JA, Boyle PA, Buchman AS, Bennett DA. Olfactory impairment in presymptomatic Alzheimer's disease. Ann N Y Acad Sci 2009;1170:730-5. PMID 19686220
136: Wilson RS, Arnold SE, Schneider JA, Tang Y, Bennett DA. The relationship between cerebral Alzheimer's disease pathology and odour identification in old age. J Neurol Neurosurg Psychiatry 2007a;78(1):30-5. PMID 17012338
137: Wilson RS, Schneider JA, Arnold SE, Tang Y, Boyle PA, Bennett DA. Olfactory identification and incidence of mild cognitive impairment in older age. Arch Gen Psychiatry 2007b;64(7):802-8. PMID 17606814
138: Wilson RS, Yu L, Schneider JA, Arnold SE, Buchman AS, Bennett DA. Lewy bodies and olfactory dysfunction in old age. Chem Senses 2011;36(4):367-73. PMID 21257733
139: Witt M, Bormann K, Gudziol V, et al. Biopsies of olfactory epithelium in patients with Parkinson's disease. Mov Disord 2009;24(6):906-14. PMID 19205070
140: Woo KA, Kim H, Yoon EJ, et al. Brain olfactory-related atrophy in isolated rapid eye movement sleep behavior disorder. Ann Clin Transl Neurol 2023;10(12):2192-207. PMID 37743764
141: Yaffe K, Freimer D, Chen H, et al. Olfaction and risk of dementia in a biracial cohort of older adults. Neurology 2017;88(5):456-62. PMID 28039314
142: Yi JS, Hura N, Roxbury CR, Lin SY. Magnetic resonance imaging findings among individuals with olfactory and cognitive impairment. Laryngoscope 2022;132(1):177-87. PMID 34383302
143: Yoneyama N, Watanabe H, Kawabata K, et al. Severe hyposmia and aberrant functional connectivity in cognitively normal Parkinson's disease. PLoS One 2018;13(1):e0190072. PMID 29304050
144: Zelaya MV, Pérez-Valderrama E, de Morentin XM, et al. Olfactory bulb proteome dynamics during the progression of sporadic Alzheimer's disease: identification of common and distinct olfactory targets across Alzheimer-related co-pathologies. Oncotarget 2015;6(37):39437-56. PMID 26517091

Patient Profile

Age range of presentation: 45 65+ years
Sex preponderance: Male=female
Heredity: Heredity may be a factor
Population groups selectively affected: None selectively affected
Occupation groups selectively affected: None selectively affected

ICD & OMIM codes

ICD-10: Anosmia: R43.0

Parosmia: R43.1

Other disturbances of smell and taste: R43.8

Unspecified disturbances of smell and taste: R43.9
ICD-11: Hyposmia: MB41.3

Anosmia: MB41.0

Parosmia: MB41.1

Other specified disturbances of smell and taste: MB41.Y

Disturbances of smell and taste, unspecified: MB41.Z

This is an article preview.
Start a Free Account
to access the full version.

Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.

Questions or Comment?

MedLink®, LLC

3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122

Toll Free (U.S. + Canada): 800-452-2400

US Number: +1-619-640-4660

Support: service@medlink.com

Editor: editor@medlink.com

ISSN: 2831-9125

Hyposmia in neurodegenerative disorders

Associated Disorders

Alzheimer disease
Corticobasal degeneration
Dementia with Lewy bodies
Frontotemporal dementia
Multiple system atrophy
- Parkinson disease
- REM sleep behavior disorder

Differential Diagnosis

Corticobasal degeneration
Presbyosmia

Also Relevant

Alzheimer disease
Corticobasal degeneration
Dementia with Lewy bodies
Frontotemporal dementia
Multiple system atrophy
- Parkinson disease
- Presbyosmia
- Rapid eye movement sleep behavior disorder

Clinical Categories

Neurobehavioral & Cognitive Disorders

Hyposmia in neurodegenerative disorders …

Hyposmia in neurodegenerative disorders

Introduction

Overview

Key points

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Differential diagnosis

Diagnostic workup

Management

References

Contributors

Author

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Wilson disease

Anti-LGI1 encephalitis

Fatal familial insomnia

Hyperventilation syndrome

Apraxia

Neurologic disorders associated with behavioral symptoms

Cortical blindness

Leukodystrophies

Hyposmia in neurodegenerative disorders

Introduction

Overview

Key points

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Differential diagnosis

Diagnostic workup

Management

References

Contributors

Author

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Wilson disease

Anti-LGI1 encephalitis

Fatal familial insomnia

Hyperventilation syndrome

Apraxia

Neurologic disorders associated with behavioral symptoms

Cortical blindness

Leukodystrophies

This is an article preview.
Start a Free Account
to access the full version.