Vagus Somatosensory Evoked Potentials and Near-infrared Spectroscopy in the Early Diagnosis of Dementia
Condition: Alzheimer´s Disease
MeSH terms: Alzheimer Disease
Study type: Observational

Summary: 
      In its long preclinical course, AD shows a spreading pattern of specific pathology in a
      uniform sequence of predictable steps including brainstem nuclei in early stages. Many of
      these nuclei which are early involved in AD take equally part in the afferences of the Xth
      cranial nerve, the Vagus nerve. A method for the functional assessment of Vagus-related
      nuclei in the lower brainstem is the technique of somatosensory evoked potentials of the
      Vagus nerve (VSEP). This method targets the accessibility of early functional changes by
      evoked potentials on one hand and the early affection of specific brainstem nuclei comprising
      Vagus afferences in the course of AD on the other hand. The method of VSEP takes advantage of
      the transcutaneous stimulation of the auricular branch of the Vagus nerve (ABVN) which is
      presumed to be the only sensory part of this nerve innervating parts of the outer meatus
      acoustics at the tragus. This cutaneous branch was shown to gain access to Vagus afferences
      via brainstem regions which are affected in the course of AD. VSEP latencies in AD were shown
      to be significantly longer as compared to healthy controls. Yet, if VSEP really are suited
      for the early detection of AD is still not known.

      Functional near-infrared spectroscopy (fNIRS) measures changes in cerebral oxygenation by
      means of near-infrared light using wavelengths of 650-850 nm. The principle of fNIRS is based
      on the principle that regional neuronal activation of the brain leads to an increase in
      metabolism and oxygenation of brain tissue in that region which is accompanied by an elevated
      regional cerebral blood flow. In AD, there is a growing body of literature reporting deviant
      fNIRS activation patterns for a variety of tasks. For example, it was shown that the fNIRS
      activation pattern in frontal and parietal cortex areas in subjects with AD performing the
      line orientation paradigm is clearly different from healthy controls. Yet, if fNIRS is suited
      as a means of early detection of AD is not known.

      Therefore we aimed at testing the predictive value of VSEP and fNIRS in the early detection
      of AD. The hypothesis to be tested within this study states that subjects developing AD or
      MCI within an observation period of 6 years depict longer VSEP latencies, a different fNIRS
      oxygenation pattern and a lower performance in neuropsychologic rating below the level of
      dementia at baseline than those who remain cognitively stable.
    

Detailed description: 
      With the increasing life span of our population, the prevalence of dementia syndromes is
      increasing. The most frequent cause of dementia is Alzheimer´s disease (AD), and still, it is
      not curable. Thus, AD is of increasing medical, social and economic importance.

      Intensive scientific work within the past 30 years has identified a range of different
      factors contributing to the pathogenesis of AD. These complex processes result in specific
      therapeutic options which are currently investigated in clinical trials. Regardless of the
      considered risk factor or the specific therapeutic intervention, treatment should be started
      as early in the excessive preclinical process of AD as possible since it can interfere with
      the formation of amyloid plaques or neurofibrils. Especially neuroprotective interventions
      are more effective the less neurons are irreversibly damaged.Therefore, an early diagnosis of
      developing or incipient AD should be of utmost importance. Likewise, in the light of
      therapeutic options specific for AD, its differential diagnosis from other forms of dementia
      seems important.

      Therefore, an ideal examination method should not only be easy to conduct, cost effective,
      repeatable, non-invasive and without discomfort for patients, but it should in particular
      detect early stages of disease and it should, if possible, consider the development of
      AD-specific changes. Obviously, today´s routine examination methods in the diagnosis of AD or
      MCI such as magnetic resonance imaging, cerebrospinal fluid analysis or positron emission
      tomography do not fulfil all of these requirements. Thus, in the absence of a single
      diagnostic test and realizing the necessity to combine biomarkers to increase the diagnostic
      accuracy there is still need for methods that circumvent all those disadvantages.

      Since early cellular changes of the disease are expected to impact brain function long before
      severe morphological alterations occur, these changes should primarily be investigated using
      functional examination which can be conducted with neurocognitive methods such as intensive
      neuropsychological rating or with electrophysiological or functional brain imaging methods.

      Neuropsychological rating Prior studies investigated the predictive validity of different
      cognitive measures for the development of AD such as associative learning, verbal fluency and
      constructive praxis. As such, verbal and non-verbal memory, visual-spatial and executive
      functions and verbal fluency with executive component seem to be suited for following the
      deterioration of cognition. In subjects who later develop AD or MCI as compared to a healthy
      controls, worse performance in episodic memory according (Delayed Verbal and Visual Memory
      und Associative Learning) and in semantic verbal fluency are known to be characteristic. An
      extended neuropsychologic testing to measure these cognitive processes thus seems reasonable
      in particular to evaluate the additional benefit of other diagnostic methods.

      Vagus somatosensory evoked potentials (VSEP) As we know today, AD has a long preclinical
      course with a spreading pattern of specific AD pathology such as neurofibrillary tangles in a
      uniform sequence of predictable steps. Many of these nuclei which are early involved in AD
      like the Locus caeruleus, parabrachial nucleus or Raphe nuclei take equally part in the
      afferences of the Xth cranial nerve, the Vagus nerve. Our laboratory used a hypothesis-driven
      approach to develop a method for the functional assessment of Vagus-related nuclei in the
      lower brainstem which resulted in the technique of somatosensory evoked potentials of the
      Vagus nerve (VSEP). This method targets the accessibility of early functional changes by
      evoked potentials on one hand and the early affection of specific brainstem nuclei comprising
      Vagus afferences in the course of AD on the other hand.

      The method of VSEP takes advantage of the transcutaneous stimulation of the auricular branch
      of the Vagus nerve (ABVN). It is presumed to be the only sensory part of this nerve
      innervating parts of the outer meatus acoustics at the tragus. This cutaneous branch was
      shown to gain access to Vagus afferences via the Solitary tract nucleus which is affected in
      the course of AD as well.

      The technique of VSEP meanwhile is well characterized from a methodological point of view.
      There are numerous findings suggesting that observed potentials are generated at brainstem
      level and can be detected as far field potentials at the scalp without any side effects. VSEP
      are reproducible and amplitudes as well as latencies are in the range of corresponding
      parameters of acoustic evoked potentials. Detailed examinations with functional magnetic
      imaging revealed a cortical activation pattern upon ABVN stimulation comparable to the
      activation pattern as response to the conventional invasive stimulation of the main Vagus
      branch. In a subsequent work, even involvement of brainstem activation was demonstrated that
      could be related to ascending Vagus nerve projections.

      As such, VSEP were proposed as a possible means for the early detection of AD and mild
      cognitive impairment (MCI). VSEP latencies in both groups were shown to be significantly
      longer as compared to healthy controls. No difference in VSEP parameters was found in
      patients with Vascular dementia and Major depression.

      Near-infrared spectroscopy (NIRS) NIRS measures changes in cerebral oxygenation by means of
      near-infrared light using wavelengths of 650-850 nm. The principle of NIRS is based on the
      principle of neurovascular coupling stating that regional neuronal activation of the brain
      leads to an increase in metabolism and oxygenation of brain tissue in that region which is
      accompanied by an elevated regional cerebral blood flow. This in turn leads to an increased
      oxygen saturation with elevated concentrations of oxygenated haemoglobin and diminished
      concentrations of deoxygenated haemoglobin.

      In the last years, functional NIRS (fNIRS) was increasingly applied to measure changes in
      oxygen saturation of cortical areas during a variety of cognitive tasks such as for example
      verbal fluency test and thus to detect specific cortical activation not only in the visual
      and the motor system, but also in cortical areas relevant for cognitive tasks such as
      prefrontal and parietal cortex that remain stable and are replicable. In AD, there is a
      growing body of literature reporting deviant fNIRS activation patterns for a variety of
      tasks. For example, young healthy subjects displayed a distinct activation pattern of the
      prefrontal cortex during a verbal fluency test (VFT) showing a left hemispheric
      lateralization which decreased with age without a decline in behavioural performance. In
      contrast, subjects with AD showed a worse behavioural performance and an even more severe
      decrease of prefrontal activation as well as a reduced left lateralization as compared to an
      age-adjusted healthy control group. Likewise, it was shown that the fNIRS activation pattern
      in frontal and parietal cortex areas in subjects with AD performing the line orientation
      paradigm is clearly different from healthy controls.

      Aim of the study To summarize, VSEP, fNIRS and neuropsychological rating are able to
      differentiate AD from healthy controls. From a theoretical point of view, these methods
      should even be suited as a means of detection of the disease in early phases as well. If they
      are really suited as means for that purpose is to be examined in the here presented study.
      Therefore we aimed at testing the predictive value of these methods in the early detection of
      AD. In the here presented research project, 600 subjects examined at baseline by means of
      VSEP, fNIRS and extended neuropsychological, somatic and laboratory examination are to be
      reexamined 3 and 6 years later. The hypothesis to be tested within this study states that
      subjects developing AD or MCI within the observation period depict longer VSEP latencies, a
      different fNIRS oxygenation pattern and a lower performance in neuropsychologic rating below
      the level of dementia at baseline than those who remain cognitively stable.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Inhabitants of Wuerzburg, the 130 000 inhabitants capital of the german district Lower
        Franconia who are born between 1.4.1936 and 31.3.1941
      
Biospecimen description: 
      whole blood, serum
    
Keywords: Alzheimer´s disease; early diagnosis; evoked potentials; near-infrared spectroscopy