Cerebral Haemodynamic Changes During Cognitive Testing: A fTCD Study
Condition: Mild Cognitive Impairment; Alzheimer Disease; Vascular Dementia; Healthy Controls
MeSH terms: Alzheimer Disease; Dementia, Vascular; Cognitive Dysfunction
Study type: Observational

Summary: 
      850,000 people live with dementia in the UK, with that number expected to rise to more than 1
      million within the next 5 years. The most common type of dementia (55%) is Alzheimer's
      dementia, and vascular dementia is the second commonest type (15%). Mild cognitive impairment
      (MCI) affects up to 20% of older adults and describes a set of symptoms rather than a
      specific medical condition or disease. A person with MCI has subtle problems with one or more
      of the following: day-to-day memory, concentrating, planning or organising, language (eg
      struggling to find the right word), and judging distances and seeing objects properly.
      Although MCI significantly increases the risk of developing dementia (by up to 5 times), at
      present it is not possible to accurately predict which patients with MCI will progress to
      dementia. In recent times there has been an increasing awareness that problems with brain
      blood flow may contribute to the development, or progression, of dementia. Tests of mental
      abilities, with standardised questions and pen-and-paper tests are a key component of the
      formal diagnosis of dementia, yet little is known of the effects of these tests on brain
      blood flow. Brain blood flow can be can be assessed non-invasively by the use of Trans
      Cranial Doppler (TCD). This means using ultrasound probes over both sides of the head to
      measure changes in blood flow in one of the main brain arteries (the middle cerebral artery).
      This proposed study will therefore use TCD to evaluate changes in brain blood flow during
      performance of the Addenbrooke's-III (ACE-III) cognitive assessment in four key groups of
      patients, specifically:

        1. Healthy older adults

        2. Patients with mild cognitive impairment (MCI)

        3. Patients with vascular dementia

        4. Patients with Alzheimer's dementia
    

Detailed description: 
      Dementia is the most common neurodegenerative disorder in the United Kingdom (UK); 850,000
      people currently live with dementia in the UK, and that number is expected to rise to more
      than 1 million within the next 5 years. The annual cost to the UK of dementia is £23.6
      billion. The most common type of dementia in the population (55%) is Alzheimer's dementia
      (AlzD). AlzD typically has a gradual onset and a slow progression. Vascular dementia (VascD)
      is the second commonest form of dementia (15%), and is suggested by the presence of vascular
      risk factors such as high blood pressure, high cholesterol, smoking and heart disease. The
      onset of vascular dementia is often abrupt, and the progression stepwise and irregular;
      cognitive deficits are often less uniform than those of Alzheimer's dementia. Mild cognitive
      impairment (MCI) affects up to 20% of older adults and describes a set of symptoms rather
      than a specific medical condition or disease. A person with MCI has subtle problems with one
      or more of the following: day-to-day memory, planning, language, attention and visuospatial
      skills. Although MCI significantly increases the risk of developing dementia at present it is
      not possible to accurately predict which patients with MCI will progress to dementia.

      In recent times, our knowledge regarding the mechanisms of dementia development has changed
      considerably. In contrast to previous thoughts, there is now a growing understanding that
      problems with blood vessels (vascular dysfunction) and brain blood flow (cerebral
      haemodynamics) are present in AlzD as well as in VascD. Research studies investigating the
      vascular contributions to dementia generally report low blood flow (cerebral hypoperfusion).
      It is thought that this hypoperfusion affects cellular health which in turn triggers
      neurodegenerative pathways.

      Brain blood flow is directly linked to brain activity, a concept known as 'neurovascular
      coupling'. Brain activation can be achieved through various cognitive and visual tasks (e.g
      reading and writing), and also by sensorimotor tasks (e.g. movement or touch). Cognitive
      assessments are routinely used in the diagnosis of dementia. Brain blood flow can be studied
      using techniques such as functional magnetic resonance imaging (fMRI), positron emission
      tomography (PET) or single-photon emission computed tomography (SPECT). However, these
      techniques are expensive, in the case of SPECT involve radiation, and there are feasibility
      issues which are particularly problematic for older populations, including the need to lie
      still for prolonged periods and have no metal implants. Transcranial Doppler (TCD) ultrasound
      is a simple, non-invasive imaging technique which allows for the continuous and bilateral
      recording of brain blood flow velocity through the major arteries in the brain.

      Cognitive testing with standardised assessment tools such as the Mini Mental State
      Examination, Montreal Cognitive Assessment and Addenbrooke's-III Cognitive Examination
      (ACE-III) is a key component of the formal diagnosis of dementia, yet the effects of these
      tests on brain blood flow and haemodynamics is unknown. The ACE-III is a widely used,
      validated, cognitive screening tool recommended for use by health practitioners and
      researchers in patients over 50 years old with suspected dementia. The ACE-III is available
      for free. The copyright is held by Professor John Hodges, ARC Federation Fellow and Professor
      of Cognitive Neurology at Neuroscience Research Australia, who is happy for the test to be
      used in clinical practice and research projects.

      This protocol has been used successfully by this group to examine changes in CBFv in 40
      healthy volunteers from the University of Leicester. The data from this analysis has been
      presented at an international conference and is currently undergoing peer review for
      publication. Therefore, this protocol has demonstrated feasibility in a healthy population
      and warrants further investigation for the utility in a patient population.

      This research will therefore use transcranial Doppler ultrasound to study the brain blood
      flow responses of healthy controls, patients with AlzD, patients with VascD, and patients
      with MCI, in response to performance of the ACE-III cognitive examination.
    

Intervention name(s): Transcranial doppler ultrasonography; Blood pressure monitoring; Heart rate monitoring; End tidal CO2 monitoring; Addenbrooke's cognitive examination
Intervention type(s): Other; Other; Other; Other; Other
Intervention description(s): Measurement of cerebral blood flow whilst undertaking cognitive tasks with TCD monitoring.; Continuous blood pressure recording; Continuous heart rate monitoring; Continuous ETCO2 monitoring; Performance of a memory test
Other intervention name(s): TCD; Finometer; Electrocardiogram; Capnography; ACE III
Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Healthy controls - age, sex and co-morbidity matched. Patients with Alzheimer's dementia,
        vascular dementia, and mild cognitive impairment