Non Invasive Device for Early Stage Alzheimer's and Neurodegenerative Disease Detection

Abstract

A disease, by definition, is an undesired or abnormal state. Diseases are characterized by symptoms that may change during disease progression. But each symptom is underpinned by at least one factor that alters metabolism within cells of the body. Without at least one change in cell activity (metabolism) there would be no symptoms. These metabolic alterations involve modified rates or occurrence of alternate biochemical reactions. Disease-associated patterns of reactions (metabolisms) produce a characterizing or signature pattern of reaction products and byproducts. These metabolites, especially volatile organic metabolites (VOCs), may be assayed using a device of this invention to produce results that indicate a subject's disease or class of diseases and to differentiate between diseases.

Claims

1. A sniffer device for early stage autoimmune and/or neurodegenerative disease detection, said device comprising: a portal, sized to enter the ear canal and configured to collect gas therefrom; a passage connecting said portal to an array of nanosensing elements sensitive to at least one volatile organic compound (VOC) flowing through said passage to become available to said array; said array configured to produce data output in response to interaction with said at least one VOC; a processor receiving said data output, said processor processing said data output to form a profile or signature characterizing the VOC content within said ear canal; and an interface capable of outputting said signature or profile for further analysis.

2. The sniffer device of claim 1, further comprising a data analyzer capable of receiving a signature or profile developed by the device.

3. The sniffer device of claim 2 further comprising an interface with a library of profiles or signatures associated with at least one disease.

4. The sniffer device of claim 3 wherein said library comprises profiles or signatures of a plurality of diseases.

5. The sniffer device of claim 1, further comprising a heater component.

6. The sniffer device of claim 5 wherein said heater component operates using radiant heat.

7. The sniffer device of claim 5 wherein said heater component operates using a laser heating element.

8. The sniffer device of claim 5 wherein said heater component operates using resistive heating element.

9. The sniffer device of claim 1 comprising a sensing surface external to the otic meatus.

10. The sniffer device of claim 9 further comprising a tube extending from said portal to said array of nanosensing elements.

11. A sniffer device for early stage autoimmune and neurodegenerative disease detection, said device comprising: a shield, sized and shaped to enclose or cover the ear canal and configured to collect gas therefrom; a passage through said shield to an array of nanosensing elements sensitive to at least one volatile organic compound (VOC) flowing through said passage to become available to said array; said array configured to produce data output in response to interaction with said at least one VOC; a processor receiving said data output, said processor processing said data output to form a profile or signature characterizing the VOC content within said ear canal; and an interface capable of outputting said signature or profile for further analysis.

12. The sniffer device of claim 11 further comprising a cartridge comprising a VOC adsorbent.

13. The sniffer device of claim 12 wherein said cartridge is removable.

14. The sniffer device of claim 12 wherein said VOC adsorbent comprises a compound or composition selected from the group consisting of: cotton, aliphatic methacrylates, carbon, PVDF, zeolites, microporous silica, aromatic polydivinylbenzenes polystyrenic-polydivinylbenzene matrices, and highly cross-linked styrenic polymers.

15. The sniffer device of claim 11 further comprising a deformable membrane.

16. The sniffer device of claim 14 wherein said deformable membrane functions as a pulsatile gas driver.

17. The sniffer device of claim 11 said shield comprises a heated enclosing portion.

18. The sniffer device of claim 17 wherein said headgear is in a form selected from the group consisting of: a headset, form fitting cap, and earmuffs.

19. The sniffer device of claim 18 wherein said collector module comprises a port for a removable cartridge.

20. The sniffer device of claim 12 wherein said VOC adsorbent comprises a compound or composition selected from the group consisting of: cotton, aliphatic methacrylates, carbon, PVDF, zeolites, microporous silica, aromatic polydivinylbenzenes polystyrenic-polydivinylbenzene matrices, and highly cross-linked styrenic polymers.

Description

EXAMPLES

[0038] A panel of patients is chosen. Informed consent is obtained. Patients are associated with one or more disease(s). When patients have agreed, both swab samples (earwax) and otic canal gasses are collected. Samples are analyzed and a signature pattern output is obtained. It is not essential to identify any specific VOC, the sensing pattern obtained by passing the sample over the block provides sufficient distinguishing data even when the chemical structure of one or more of the VOCs is unknown. Patients with a particular diagnosis are associated with that disease. Patients without that diagnosis (but possibly, and most likely, with a diagnosis for one or more other disease(s) can serve as control for each disease in the panel of patients.

[0039] While otic gas is targeted for analysis, the process of using the device may involve analyzing a gas sample outside the otic canal as a control factor. The sensor device used for obtaining and analyzing otic gas may be activated outside the canal to collect control samples. For example, a sample of gas from the auricular area, the external meatus, etc., may serve to control for ambient gases the subject may be immersed in.

[0040] The data are fed into a processor either in the collection device itself or an associated component which applies artificial intelligence or machine learning to identify portions of each patient's signature may be associated with a particular diagnosis. In some circumstances a part of the signature, e.g., a ratio of VOC A to VOC B may be similar between a plurality of diseases. Gross outputs, the interactions with sets of sensors with a collection of VOCs that pass over each set can be processed and analyzed to form signatures. A multi-channel, e.g., 256 sensor chip bearing, e.g., 16 channels of 16 sensing elements (1616) can from a pattern of responses in 16 dimensions across a pre-selected sampling time. Rates of signal changes caused by the collection of VOCs passing by each channel can form robust signals for analyzing disease presence, severity, status, and changes in repeated analyses from the same source.

[0041] A library of signature patterns is thus collected with characteristic signature elements being associated with a disease as signature for that disease. Earwax and otic canal gasses are separately analyzed but may be correlated or cross-referenced. Left- and right-side readings are cross-referenced and correlated when possible. Differences may be indicative of disease differences between hemispheres, circulatory aberrations, previous injury, sleep positions, headset wearing, etc. Data may show that left-right differences can provide information suggesting lesion location, or may suggest preferences for using the right or left ear for testing depending on the subject's behaviors, habits, and activities.

[0042] A second group of patients is similarly evaluated to confirm or adjust disease signatures. The system is then used for diagnosing patients. In preferred practice, over a period of years, the data are periodically reevaluated and refined. For example, patients who are diagnosed with a disease months or years after the initial signature development may have their data reevaluated for potential indication of a pre-disease state or early disease detection. Having a signature library available, a patient comes to clinic and as a part of screening has an otoscope like device inserted in the ear canal.

[0043] The device, in this example, actually includes an otoscope function incorporating a light and a view-port. The medical provider uses the optics of the otoscope to center the device within the canal. A gas sample is drawn into and analyzed in the otoscope device. The device communicates the patient's otic gas signature electronically to a home device which displays and/or prints out a report. A clinician then counsels the patient with emphases on current and developing disease(s) that are indicated or suggested through the device's comparison of the patient's VOC signature to the signature library for diseases.

[0044] As an alternative to an otoscope like device to access the otic canal, a probe shaped similar to an earbud or earplug may be inserted into the ear to access otic gases. The earbud or earplug shaped device may be self contained, e.g., including an integral power source, sensor surfaces, data processor, amplifier, data storage, a signal transducer, and/or a communication interface. Such bud may remain in the ear for an extended period reducing or minimizing a preference for a gas driving component.

[0045] In some embodiments, rather than a sampling element being inserted in the canal, a headphone like device may be placed over the external ear(s). This device optionally incorporates a driver device to move the gases. The driver device may slowly exhaust gas helping to drive gas across sensor surfaces. The driver device may comprise a deformable membrane, e.g., a speaker to deliver tones, music, instructions, and/or other sound to the subject. The device bearing a deformable membrane may appear in many formats, for example, as cups similar to those in sound delivery system or sound deadening headphones. A cap with cups to situated closer to the ear canal may provide better comfort for longer wear, e.g., during sleep. Components that cover and/or provide access to canal gases may sport heating capacities that may improve comfort and may be employed to accelerate off-gassing of VOCs. A warming heater may be present in padding material that contacts the head or the confined gasses may be heated, e.g., by a pulse generating device. The headphones may be coupled with a sound content provider, e.g., music, book, news, verbal instructions, blog, etc., selected by the wearer or technician. Sound content may be included in the device or provided from a remote source, preferably wirelessly. A device worn over the ear may or may not itself comprise data analysis and/or data processing capacities. For example, the covering may contain a cartridge, preferably an exchangeable or removable cartridge that captures the emitted VOCs.

[0046] VOCs may be captured in a gaseous form in a sealed container. The VOCs may also be captured on a solid or gel support that can be removed and delivered to the assay portion of the device. Many fibers are known to capture odors or VOCs. The format is a designers choice and may include natural or artificial membranes or fibers that have been degassed. Materials including, but not limited to: cotton, aliphatic methacrylates, carbon, PVDF, zeolites, microporous silica, aromatic polydivinylbenzenes polystyrenic-polydivinylbenzene matrices, highly cross-linked styrenic polymers, etc. may be formed as capture filters. VOCs may be desorbed or harvested from such filters or capture elements, e.g., using heat, gas or liquid purge or flush, vacuum, CO.sub.2, nitrogen displacement, etc., for presentation to sensor element arrays.

[0047] Such deformable membrane may participate in gas delivery to sensors of the device. A bud like device component or headphone like covering may be worn for relatively short assays, e.g., over the order of minutes to longer sample sessions, e.g., 30-45 minutes, 1 or more hours, a half day (about 2, 3 or 4 hours before or after lunch), a full day, e.g., 6, 7, 8 or more hours, including overnight, and occasionally for longer period such as extended EEG sessions or clinic stays.

[0048] In another example, a device component fitting around or over the head, may be worn for a predetermined length of time. While the device in some examples incorporates the sensors and electronics for assaying VOCs, in this example, the headset shaped device collects sample(s) that is then delivered to a sensing component that is not physically attached to the head worn component. In a first format, the subject or an assistant removes the head component from its packaging. The component may be adjusted for comfort and/or proper alignment over the ear canal(s). A covering is removed or reconfigured to expose a sampling cartridge to the outside air or eargas. The sampling component is fitted over the head. After a predetermined length of time, the component is removed fro the head with its sampling chamber appropriately resealed. The entire headset package component is repackaged for delivery to the lab for VOC analysis. In some embodiments a sample collector module provides a port for a cartridge that is removable or exchangeable. The cartridge(s) is/are removed from the headset holder and packaged for delivery to the lab for analysis. A cartridge may be retained by any suitable means, e.g., by friction, by one or more clips, by a stretch fiber or crevice, by a screw mechanism, etc. The headset may be retained for insertion of additional cartridge(s) when a retest, e.g., monitoring disease progression is performed. A head covering or cap may be substituted for the headset shaped component in some embodiments.

[0049] A similar process, involves a subject accepting delivery or accessing an earbud or earplug configured device (one or two for a single ear or for a bilateral assay) for insertion in one or both ears. The subject then wears the bud or plug for a predetermined or suggested length of time, removes the plug or bud, and inserts the device(s) in a package to be delivered to a lab where the device(s) are fed into an entry port of a VOC assay device for analysis and characterization.

[0050] An alternative format of the present invention comprises a gas driver that draws otic canal gases through the collection portion of the device into an accessory device containing one or more sensing blocks. The gas replacing the gas removed by the device may be ambient air or a selected gas or mixture of gases. For example, an inert gas (may or may not be a noble gas) in provided at a temperature or range of temperatures to optimize testing protocols, e.g., for speed, patient comfort, quality of results.

[0051] As the gases are drawn through the accessory device the depth of the otic probe may be adjusted. A low-volume transit tube, e.g., short with small inner diameter, allows obtention of results at a quicker pace and decreases temperature effects from gases flowing into the ear canal when these flows are not otherwise controlled. To the extent that colder air may be annoying to the subject, a heating coil or feeding line may reduce the irritative cold sensation. Slightly warming the air may also be advantageous for subliming or evaporating additional VOCs. Humidity may also be a controlled testing parameter. Polar vapors, water or otherwise, may encourage release or VOCs from the otic coating. Volunteer subjects or patients of different sizes, genders, races, and cultures are tested using probes with flowing gas.

[0052] The art mentioned above employed different means for assaying volatile compounds. The different means would be expected to have different sensitivities to different VOCs. In this current example, temperature is a variable that can change the signature profile. Accordingly, a VOC pattern associated with a disease, e.g., Alzheimer's Disease obtained, for example through GC-MS, cannot be assumed to be the same pattern when assayed with another sensor format. Thus, signatures should be clearly identified with the process under which they were obtained.

[0053] Nano FETs and other nano-sensor formats generally operate by changing electrical properties as a substance comes in close proximity to the sensor. The interaction between electrons of the sensed molecule and the sensor surface perturbs the steady state of that surface to elicit its signal. The altered distribution of electrons induced by a proximal molecules, (depending on the design of the nano-sensor) changes one or more electrical properties, e.g., impedance, resistance-conductivity, capacitance, inductance, etc. and thus the physical movement of a detectable particle, e.g., an electron, a photon, etc.

[0054] Specificity of coordination (interaction) between sensor surface and VOC molecule may be provided by functionalizing or decorating the carbon gate electrode. For example, many sequences of nucleic acid such as DNA or RNA will stringently coordinate or bind with the SWNT structure. These nucleic acids may be naturally occurring or synthetic. The ringed structures of the nucleic acids or other molecules such as peptides containing a large fraction of ringed structures associate strongly with the nanotubular structures. These functionalizing, or decorating, additions to the SWNTs serve to selectively capture proximal molecules. When the chemical geometry is changed, the gating characteristic of the associated carbon bridging the input and output electrodes is modulated. Differently decorated or heated elements respond differently different proximal VOC. A single element may be associated with a single sequence or a plurality of functionalizing sequences. Output characteristics of gating in response to one or more gaseous compounds, e.g., VOCs are then collated into a data library. When that NSE responds in the same manner, presence of the VOC is confirmed. Stringent selection of element functionalizations, and subsequent application of the controllable assay variables can optimize certainty of VOC identification at a desired level, for example, increasing manipulation of the variable parameters can achieve certainty of 99+%. In special circumstances, for example to develop rapid profiling of a new VOC signature (i.e., pathogen), a simplified screening protocol or developmental process may begin with a lower level of certainty, e.g., 85%, 95%, etc. Subsequent refinements then could be applied to raise the level of certainty until reaching a mathematical and chemical sensitivity to an acceptable level, e.g., a 99+% certainty. while also minimizing false positives

[0055] A single element may be capable of indicating the presence of more than one compound. For example, similar compounds may not be distinguished in their association/coordination with the element surface and therefore may in certain circumstances produce indistinguishable signals on their own. But the single element may, for example, in conjunction with one or more other elements provide definitive results with respect to the VOCs that may interact with any one element. Alternatively, the single element when operated at a different temperature, voltage or other variable may distinguish between the different compounds binding the element under static conditions. The discussion above describing the variable inputs and input patterns and different resulting outputs relates to such differentiation capabilities.

[0056] In another example, an individual is identified as a candidate for assessment of VOCs from the head area The assessment is to be derived from inner ear gases. A cap similar in shape to the protective headgear worn in water polo matches is provided. The version in this example is a Lycra or elastic fabric based form-fitting headgear. Where the water polo cap incorporates rigid or semi-rigid cups that protect the ears from impacts or shear forces, the device of the present invention incorporates the VOC component. The VOC component can take on different formats depending on the choice of the user(s). The cup portion may be rigid, semi-rigid, padded or semi-soft. It may be integral in the headgear. Preferably the cup is identical in design save in some embodiments a marking to designate left or right. In some embodiments the attachment means will only allow a side designated component to be attached to the designated side. Attachment in a primary example uses a simple slot for alignment with a turn to secure the device. A tab may be incorporated to prevent accidental release. A screw-in or snap-in format may be provided as alternative selections.

[0057] The cup may contain a solid or gel to adsorb VOCs from the cup (ear) area. More elegant examples include one or more features selected from the group consisting of: a sound speaker that may provide entertainment, a lesson, and/or instruction; a slow pulsing gas driver to reduce and increase air pressure movement of VOCs to the retainer; a heater to stabilize temperature and/or to increase VOC emission; VOC sensors; a data collector; a data processor; a data receiver and/or transmitter; an alarm (e.g., to signal end of trial); etc.

[0058] The subject wears the device for a preselected period of time, for example the length of an office or clinic visit, the length of a movie, a sleep period (e.g., overnight), etc.

[0059] Embodiments may incorporate accessories including, but not limited to: a convective gas driver for introducing gas into the otic canal; a convective gas driver driving gas from the otic canal; a gas driver to move the air that is selected from the group consisting of: a syringe, a fan, and a pump; etc.

[0060] Embodiments may incorporate a sample collector module for sample retention for historical or remote analysis. Some embodiments may be shaped as or incorporated in a headgear that covers at least one otic meatus.

[0061] The device may feature one or more pulsatile gas drivers for driving gas in said otic canal in a pulsatile fashion. The pulsation may result from a deformable membrane, a cycling valve, etc. A sample cartridge holder may help contain or support a collector/retention cartridge which may be associate with a cartridge sealer to isolate the sample(s). The unit or parts thereof can be similar in configuration to an otoscope, an earbud, an earplug, etc., optionally featuring a heater to heat a portion internal to the otic meatus. Such heater may be associated with a pulsatile air driver for convective air heating, may be radiant heat, and/or may contact the skin.

[0062] Since the manner through which a signature is obtained is determinative of the signature outcome, a different assay technique or device format thus requires validation processes to form and confirm VOC signatures for each disease of interest. While animal models may be illustrative, human data are preferred for better relevance to human diseases.