WO2014113645A1 - Procédés et tests pour troubles dégénératifs du système nerveux central - Google Patents

Procédés et tests pour troubles dégénératifs du système nerveux central Download PDF

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WO2014113645A1
WO2014113645A1 PCT/US2014/012002 US2014012002W WO2014113645A1 WO 2014113645 A1 WO2014113645 A1 WO 2014113645A1 US 2014012002 W US2014012002 W US 2014012002W WO 2014113645 A1 WO2014113645 A1 WO 2014113645A1
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nostril
patient
odorant
odor
disease
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Jennifer STAMPS
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University of Florida
University of Florida Research Foundation Inc
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University of Florida
University of Florida Research Foundation Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/40—Detecting, measuring or recording for evaluating the nervous system
    • A61B5/4005—Detecting, measuring or recording for evaluating the nervous system for evaluating the sensory system
    • A61B5/4011—Evaluating olfaction, i.e. sense of smell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/40—Detecting, measuring or recording for evaluating the nervous system
    • A61B5/4076—Diagnosing or monitoring particular conditions of the nervous system
    • A61B5/4088—Diagnosing of monitoring cognitive diseases, e.g. Alzheimer, prion diseases or dementia

Definitions

  • AD Alzheimer's disease
  • this test may also be positive in other dementing diseases such as Lewy body dementia, and is thus not specific for AD.
  • many of the clinical and diagnostic tests currently used to help diagnose AD are expensive and require highly trained personnel or equipment available only in limited locations. Except for the lumbar puncture tests, which are invasive with potential complications, most of the procedures discussed above are not readily available, highly sensitive, or specific for AD.
  • embodiments of the present disclosure provide methods, kits, and systems for diagnosing and characterizing degenerative disorders of the central nervous system (CNS), such as, Alzheimer's disease, Parkinson's disease, and other CNS disorders.
  • CNS central nervous system
  • the present disclosure provides embodiments of methods of diagnosing Alzheimer's disease in a patient, the method including the following steps: placing a container containing a pure odorant under a nostril of a patient suspected of having Alzheimer's disease, where the container is placed at a sufficient distance that the patient cannot detect the odorant, the patient's other nostril is closed and the patient cannot see the odorant, and the odorant is not capable of detection by trigeminal nerve stimulation; moving the container closer to the nostril of the patient at a consistent rate until the patient detects the odor; measuring the odor detection distance between the patient's nostril and the location of the container where the patient first detected the odor; repeating the above steps with the other nostril; and determining the difference between the odor detection distance for each nostril, where an odor detection difference of at least about 5 cm in favor of the right nostril (e.g., the odor detection difference for the left nostril is at least about 5cm less than the odor detection distance of the right nostril) indicates a likelihood of Alzheimer
  • the present disclosure also provides methods of diagnosing a degenerative disease of the central nervous system (CNS) in a patient, the methods including the following steps: placing a container containing a pure odorant under a nostril of a patient suspected of having a degenerative disease of the CNS, where the container is placed at a sufficient distance that the patient cannot detect the odorant, the patient's other nostril is closed and the patient cannot see the odorant, and the odorant is not capable of detection by trigeminal nerve stimulation; moving the container closer to the nostril of the patient at a consistent rate until the patient detects the odor; measuring the odor detection distance between the patient's nostril and the location of the container where the patient first detected the odor; repeating the above steps with the other nostril; and comparing the odor detection distance for each nostril, where a difference of at least about 5 cm between the detection distance for each nostril or a difference of at least about 10 between the odor detection distance for the patient and the average odor detection distance for a control patient
  • the patient has a likelihood of Alzheimer's disease.
  • the odor detection difference between the right and left nostrils is less than or equal to about 3 cm, and wherein the average odor detection distance for both nostrils of the patient is at least about 10 cm worse than the average odor detection distance of a control patient, the patient has a likelihood of Parkinson's disease.
  • the present disclosure also provides embodiments of methods of determining the hemisphere of a patient's brain affected with CNS disorder, the method including the following steps: placing a container containing a pure odorant under a nostril of a patient having a CNS disorder selected from the group consisting of: epilepsy, cerebellar tumor and ataxia, where the container is placed at a sufficient distance that the patient cannot detect the odorant, the patient's other nostril is closed, the patient cannot see the odorant, and the odorant is not capable detection by trigeminal nerve stimulation; moving the container closer to the nostril of the patient at a continuous rate until the patent detects the odor; measuring the odor detection distance between the patient's nostril and the location of the container where the patient first detected the odor; repeating the above steps with the other nostril; and comparing the odor detection distance for each nostril, where the identity of the more impaired nostril indicates the hemisphere affected by the CNS disorder.
  • a CNS disorder selected from the group consisting of
  • the odorant is peanut butter or the odorant compound in peanut butter.
  • the odorant material is selected from the group including: coffee grounds and chocolate.
  • the odorant does not contain alcohol.
  • kits for testing or diagnosing a degenerative disease of the central nervous system (CNS) in a patient including a sealed container including a pure odorant that is not capable of detection by trigeminal nerve stimulation, and instructions for use including the following steps: instructing a patient having a CNS disorder to seal one nostril or sealing the patient's nostril with a device, while leaving the other nostril open; placing the container containing the pure odorant under the open nostril of the patient, where the container is placed at a sufficient distance that the patient cannot detect the odorant, and where the patient cannot see the odorant; moving the container closer to the open nostril of the patient at a continuous rate until the patent detects the odor; measuring the odor detection distance between the patient's nostril and the location of the container where the patient first detected the odor; repeating the above steps with the other nostril; and comparing the odor detection distance for each nostril and calculating an odor detection difference for the patient, where the odor detection distance and
  • the present disclosure also provides systems for testing or diagnosing a degenerative disease of the central nervous system (CNS) in a patient, the system including a device capable of being mounted on a subject's head, where the device includes the follwoign: a portion that removably secures the device to the subject's head; a nose plug for closing one nostril of a subject at a time; a distance-measuring device; and a receptacle coupled to the distance-measuring device, where the receptacle is adapted to hold a disposable container of odorant material, and where the receptacle can be moved along the distance-measuring device to measure the distance of the odorant container to an open nostril of the subject.
  • CNS central nervous system
  • FIG. 1 is a graph illustrating the mean L - R nostril odor detection difference (cm) for each group.
  • AD Alzheimer's disease
  • MCI mild cognitive impairment
  • OD other dementias
  • OC older controls.
  • FIG. 2 illustrates the frequency distribution of the difference score of the L - R nostril detection distance (cm) for each group.
  • the frequency distribution of the AD group is significantly different from all other groups, Fisher exact of the ⁇ 2, p ⁇ 0.0001.
  • FIG. 3 is a bar graph illustrating the mean L - R nostril odor detection difference (cm) for each group, including PD, showing the odor detection is asymmetrically impaired in AD and symmetrically impaired in PD.
  • AD Alzheimer's disease
  • MCI mild cognitive impairment
  • OD other dementias
  • PD Parkinson's disease
  • OC older controls.
  • FIG. 4 illustrates the mean L - R nostril detection difference for the groups, including PD, demonstrating that the left nostril relatively worse (shorter detection distance) than right nostril odor detection by an average of 10 cm in the patients with AD.
  • FIG. 5A illustrates the mean odor detection distance
  • FIG. 5B illustrates the mean L - R odor detection distance for groups including CBD separated out from the OD group.
  • FIGS. 6A and 6B are graphs illustrating the number of participants who correctly or incorrectly identified the odor as peanut butter in each group with their left vs. right nostril.
  • FIG. 6B shows the data with the CBD patients separated out from the OD group.
  • FIGS. 7A and 7B are bar graphs illustrating average distance (cm) of odor recognition for the left and right nostril of each group, showing that odor recognition distance follows the same pattern as odor detection distance for all groups.
  • FIG. 7B includes and FIG. 7A does not include the PD group.
  • Embodiments of the present disclosure will employ, unless otherwise indicated, techniques of medicine, biology, statistics, biochemistry, molecular biology, and the like, which are within the skill of the art. Such techniques are explained fully in the literature.
  • pure odorant refers to an aromatic compound detectable by a patient via olfactory nerve stimulation that does not simultaneously stimulate the trigeminal nerve. Since alcohol can stimulate the trigeminal nerve, alcohol-based odorants are not considered “pure odorants” for purposes of the present disclosure.
  • odor detection refers to the point at which a patient realizes (e.g., becomes aware of) the presence of an odorant.
  • the "odor detection distance” refers to the distance between the source of the odorant (e.g., container containing the odorant compound) and the patient's nostril at the point of odor detection.
  • odor recognition refers to the point at which a patient can identify the source of an odor that has been detected.
  • odor recognition differs from odor detection in that odor recognition includes the further step of recognizing/identifying the particular odor (e.g., peanut butter or coffee vs. just “an odor”).
  • the "odor recognition distance” refers to the distance between the source of the odorant and the patient's nostril at the time that "odor recognition" occurs.
  • tests and methods of the present disclosure encompass methods and tests for degenerative and/or cognitive disorders of the central nervous system.
  • tests and methods of the present disclosure can diagnose or aid in diagnosing Alzheimer's disease (AD), can distinguish between AD and other forms of degenerative disorders of the CNS, can help to identify the location of injury and/or impairment in CNS disorders characterized by unilateral and/or asymmetrical localization, such as epilepsy, tumor, or other brain injury.
  • AD Alzheimer's disease
  • CNS disorders characterized by unilateral and/or asymmetrical localization such as epilepsy, tumor, or other brain injury.
  • AD Alzheimer's disease
  • olfactory cortex 8 Many of the eight structures lying on the surface of the basal forebrain and within the mesial temporal lobes that comprise olfactory cortex 8,9 are the sites of initial pathology in AD 10" 12 . Because olfactory dysfunction occurs in preclinical AD 13,14 , assessing olfactory sensitivity during the neurologic examination could prove especially helpful for early diagnosis.
  • olfactory cortex Portions of olfactory cortex are the initial sites of AD pathology and people with AD often have more degeneration of their left than right hemisphere. Since the olfactory epithelium projects mainly to the ipsilateral olfactory cortex, patients with AD may demonstrate an asymmetrical (left greater than right) decrement of odor detection sensitivity.
  • the present disclosure provides a quick, accurate and sensitive test based on this asymmetrical degeneration of odor detection.
  • Exemplary odorants for use in the methods and tests of the present disclosure include pure odorants such as peanut butter, the primary odorant compound in peanut butter (e.g., non-alcohol based 2-ethyl-pyrazine (also sometimes called 2-ehtyl-1 ,4- diazine; 2-ethylpyrazine; and pyrazine, 2-ehtyl) chemical compound C 6 H 8 N 2 , MW 108.14), coffee grounds, chocolate, pure peach, and other pure, non-alcohol based odorants.
  • Example 1 describes in greater detail embodiments of the present disclosure using peanut butter as the odorant. To test for asymmetry, the test was conducted unirhinally, one nostril at time.
  • VBM voxel-based morphometric
  • Example 1 Participants with probable AD, mild cognitive impairment (MCI), other causes of dementia (OD), Parkinson's disease (PD), and matched controls (OC) were tested, with closed eyes, for their ability to detect an odor, one nostril at a time, as described in greater detail in Example 1 and the corresponding figures. Briefly, a small container of peanut butter was opened, held medially at the bottom of a 30 cm ruler, and moved up 1 cm at a time during the participants' exhale. Upon odor detection, the distance between the subject's nostril and container was measured. This non-invasive and inexpensive left-right nostril odor detection test appears to be a sensitive and specific test for probable AD as well as other CNS disorders.
  • MCI mild cognitive impairment
  • OD other causes of dementia
  • PD Parkinson's disease
  • OC matched controls
  • embodiments of the present disclosure include methods of diagnosing and/or testing Alzheimer's disease in a patient.
  • such methods include the following steps: placing a container containing a pure odorant under a nostril of a patient suspected of having Alzheimer's disease at a sufficient distance that the patient cannot detect the odorant, moving the container closer to the nostril of the patient at a consistent rate until the patient detects the odor, measuring the odor detection distance between the patient's nostril and the location of the container where the patient first detected the odor, repeating the above steps with the other nostril; and determining the difference between the odor detection distance for each nostril.
  • odorant container e.g., so that the patient will not see the container and confuse sight detection with odor detection.
  • the patient may also be instructed to close the mouth to prevent any airflow through the closed nostril via the mouth or any other odor stimulus via the lower nasal passages at the back of the throat.
  • the odorant is not capable detection by trigeminal nerve stimulation.
  • odorants appropriate for use in the present disclosure that stimulate the olfactory nerve (CN1 ) without simultaneous trigeminal nerve stimulation include pure odorants that do not contain alcohol.
  • pure odorants include, but are not limited to, peanut butter, the odorant compound from peanut butter, coffee (e.g., coffee, coffee grounds, etc.), chocolate (in various forms), peach, and the like.
  • an odor detection difference at least about 5 cm in favor of the right nostril indicates a likelihood of Alzheimer's disease.
  • the container of pure odorant is moved closer to the test nostril at a rate of about 1 cm/exhale.
  • the present disclosure also includes methods of testing and/or diagnosing a degenerative disease of the central nervous system (CNS) in a patient.
  • such methods include the following steps: placing a container containing a pure odorant under a nostril of a patient suspected of having a degenerative disease of the CNS disease at a sufficient distance that the patient cannot detect the odorant and where the odorant is not capable of detection by trigeminal nerve stimulation, moving the container closer to the nostril of the patient at a consistent rate until the patient detects the odor, measuring the odor detection distance between the patient's nostril and the location of the container where the patient first detected the odor, repeating the steps above with the other nostril, where each nostril not being tested is closed (e.g., not exposed to odor stimulation) during the testing of the other nostril.
  • the container of pure odorant is moved closer to the test nostril at a rate of about 1
  • the method then includes comparing the odor detection distance for each nostril, wherein a difference between the detection distances for each nostril or a difference between the odor detection distance for the patient and the average odor detection distance for a control patient indicates the presence of a neurodegenerative disease.
  • a difference between the detection distance for each nostril in the patient being tested may indicate the presence of a neurodegenerative disease such as AD (where the left nostril is more impaired, Table 1 ), or epilepsy or tumor where the epilepsy, injury, or tumor is located on the hemisphere of the brain associated with the impaired nostril.
  • symmetric impairment may indicate other cognitive degenerative disorders, such as Parkinson's disease (PD) where symmetric but significant impairment was observed (Table 3).
  • the degenerative CNS disease being tested is Alzheimer's
  • the odor detection distance of the left nostril is at least about 5 cm worse (e.g., at least about 5 cm less than/shorter than) than the odor detection distance for the right nostril
  • the patient has a likelihood of Alzheimer's disease.
  • the odor detection distance of the left nostril is at least bout 10 cm less than the odor detection distance for the right nostril
  • the patient has a likelihood of
  • the methods of the present can be used to diagnose early or moderate Alzheimer's disease.
  • an odor detection difference of at least about 5 cm in favor of the right nostril e.g., the detection difference of the left nostril is less than the detection difference of the right nostril by at least about 5 cm
  • the patient may be preliminarily diagnosed with Alzheimer's disease and referred for further testing with conventional tests for AD.
  • the patient is preliminary diagnosed with AD and referred for further testing when the odor detection difference is at least about 10 cm in favor of the right nostril.
  • Embodiments of the present disclosure also include method of diagnosing a degenerative disease of the central nervous system (CNS) in a patient using the methods described herein, where a difference of at least about 5 cm between the detection distance for each nostril or a difference of at least about 10 between the odor detection distance for the patient and the average odor detection distance for a control patient indicates the presence of a neurodegenerative disease.
  • a difference of at least about 5 cm between the detection distance for each nostril or a difference of at least about 10 between the odor detection distance for the patient and the average odor detection distance for a control patient indicates the presence of a neurodegenerative disease.
  • the odor detection difference of the left nostril is at least about 5cm worse than the odor detection distance for the right nostril, then the patient has a likelihood of AD as the diagnosed degenerative disease of the CNS.
  • the degenerative CNS disease is Parkinson's disease
  • the odor detection difference between the right and left nostrils is less than or equal to about 3 cm
  • the average odor detection distance for both nostrils of the patient is at least about 10 cm less than (e.g., a shorter detection difference, which indicates increased impairment) the average odor detection distance of a control patient
  • the patient has a likelihood of Parkinson's disease.
  • Embodiments of the present disclosure also include methods of determining the hemisphere of a patient's brain affected with CNS disorder.
  • such methods include similar steps as described above.
  • a container containing a pure odorant is placed under a nostril of a patient having a CNS disorder, such as but not limited to epilepsy, cerebellar tumor, injury, and ataxia.
  • the container is placed at a sufficient distance that the patient cannot detect the odorant, and the patient's other nostril is closed (or otherwise shielded from odor detection).
  • the patient is unable to see the odorant or the container holding the odorant.
  • the odorant is not capable detection by trigeminal nerve stimulation.
  • the odorant is a pure odorant such as, but not limited to peanut butter, coffee, chocolate, and the like.
  • the odorant is moved closer to the nostril of the patient at a continuous rate (e.g., 1 cm/exhale) until the patent detects the odor.
  • the odor detection distance (the distance between the patient's nostril and the location of the container where the patient first detected the odor) is measured, and then the steps are repeated with the other nostril. After performing the method on both nostrils, the odor detection distances for each nostril are compared, where the identity of the more impaired nostril indicates the hemisphere affected by the CNS disorder.
  • kits for the conduction of the above described tests of the present disclosure might include a sealed container including a pure odorant (e.g., peanut butter, a composition including a pure peanut butter odorant compound, coffee grounds, chocolate, or other pure odorant-containing
  • the kit may also include a measuring device (e.g., a ruler, tape measure, etc.) and instructions for use of the kit and conduction of the test. If convenient, the kit may also include a blindfold or other eye shielding device and a single-nostril nose-clip or other device for closing or obstructing one nostril of a patient while leaving the other nostril accessible for odor detection.
  • a measuring device e.g., a ruler, tape measure, etc.
  • the kit may also include a blindfold or other eye shielding device and a single-nostril nose-clip or other device for closing or obstructing one nostril of a patient while leaving the other nostril accessible for odor detection.
  • the present disclosure also includes devices and systems that could be used to carry out the tests and methods described above.
  • such devices can help reduce the possibility of human error in administering the test. For instance, one
  • a system including a head mounted device having a head-mounting portion that removably secures the device to the subject's head, a nose plug for independently sealing one nostril at a time (optionally with a sterile disposable nostril portion that is replaced with a new sterile disposable nostril portion for each nostril for each patient), and a distance-measuring device (e.g., a ruler) with an attached receptacle for holding a disposable container containing an odorant material (e.g., peanut butter).
  • a head mounted device having a head-mounting portion that removably secures the device to the subject's head
  • a nose plug for independently sealing one nostril at a time (optionally with a sterile disposable nostril portion that is replaced with a new sterile disposable nostril portion for each nostril for each patient)
  • a distance-measuring device e.g., a ruler
  • an attached receptacle for holding a disposable container containing an odorant
  • the receptacle is coupled to the distance-measuring device in such a way that the receptacle can be moved along the distance-measuring device to measure the distance of the odorant container to an open nostril of the subject (e.g., the nostril that is not closed with the nose plug).
  • the receptacle can be mounted on a slide that is coupled to the ruler so that it is capable of being advanced along the ruler.
  • the slide-mounted receptacle can be automatically advanced each time sensors detect an exhale from the subject.
  • One of skill in the art can imagine other embodiments and adaptations to such a device to increase testing consistency and automation.
  • the methods and test of the present disclosure can also be adapted to provide an odor threshold related to concentration rather than distance from the nostril. Although such test may require more complicated equipment, the detection difference concept can be applied to odorant concentration.
  • the present disclosure also provides methods and tests for diagnosing a degenerative disease of the central nervous system (CNS) in a patient via odor detection threshold.
  • CNS central nervous system
  • such methods include exposing one nostril of a patient suspected of having a degenerative disease of the CNS to a concentration of a pure odorant below the patient's detection threshold, where the odorant is not capable of detection by trigeminal nerve stimulation.
  • the concentration of the odorant is gradually increased over separate trials and at a consistent rate until the patient detects the odor.
  • odor detection threshold is tested using a forced choice task in which the patient is asked to compare and determine which of two samples of air has an odor and which does not.
  • the odor concentration is increased at set increments until the patient is able to reliably identify over consecutive trials which air sample contains the odorant.
  • the concentration of the odorant is recorded/measured at the point when the patient first detects the odor, and then the steps are repeated with the other nostril.
  • odor detection concentrations for each nostril are compared, where a difference between the detection concentrations for each nostril or a difference between the odor detection concentration for the patient and the average odor detection concentration for a control patient indicates the presence of a neurodegenerative disease.
  • Such analysis is conducted in a similar manner as described above for detection distance.
  • a system could include a device for providing a regulated concentration of a pure odorant, wherein the pure odorant compound can be inserted into a compartment or receptacle of the device.
  • the system also includes tubes or other via for transporting the odorant to the nostril(s) of the patient.
  • the system also includes a dial or interface for controlling the concentration and timing of release of odorant and for recording and/or displaying the concentration level at given intervals during the test such that the concentration of the odorant can be determined at each trial of the test (e.g., by a user or a program).
  • ratios, concentrations, amounts, and other numerical data may be expressed herein in a range format. It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited.
  • a concentration range of "about 0.1 % to about 5%” should be interpreted to include not only the explicitly recited concentration of about 0.1 wt% to about 5 wt%, but also include individual concentrations (e.g., 1 %, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.5%, 1.1 %, 2.2%, 3.3%, and 4.4%) within the indicated range.
  • the term "about” can include traditional rounding according to significant figures of the numerical value.
  • the present example describes a quick clinical test of the CN1 odor detection in patients for the testing, diagnosis, localization and/or classification of cognitive disorders of the CNS, including Alzheimer's disease (AD).
  • AD Alzheimer's disease
  • Gerstmann's syndrome is commonly seen in Alzheimer's patients and so within the FMSE this syndrome is actually scored with a possible 5 points given for the ability to calculate, 3 possible points given for the ability to tell left from right, and 1 possible point given for the ability to properly name the index finger.
  • a brain MRI scan and diagnostic laboratory studies were obtained to evaluate for reversible causes of dementia.
  • the patients in this study diagnosed with probable Alzheimer's disease had 1 ) an insidious onset; 2) a clear-cut history of worsening of cognition by report or observation; 3) the initial and most prominent cognitive deficits on history and examination was amnesia (defective episodic memory) and cognitive dysfunction, such as disorders of language (e.g., anomia) and/or visuospatial disorders; and 4) did not have evidence of a stroke, Lewy body dementia, frontotemporal lobar degeneration, or other known neurological diseases that can cause a cognitive decline.
  • the eligible patients were grouped into three groups; 18 diagnosed with probable AD (AD) 2, 3 , 24 diagnosed with amnestic mild cognitive impairment (MCI) 27 , and 26 patients diagnosed with various other causes of dementia (OD).
  • the number of patients in each group was determined by the number of patients seen during the specified time period and by their diagnoses. Because this was a retrospective study on an existing data set, a power analysis was not done. A large effect would indicate clinical relevance, and, according to Keppel, the effect would need to reach significance with a number of 17 in each group to achieve a power of 0.80 29 .
  • the 26 cognitively normal control participants recruited from the community were age and gender matched to the AD patients, cognitively assessed with the FMSE, and screened using the same exclusionary criteria. All gave written, informed consent a HIPAA waiver of consent was obtained for all patients, and the University of Florida Institutional Review Board approved the study. We followed the reporting guidelines set forth by the STROBE Statement for case-control, observational studies 30 .
  • the metric ruler was held up next to their open nostril and carefully aligned within the participants' sagittal plane to avoid potential effects from possible hemispheric neglect. They were asked to inform the examiner when they first detected an odor and if possible, to identify it.
  • the container of peanut butter was opened at the bottom of the ruler and moved up 1 cm upon each exhale until the person indicated that they detected the odor. The distance between the edge of the nostril and the top of the container was measured and recorded. The procedure was repeated with the other nostril after a 90 sec delay. In addition to providing precision, moving the stimulus up 1 cm/exhale helps provide equality of space and time of the odor plume for each patient.
  • the person testing odor detection was never the same person who performed the cognitive testing, the physical neurological exam, or gathered any patient history and was blind to the diagnosis at the time of the testing. Additionally, the diagnosis of our patients was usually not confirmed until months after our initial clinical testing when these patients' lab and imaging results had been received.
  • T-tests were used to test whether handedness was related to the first nostril chosen and whether the nostril chosen by the patients differed from that assigned by random order.
  • ANOVA analysis of variance
  • MANOVA 2-way interaction multivariate analysis of variance
  • AD is more commonly diagnosed in women than men, possibly related to women having longer life expectancy 31 .
  • the OD participants' performance on the UPBODT could also be divided into two major groups; 15 were symmetric across nostrils and 11 were asymmetric with the left nostril being better than the right, a pattern opposite of the participants with AD (Table 2).
  • a left nostril impairment of odor detection was present in all the patients with probable AD. This pattern of odor detection was not present in the older control group in which detection distances were symmetric across the nostrils and was absent in the patients with other dementias whose detection distances were either symmetric or slightly asymmetric with a right nostril impairment. Thus, the sensitivity and specificity of this peanut butter odor detection test appear promising for accurately diagnosing AD. Further analysis of these odor detection test results and correlation with these participants' neuropathology or laboratory markers such as spinal fluid assays for amyloid-3i_ 4 2 /tau has not yet been conducted.
  • this simple diagnostic tool may also help track the course of the disease.
  • the asymmetry was greatest at the earlier phases of the disease course. As the disease progressed, the right nostril became more impaired at odor detection and the asymmetry decreased.
  • left hemisphere deficits are more easily detected by patients and their loved ones than right hemisphere deficits. This detection asymmetry may induce AD patients with left hemispheric dysfunction to seek medical attention sooner than those with right hemispheric dysfunction.
  • Primary olfactory cortex is one of the first sites of pathology in AD 10"12 .
  • the primary visual and auditory cortices are usually spared in people with AD.
  • the olfactory cortex it is primarily the hippocampus, portions of the default network, and sensory association cortices that deteriorate in patients with AD.
  • the only sensory test that may be sensitive and specific for AD are tests of olfaction, and this quick, non-invasive, left-right nostril peanut butter odor detection test may be an ideal instrument for the early detection of AD.
  • Table 1 Characteristics of the participants & Correlations between odor detection distances and cognitive test scores.
  • AD Alzheimer's disease
  • MCI mild cognitive impairment
  • OD other dementias
  • OC matched controls
  • the difference between the R and L nostril odor detection distance was ⁇ 3 cm.
  • the difference between a person's R and L nostril odor detection distance was ⁇ 4 cm.
  • Example 2 describes the clinical test and uses the same methodology as set forth above in Example 1 , but includes data for patients with Parkinson's disease (PD) as well as additional subjects in the other test groups.
  • PD Parkinson's disease
  • CBD patients were further subdivided into a subset of 8 patients that were diagnosed with corticobasal degeneration (CBD), and the remaining 15 with other, specified causes of dementia (OD).
  • CBD patients were separated out to compare their results to the PD patients' results.
  • CBD can start with memory impairment and be difficult to distinguish from AD but it can also start with motor symptoms such as rigidity, akinesia, poor coordination, and impaired balance, which can make it difficult to clinically differentiate from PD.
  • the data were analyzed with the small sample of CBD patients separated out from the OD group.
  • FIG. 5A & 5B illustrate that patients with PD are more symmetric and more impaired at odor detection than those with CBD.
  • CBD follow the same pattern as the remaining OD.
  • Left Nostril The mean, standard error, and 95% C.I. for CBD: 18.6 ⁇ 2.8 (13.0,24.3); for OD without CBD: 24.6 ⁇ 2.1 (20.5,28.7). PD worse than CBD, p ⁇ 0.0001.
  • FIG. 5A Right Nostril: The mean, standard error, and 95% C.I. for CBD: 18.6 ⁇ 2.8 (13.0,24.3); for OD without CBD: 24.6 ⁇ 2.1 (20.5,28.7). PD worse than CBD, p ⁇ 0.0001.
  • the UPBODT dichotomizing variable.
  • Four PD patients had normal and symmetrical odor detection of peanut butter and four PD patients had asymmetrical odor detection.
  • the UPBODT was 69.2% sensitive and 84.8% specific for Parkinson's disease.
  • the UPBODT was 69.2% sensitive and 100% specific for Parkinson's disease.
  • AD Alzheimer's disease
  • MCI mild cognitive impairment
  • OD other dementias
  • PD Parkinson's disease
  • OC matched controls
  • MMSE Mini Mental State exam
  • the difference between the R and L nostril odor detection distance was ⁇ 3 cm.
  • the difference between a person's R and L nostril odor detection distance was ⁇ 4 cm.
  • the UPBODT appears to track the progression of Alzheimer's disease.
  • This table contains data analyzed from the AD group only.
  • the present example uses the same methodology as set forth above in Example 1 , except odor recognition/identification was also tested/recorded and analyzed and correlated with the odor detection results above.
  • Example 1 Testing procedures, statistical methods, and analytical methods were the same as set forth in Example 1 , above, except that after odor detection, the clinician continues to move container of odorant (peanut butter) closer to the patient's nostril at a rate of 1 cm/exhale after detection until the patient is able to correctly identify the odor (in this case, peanut butter.
  • the odor recognition distance is the distance recorded at which the subject correctly identified the odor (if at all).
  • FIGS. 6A, 6B, and 7A and 7B The results of the testing and statistical analysis are presented in FIGS. 6A, 6B, and 7A and 7B.
  • FIGS. 7A and 7B compare the average distance of odor recognition for the left and right nostril of each group, with FIG. 7B including additional subjects with PD into the analysis.
  • the odor recognition distance of the right nostril was not different between groups in FIG. 7A.
  • the other groups were not different from each other.
  • the AD patients' left nostril and the PD patients' left and right nostril odor detection impairment had the expected effect on odor recognition distance and the results of this measure followed the same pattern as odor detection distance.
  • ADAR Alzheimer's Disease Education & Referral
  • Alzheimer's Disease Fact Sheet Avialable from:

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Abstract

La présente invention concerne des procédés et des tests pour le diagnostic et le dépistage de troubles dégénératifs du système nerveux central, tels que la maladie d'Alzheimer et la maladie de Parkinson. Le procédé comprend les étapes suivantes consistant à : placer un récipient contenant un odorisant pur sous une narine d'un patient ; rapprocher le récipient de la narine du patient ; mesurer la distance de détection de l'odeur entre la narine du patient et la position du récipient à laquelle le patient a initialement détecté l'odeur ; répéter les étapes ci-dessus sur l'autre narine ; et déterminer la différence entre la distance de détection de l'odeur de chaque narine, une différence de détection de l'odeur d'au moins environ 5 cm à l'avantage de la narine droite indiquant une probabilité de maladie d'Alzheimer.
PCT/US2014/012002 2013-01-18 2014-01-17 Procédés et tests pour troubles dégénératifs du système nerveux central Ceased WO2014113645A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
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US20150177202A1 (en) * 2013-12-20 2015-06-25 University Of Tennessee Research Foundation Odor threshold test
WO2020072448A1 (fr) * 2018-10-01 2020-04-09 University Of Kansas Kits et procédés de diagnostic et d'entraînement olfactifs
CN114531847A (zh) * 2019-09-27 2022-05-24 爱设株式会社 痴呆检查装置、痴呆诊断装置及包括其的痴呆诊断系统

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US3885550A (en) * 1972-12-08 1975-05-27 Commissariat Energie Atomique Method and device for differential olfactometry
US20030113701A1 (en) * 2001-12-13 2003-06-19 William Gartner Self-scoring method and apparatus for early self-screening of neurological disease
US20030225335A1 (en) * 2002-05-28 2003-12-04 Njemanze Philip Chidi Transcranial doppler ultrasound device for odor evaluation
US20070077204A1 (en) * 2005-06-10 2007-04-05 The Trustees Of Columbia University In The City Of New York Olfactory identification tests for cognitive diseases and disorders
CN202568210U (zh) * 2012-05-16 2012-12-05 马在臣 嗅神经检查器

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3885550A (en) * 1972-12-08 1975-05-27 Commissariat Energie Atomique Method and device for differential olfactometry
US20030113701A1 (en) * 2001-12-13 2003-06-19 William Gartner Self-scoring method and apparatus for early self-screening of neurological disease
US20030225335A1 (en) * 2002-05-28 2003-12-04 Njemanze Philip Chidi Transcranial doppler ultrasound device for odor evaluation
US20070077204A1 (en) * 2005-06-10 2007-04-05 The Trustees Of Columbia University In The City Of New York Olfactory identification tests for cognitive diseases and disorders
CN202568210U (zh) * 2012-05-16 2012-12-05 马在臣 嗅神经检查器

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150177202A1 (en) * 2013-12-20 2015-06-25 University Of Tennessee Research Foundation Odor threshold test
WO2020072448A1 (fr) * 2018-10-01 2020-04-09 University Of Kansas Kits et procédés de diagnostic et d'entraînement olfactifs
US12070319B2 (en) 2018-10-01 2024-08-27 University Of Kansas Olfactory diagnostic and training kits and methods
CN114531847A (zh) * 2019-09-27 2022-05-24 爱设株式会社 痴呆检查装置、痴呆诊断装置及包括其的痴呆诊断系统

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