Olfactory evoked potentials in Parkinson's disease, Alzheimer's disease and anosmic patients

Abstract Olfactory evoked potential (OEP) recordings were undertaken using amyl acetate stimulation in 20 patients with Parkinson's disease, nine patients with Alzheimer's disease, seven patients with olfactory dysfunction with no other neurological disorder, and 17 control subjects. In order to eliminate the somatosensory factor from the combined somatosensory and olfactory components produced by amyl acetate stimulation, we subtracted the potentials using odorless air from those using amyl acetate. In normal subjects, three components were observed, the mean latencies of which were 309 ± 46, 484 ± 61 and 710 ± 55 ms. In all subjects with anosmia ( n = 7), no responses were observed. In the patients with Alzheimer's disease, the components were fewer despite having no olfactory dysfunction. In the 20 patients with Parkinson's disease, four patients showed no components, seven patients showed one component and eight patients showed two components. The components rarely were detected in spite of whether the patients had olfactory dysfunction or not. Olfactory evoked potentials are useful in detecting olfactory dysfunction and the early stages of Alzheimer's disease and Parkinson's disease.     

Olfactory Dysfunction in Parkinson's Disease Patients with the LRRK2 G2385R Variant

Olfactory dysfunction has been reported in Parkinson's disease(PD) patients carrying the LRRK2G2019 S variant in Caucasians but rarely in those with die LRRK2 G2385 R variant.In this study,we performed genotyping for the LRRK2 G2385 R variant in PD patients recruited from the Movement Disorder Clinic of Xuanwu Hospital in Beijing and in healthy controls randomly selected from the Beijing Longitudinal Study on Aging cohort.The "five-odor olfactory detection array",an olfactory threshold test,was used to assess olfactory function.One hundred and eighty-six participants were enrolled,comprising 43 PD patients without(iPD) and 25with(LRRK2-PD) the LRRK2 G2385 R variant,and 118 healthy controls.Our results showed mat the threshold of olfactory identification was significantly worse in PD patients than in controls,but not significantly different between me iPD and LRRK2-PD groups.These findings suggested that although olfactory function in LRRK2-PD patients is impaired,it is similar to that in iPD patients.     

Analysis of olfactory function and the depth of olfactory sulcus in patients with Parkinson's disease.

Olfactory deficit is known to occur frequently in Parkinson's disease (PD). This study aimed to explore olfactory deficit in PD and to investigate its possible correlation with the disease severity or the depth of the olfactory sulcus. Fifty-nine PD patients and 25 normal controls were examined by the odor identification test with the crosscultural smell identification test (CC-SIT). Among these subjects, the depth of the olfactory sulcus of 42 PD patients and 8 controls was measured in the plane of the posterior tangent through the eyeballs using the coronal view brain MRI. The CC-SIT scores of the PD patients were significantly lower than those of the normal control (P<0.001). However, CC-SIT did not correlate with the disease duration, H-Y stage, score of UPDRS Part III, or the depth of either side of the olfactory sulcus (P>0.05). Our study confirms that CC-SIT is a helpful test in detecting the olfactory deficit in Korean PD patients. The absence of correlation of olfactory deficit with the disease severity or the depth of olfactory sulcus may suggest that olfactory loss precede the development of motor signs and not be a primary consequence of damage to the olfactory sulcus.     

Olfactory deficits and sleep disturbances in Parkinson's disease: a case-control survey

BACKGROUND: Olfactory and sleep disturbances are common in Parkinson's disease, and may be early disease indicators. OBJECTIVE: To obtain information about olfactory and sleep deficits preceding the onset of motor symptoms in Parkinson's disease. SUBJECTS: 38 community dwelling patients with Parkinson's disease (73% response rate) and 32 age matched controls (60% response rate). METHODS: Using a questionnaire survey, the frequencies, timing, and relations between olfactory and sleep disturbances, drug treatment, mood, and motor deficits in Parkinson's disease were compared with those in age matched controls. Reliability of information was validated by informant interview in 9% of the sample. Interdependency of factors was assessed using Fisher's fourfold table test, and differences between populations were analysed using chi(2) and unpaired t tests. RESULTS: Microsmia was reported by 26 patients (68%) (and only one control), on average within a year of the diagnosis of Parkinson's disease. More patients than controls had excessive daytime somnolence (45% v 6%), restless legs (50% v 19%), and abnormal movements during sleep (34% v 0%), which generally occurred three to five years after diagnosis and were independent of mood disorders and drug treatment. CONCLUSIONS: Many patients with Parkinson's disease have microsmia at the onset of motor deficits, but some sleep disorders are a subsequent occurrence.     

帕金森病患者的嗅觉功能评价及其影响因素

目的探讨帕金森病患者嗅觉障碍的发生率和特点及其可能的影响因素。方法采用12项气味识别能力测试(12 Item odor identification test from Sniffin’Sticks,SS-12)对106例帕金森病患者和110名正常志愿者进行嗅觉评估,比较两组的嗅觉功能,分析年龄、性别、文化程度、吸烟史、帕金森病病程、Hohn-Yahr分期、UPDRS-Ⅲ评分、左旋多巴用量与嗅觉的相关性。结果帕金森病组嗅觉得分(5.97±2.27)明显低于对照组(8.04±2.00),差异有统计学意义(P=0.000);帕金森病组对一些气味的识别(薄荷、香蕉、甘草、咖啡、菠萝、玫瑰、鱼)明显差于对照组(P0.05);ROC曲线分析显示,7.5分是嗅觉障碍的最佳诊断界值,其敏感度为67.3%,特异度为73.6%,由此得出帕金森病组中嗅觉障碍的发生率为73.6%;相关性分析结果显示,帕金森病组性别(rs=-0.243)、文化程度(rs=0.208)及吸烟史(rs=-0.279,)与气味识别能力相关(P0.05),而年龄、病程、Hohn-Yahr分期、UPDRS-Ⅲ评分及左旋多巴用量与气味识别能力不相关(P0.05)。结论帕金森病患者嗅觉障碍发生率较高,帕金森病患者的嗅觉功能与疾病病程、Hohn-Yahr分期、UPDRS-Ⅲ评分及左旋多巴用量无关。     

Olfactory dysfunction as a predictor of neurodegenerative disease

Olfactory dysfunction is present in patients diagnosed with Alzheimer's disease or idiopathic Parkinson's disease and can differentiate each of these disorders from related disorders with similar clinical presentations. The pathologic hallmarks of each disease are present in brain regions involved in processing olfactory input. Both the olfactory functional deficits and the corroborating pathologic lesions are present in asymptomatic subjects with increased risk of developing these diseases. Preclinical detection of neurodegenerative diseases is necessary to control their devastating effects on individuals and societies. We address whether olfactory dysfunction can be used to assess risk for developing Alzheimer's disease or Parkinson's disease in asymptomatic individuals. We argue that further characterization and a deeper understanding of olfactory deficits in these neurodegenerative diseases at the molecular, cellular, and systems levels will augment our acumen for preclinical detection and elucidate pathogenic mechanisms to guide the development of new therapeutic modalities.     

Extended testing across,not within,tasks raises diagnostic accuracy of smell testing in Parkinson's disease

The aim of this study was to determine whether extended olfactory testing within a single olfactory task and/or across olfactory tasks increases diagnostic accuracy of olfactory testing in Parkinson's disease (PD). Olfactory function was assessed using an extended version of the “Sniffin' Sticks”, comprising 32‐item odor identification and discrimination tasks, and a detection threshold task in 52 PD patients and 50 controls, all aged between 49 and 78 years. ROC curves based on sensitivity and specificity estimates were used to compare the diagnostic accuracy of extended and combined olfactory testing. There was no significant difference in diagnostic accuracy between the 16‐item and the 32‐item versions of the odor identification or discrimination test. The single olfactory test that was best in discriminating between PD patients and controls was a 16‐item odor identification test. A combination of the 16‐item identification test and the detection threshold task had a significantly higher area under the curve than the 16‐item odor identification test alone. In conclusion, extended testing across, and not within, olfactory tasks increases diagnostic accuracy of olfactory testing in PD. A combination of an odor detection threshold task and a 16‐item odor identification test had the highest sensitivity and specificity in distinguishing between PD patients and controls. © 2008 Movement Disorder Society     

Riechstörungen bei Morbus Parkinson

Olfactory dysfunction is a prominent symptom in Parkinson's disease (PD) and found in about 70-100% of patients. In earlier studies significant loss of olfactory function seemed to be unrelated to disease duration, did not correlate with motor function, and was uninfluenced by antiparkinsonian medication. We suggest that the increase of dopaminergic cells in the olfactory bulb is responsible for the hyposmia in PD patients. Interestingly, this olfactory dysfunction is not found in progressive supranuclear palsy or corticobasal degeneration. In multiple system atrophy, the deficit is mild and indistinguishable from cerebellar syndromes of other aetiologies. Intact olfaction has also been reported recently in Parkin disease (PARK 2) and vascular parkinsonism. Olfactory tests may significantly enhance the diagnostic armamentarium in the differential diagnosis of parkinsonian syndromes and indeterminate tremors. Furthermore, olfactory testing may also prove to be a useful aid in the early or "preclinical" detection of PD, once effective disease-modifying therapies are found. Braak and coworkers have confirmed the widespread, extranigral pathology in PD and suggested that pathology in the anterior olfactory region may be one of the earliest appearances of neurodegeneration in PD.     

Olfactory dysfunction in Parkinson's disease

The olfactory system is one of the nonmotor systems severely affected in Parkinson's disease (PD). Olfactory dysfunction occurs early in the disease process, is independent of disease stage, duration, and treatment. However, olfactory dysfunction appears to be dependent on disease subtype. Olfaction is mildly impaired or preserved in most of the parkinsonism-plus syndromes (PPS). This provides a means of differential diagnosis between typical PD and PPS. Olfactory function is impaired also in familial forms of parkinsonism in which the genetic defect is known. In familial parkinsonism, olfactory function is impaired in both typical PD and PPS phenotypes. Olfactory dysfunction does not appear to be a manifestation of dopamine deficiency. Olfactory dysfunction is also associated with other neurodegenerative diseases such as Alzheimer's disease (AD), Huntington's disease (HD), as well as with normal aging. The neuropathological changes observed in the olfactory system in PD and other neurodegenerative diseases appear to be disease-specific, raising the possibility that olfactory dysfunction may be the result of a central rather than a peripheral process. The cellular and molecular mechanisms underlying olfactory dysfunction in PD and other neurodegenerative diseases remain unknown.     

Olfactory event-related potentials to amyl acetate in congenital anosmia

Olfactory function was evaluated by olfactory event-related potentials and standardized psychophysical measures including the Smell Identification Test and odor detection threshold tests for 3 chemosensory stimulants in 9 subjects with isolated congenital anosmia and 9 age- and gender-matched normosmic controls. There was a significant difference in Smell Identification Test scores (P < 0.001) and odor detection thresholds for phenylethyl alcohol (P < 0.001) and isoamyl acetate (P < 0.001) between the anosmic and normosmic subjects. Detection thresholds for chloracetyl phenone, a trigeminal stimulant, did not differ between the 2 groups. Olfactory evoked potentials were recorded in response to amyl acetate and air control stimuli presented at volume flow rate of 5 l/min, stimulus duration of 40 ms, and randomized interstimulus intervals of 6–30 s. In the control subjects, evoked potentials to amyl acetate were characterized by 4 reproducible components (P1, N1, P2, and N2). In the subjects with congenital anosmia, no reproducible evoked potential components were identified in response to amyl acetate. No reproducible evoked potential components were seen in response to the air control stimulus in either the anosmic or normosmic groups. These data suggest that olfactory evoked potentials provide a specific measure of olfactory function.     

Olfactory Dysfunction in Parkinson’s Disease Patients with the <Emphasis Type="Italic">LRRK2</Emphasis> G2385R Variant

Olfactory dysfunction has been reported in Parkinson’s disease (PD) patients carrying the LRRK2 G2019S variant in Caucasians but rarely in those with the LRRK2 G2385R variant. In this study, we performed genotyping for the LRRK2 G2385R variant in PD patients recruited from the Movement Disorder Clinic of Xuanwu Hospital in Beijing and in healthy controls randomly selected from the Beijing Longitudinal Study on Aging cohort. The “five-odor olfactory detection array”, an olfactory threshold test, was used to assess olfactory function. One hundred and eighty-six participants were enrolled, comprising 43 PD patients without (iPD) and 25 with (LRRK2-PD) the LRRK2 G2385R variant, and 118 healthy controls. Our results showed that the threshold of olfactory identification was significantly worse in PD patients than in controls, but not significantly different between the iPD and LRRK2-PD groups. These findings suggested that although olfactory function in LRRK2-PD patients is impaired, it is similar to that in iPD patients.     

吸烟对帕金森病患者嗅觉障碍的影响

目的探讨吸烟对帕金森病(PD)患者嗅觉障碍的影响。方法根据吸烟情况将167例PD患者(PD组)及100例正常人(正常对照组)分为吸烟亚组及不吸烟亚组。采用TT嗅觉测试液对入组者进行嗅素识别阈值测定。结果与正常对照组比较,PD组MMSE评分及蒙特利尔认知评估(Mo CA)评分显著降低(均P0.05),两组年龄、吸烟史及男性比率未见明显差异(均P0.05)。PD组嗅素识别阈显著高于正常对照组(t=6.785,P=0.000)。与PD吸烟亚组比较,不吸烟亚组嗅素识别阈显著升高(t=-3.000,P=0.003)。正常人吸烟亚组较不吸烟亚组嗅素识别阈值减低,但无统计学意义(t=0.784,P=0.435)。PD吸烟者嗅觉阈值与吸烟年限、吸烟总量无相关(r=-0.104,P=0.441;r=-0.156,P=0.246)。结论吸烟可能对PD患者嗅觉有保护作用,并且与吸烟年限、吸烟总量无关。     

Assessing olfaction in the Italian population: methodology and clinical application

Disorders of the sense of smell are receiving growing clinical as well as experimental attention. Indeed, several neurological conditions have been associated with peripheral or central deficits of the olfactory system. In recent years, particular emphasis has been attributed to the early and severe olfactory impairment in neurodegenerative diseases, such as Alzheimer's dementia and Parkinson's disease. Olfactory assessment has also been included in comprehensive pre- and post-surgical evaluations of temporal lobe epilepsy. Moreover, the request for standardized methods of olfactory evaluation by forensic and occupational medicine is greatly increasing. Despite this requirement, there is no agreement in the Italian neurological community on olfactory assessment. This lack prompted us to generate a battery of standardized tests capable of bypassing cross-cultural differences in olfactory assessment and to be potentially useful in the clinical as well as experimental settings. Procedures of assessment of olfactory acuity (detection threshold), identification (multiple choice odor naming), discrimination (differentiation between similar/dissimilar odorants) and memory (recognition of a substance previously smelled) are fully described. In order to control bias factors depending upon the nature of the investigated disorder and the applied olfactory tasks, a minimal complementary neuropsychological assessment is recommended.     

Loss of olfaction in de novo and treated Parkinson's disease: possible implications for early diagnosis.

Olfactory dysfunction is a common finding in patients with Parkinson's disease (PD). As most studies reported on odor identification in more advanced and treated PD, we administered an odor detection, discrimination, and identification test to a heterogeneous, partly de novo, group of patients. Forty-one non-demented PD patients, 24 of whom had untreated early PD, and 18 healthy controls, were examined. Odor identification and discrimination data were corrected for odor detection scores. PD patients scored significantly lower on all olfactory tests. Interestingly, the subgroup of de novo patients with early PD also showed significant olfactory disturbances compared with healthy subjects. Within the PD group, using multiple regression analysis, we found a significant, negative correlation between odor discrimination measures and disease The present study is the first to describe decreased performance of PD patients on odor discrimination, in addition to the already well-established deficits in odor detection and identification. Furthermore, odor discrimination measures were related to disease severity, possibly indicating that at least some aspects of olfactory dysfunction in PD may be secondary to ongoing degenerative processes in PD. As significant olfactory impairments were found in early, de novo PD, olfactory tests may be useful in the early diagnosis of PD.     

Neuropsychological correlates of olfactory dysfunction in Parkinson's disease

Olfactory impairment is a common early non-motor manifestation in Parkinson's disease that has garnered interest as a clinical biomarker for early "pre-motor" diagnosis and prediction of associated clinical phenotypes. Whether olfactory impairment correlates well with motor symptoms is not yet clear, and recent interest has focused on the relationship between hyposmia and other non-motor symptoms. In this paper, we will review emerging evidence for a relationship between hyposmia and neuropsychiatric manifestations, discussing the potential pathophysiology together with challenges and opportunities for future research.     

Olfactory Disorder in Motor Neuron Disease

In Parkinson's disease and Alzheimer's disease there is profound disorder of olfaction. The extent to which this modality is involved in motor neuron disease (MND) has been studied little. To address this further we assessed olfaction by three methods—a smell identification test (“UPSIT”) in 58 patients and 135 controls; olfactory-evoked response (OEP) to H₂S in 15 patients, and pathological examination of olfactory bulbs obtained from 8 cadavers. It was found that smell identification compared with the controls was slightly worse overall in the MND group as a whole, but only the bulbar patients scored significantly less on the UPSIT. Patients displayed a subtle defect in cheese odor recognition. OEPs were normal in 9 subjects and delayed in 1 subject. The remaining 5 OEPs were unsuccessful. Histopathological studies of olfactory bulbs showed excess lipofuscin deposition in all 8 cases examined, indicating subclinical neuronal damage. Olfactory neurons with a degree of antioxidant defect may be more susceptible to cellular damage than other neuronal groups because of their direct relationship to environmental agents. Overall we found the degree of olfactory dysfunction in MND to be mild and in contrast with the marked changes described by others.     

Olfactory dysfunction in parkinsonism: a general deficit unrelated to neurologic signs, disease stage, or disease duration

To explore the nature of the olfactory dysfunction associated with Parkinson's disease (PD), 81 PD patients who scored well on a cognitive screening test were administered the 40-odorant University of Pennsylvania Smell Identification Test; 38 were additionally given a forced-choice phenylethyl alcohol odor detection threshold test. Clinical ratings of 11 neurologic symptoms (three bilateral) were obtained at the time of testing, and odor identification was retested in 24 patients at intervals ranging from 5 to 39 months. Relative to matched controls, the PD patients exhibited consistent and marked decrements on both types of olfactory tests (ps less than 0.0001). The odor identification deficit was not restricted to any subset of odorants and did not evidence longitudinal change. A factor analysis of the intercorrelations among the variables yielded six easily interpretable factors: general motor, oral motor, olfactory function, cognitive function, tremor, and gender. Olfactory test scores were independent of all other measures, including disease stage and duration. Seventy-two percent of the PD patients were unaware of a smell disorder before testing; those who were aware had significantly lower test scores. A statistical comparison of PD patients' olfactory test scores to those obtained from Alzheimer's disease patients found the olfactory disorders of these diseases to be indistinguishable. The data support the hypothesis that the olfactory deficit of PD is a general and stable one which likely occurs early in the disease process.     

Hyposmia and cognitive impairment in Gaucher disease patients and carriers

The objective of this study was to assess a cohort of Gaucher disease patients and their heterozygous carrier relatives for potential clinical signs of early neurodegeneration. Gaucher disease patients (n = 30), heterozygous glucocerebrosidase mutation carriers (n = 30), and mutation-negative controls matched by age, sex, and ethnicity (n = 30) were recruited. Assessment was done for olfactory function (University of Pennsylvania Smell Identification Test), cognitive function (Mini-Mental State Examination, Montreal Cognitive Assessment), rapid eye movement sleep disorder, autonomic symptoms, and parkinsonian motor signs (Unified Parkinson's Disease Rating Scale part III, Purdue pegboard). Olfactory function scores were significantly lower in Gaucher disease patients (P = .010) and heterozygous carriers (P < .001) than in controls. Cognitive assessment scores were significantly lower in Gaucher disease patients (P = .002) and carriers (P = .002) than in controls. Unified Parkinson's Disease Rating Scale motor subscale scores were significantly higher in Gaucher disease patients (P < .001) and heterozygotes (P = .0010) than in controls. There was no difference in scores for symptoms of rapid eye movement sleep disorder or autonomic dysfunction. Impairment of olfaction, cognition, and parkinsonian motor signs occurs more frequently in Gaucher disease patients and carriers than in controls, which may indicate the early stages of neurodegeneration.     

Olfactory function in mild cognitive impairment and Alzheimer's disease: an investigation using psychophysical and electrophysiological techniques

OBJECTIVE: To clarify the olfactory deficit hypothesis regarding Alzheimer's disease, the authors compared olfactory function in patients with Alzheimer's disease, subjects with mild cognitive impairment, and healthy comparison subjects. METHOD: Olfactory function of 14 patients with mild Alzheimer's disease, eight subjects with mild cognitive impairment, and eight healthy age-matched comparison subjects was assessed with both psychophysical tests and olfactory event-related potentials. RESULTS: Group comparison of the psychophysical test results showed a significant main effect of diagnosis for odor detection threshold, odor discrimination, and odor identification. These results correlated only partially with those obtained from olfactory event-related potentials. Seven Alzheimer's disease patients and four with mild cognitive impairment showed no olfactory event-related potentials, suggesting hyposmia, while all comparison subjects had clearly discernible responses. Patients with Alzheimer's disease were significantly more likely to be nonresponders. In the four Alzheimer's disease patients and four subjects with mild cognitive impairment who had clear electrophysiological responses, amplitudes and latencies of the various event-related potential components were normal, i.e., similar to those of the comparison subjects, although 12 of the 14 Alzheimer's disease patients and seven of the eight mildly impaired subjects were classified as functionally anosmic with psychophysical methods. CONCLUSIONS: The electrophysiological results confirm prior findings of olfactory dysfunction in patients with Alzheimer's disease and preclinical Alzheimer's disease. Investigations of larger study groups with detailed cognitive examination and postmortem diagnosis may resolve the intriguing possibility of early diagnosis and discrimination of Alzheimer's disease subtypes through chemosensory event-related potentials in addition to existing biomarkers.