Cerebral Haemodynamic Changes During Cognitive Testing: A fTCD Study

Completed

Conditions: Mild Cognitive Impairment
Alzheimer Disease
Vascular Dementia
Healthy Controls

Interventions: Other: Transcranial doppler ultrasonography
Other: Blood pressure monitoring
Other: Heart rate monitoring
Other: End tidal CO2 monitoring
Other: Addenbrooke's cognitive examination

Registration Number: NCT03134963

Lead Sponsor: University of Leicester

Brief 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 42

Inclusion Criteria

Informed volunteer consent, patient consent
Male or female, aged between 18 and 100 years of age
Able (in the Investigator's opinion) and willing to comply with all study requirements
Willing to allow his or her General Practitioner (GP) to be notified of participation in the study
Good understanding of written and verbal English

Healthy Controls-specific Inclusion Criteria

No evidence of subjective or objective memory impairment on cognitive testing
No major medical co-morbidity (outlined in detail in the exclusion criteria) or medication use that could adversely affect cognition

MCI Patient-specific Inclusion Criteria

Clinical diagnosis of MCI made by a specialist* in a patient who fulfils the established clinical consensus criteria for MCI [NIA/AA 2011] specifically:

Concern regarding a change in cognition compared to the person's previous level, by the patient and/or informant
Objective evidence of impairment of one or more cognitive domains, greater than expected for age, and educational background, over time if repeated measures are available.
Preserved independence of functional abilities and minimal to no impairment on complex instrumental functions
Not demented

Vascular Dementia Specific Inclusion Criteria

Clinical diagnosis of VascD made by a specialist* in a patient who fulfils the NINDS-AIREN criteria for VascD, specifically:

Cerebrovascular disease defined by the presence of focal signs on neurological examination consistent with stroke and evidence of cerebrovascular disease on brain imaging.
One or more of:
- Onset of dementia within 3 months of a diagnosed stroke
- Abrupt deterioration in cognitive function
- Fluctuating, stepwise progression of cognitive deficits

Alzheimer's Dementia Specific Inclusion Criteria

Clinical Diagnosis of AlzD made by a specialist* in a patient who fulfils the NIA/AA criteria for Probable AlzD, specifically:

Meets the criteria for dementia
- The memory impairment and cognitive deficits cause significant impairment in social or occupational functioning, and represent a significant decline from a previous level of functioning, not explained by a delirium or a major psychiatric disorder
- Impairment of at least two cognitive domains
Insidious or gradual onset
Clear history of worsening cognition by report or observation
The initial and most prominent cognitive deficits are evident on history and examination in one of the following domains:
- Amnestic: impaired learning and recall of recently learned information
- Non amnestic: language/visuospatial/executive dysfunction
No evidence of substantial cerebrovascular disease, core features of dementia with lewy bodies, features of frontotemporal dementia, prominent features of semantic variant primary progressive aphasia, evidence of active neurological disease, a non-neurological co-morbidity or medication that could affect cognition
- A specialist being defined as a psychiatrist or a geriatrician, or a specialist mental health nurse with a specific interest or expertise in cognitive disorders.

Exclusion Criteria

Male or Female, aged under 18 years
Unable (in the Investigator's opinion) or unwilling to comply with any study requirements
Female participants who are pregnant, lactating or planning pregnancy during the course of the study
Major co-morbidity likely to affect cerebral autoregulation; severe respiratory disease, carotid artery stenosis, atrial fibrillation, severe cardiac failure (left ventricular ejection fraction <20%), extreme frailty or multi-morbidity.

Study & Design

Study Type: OBSERVATIONAL

Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Mild cognitive impairment	End tidal CO2 monitoring	MCI Patient-specific Inclusion Criteria Clinical diagnosis of MCI made by a specialist\* in a patient who fulfils the established clinical consensus criteria for MCI \[NIA/AA 2011\] specifically: * Concern regarding a change in cognition compared to the person's previous level, by the patient and/or informant * Objective evidence of impairment of one or more cognitive domains, greater than expected for age, and educational background, over time if repeated measures are available. * Preserved independence of functional abilities and minimal to no impairment on complex instrumental functions * Not demented
Mild cognitive impairment	Addenbrooke's cognitive examination	MCI Patient-specific Inclusion Criteria Clinical diagnosis of MCI made by a specialist\* in a patient who fulfils the established clinical consensus criteria for MCI \[NIA/AA 2011\] specifically: * Concern regarding a change in cognition compared to the person's previous level, by the patient and/or informant * Objective evidence of impairment of one or more cognitive domains, greater than expected for age, and educational background, over time if repeated measures are available. * Preserved independence of functional abilities and minimal to no impairment on complex instrumental functions * Not demented
Mild cognitive impairment	Blood pressure monitoring	MCI Patient-specific Inclusion Criteria Clinical diagnosis of MCI made by a specialist\* in a patient who fulfils the established clinical consensus criteria for MCI \[NIA/AA 2011\] specifically: * Concern regarding a change in cognition compared to the person's previous level, by the patient and/or informant * Objective evidence of impairment of one or more cognitive domains, greater than expected for age, and educational background, over time if repeated measures are available. * Preserved independence of functional abilities and minimal to no impairment on complex instrumental functions * Not demented
Alzheimer disease	Addenbrooke's cognitive examination	NIA/AA criteria * Meets the criteria for dementia o The memory impairment and cognitive deficits cause significant impairment functioning, a significant decline from a previous level of functioning, Impairment of at least two cognitive domains * Insidious or gradual onset * Clear history of worsening cognition by report or observation * The initial and most prominent cognitive deficits are evident on history and examination in one of the following domains: * Amnestic: impaired learning and recall of recently learned information * Non amnestic: language/visuospatial/executive dysfunction
Alzheimer disease	End tidal CO2 monitoring	NIA/AA criteria * Meets the criteria for dementia o The memory impairment and cognitive deficits cause significant impairment functioning, a significant decline from a previous level of functioning, Impairment of at least two cognitive domains * Insidious or gradual onset * Clear history of worsening cognition by report or observation * The initial and most prominent cognitive deficits are evident on history and examination in one of the following domains: * Amnestic: impaired learning and recall of recently learned information * Non amnestic: language/visuospatial/executive dysfunction
Vascular dementia	End tidal CO2 monitoring	NINDS-AIREN criteria for VascD, specifically: * Cerebrovascular disease defined by the presence of focal signs on neurological examination consistent with stroke and evidence of cerebrovascular disease on brain imaging. * One or more of: * Onset of dementia within 3 months of a diagnosed stroke * Abrupt deterioration in cognitive function * Fluctuating, stepwise progression of cognitive deficits
Vascular dementia	Addenbrooke's cognitive examination	NINDS-AIREN criteria for VascD, specifically: * Cerebrovascular disease defined by the presence of focal signs on neurological examination consistent with stroke and evidence of cerebrovascular disease on brain imaging. * One or more of: * Onset of dementia within 3 months of a diagnosed stroke * Abrupt deterioration in cognitive function * Fluctuating, stepwise progression of cognitive deficits
Healthy controls	Transcranial doppler ultrasonography	Healthy Controls-specific Inclusion Criteria 1. No evidence of subjective or objective memory impairment on cognitive testing 2. No major medical co-morbidity (outlined in detail in the exclusion criteria) or medication use that could adversely affect cognition
Mild cognitive impairment	Heart rate monitoring	MCI Patient-specific Inclusion Criteria Clinical diagnosis of MCI made by a specialist\* in a patient who fulfils the established clinical consensus criteria for MCI \[NIA/AA 2011\] specifically: * Concern regarding a change in cognition compared to the person's previous level, by the patient and/or informant * Objective evidence of impairment of one or more cognitive domains, greater than expected for age, and educational background, over time if repeated measures are available. * Preserved independence of functional abilities and minimal to no impairment on complex instrumental functions * Not demented
Mild cognitive impairment	Transcranial doppler ultrasonography	MCI Patient-specific Inclusion Criteria Clinical diagnosis of MCI made by a specialist\* in a patient who fulfils the established clinical consensus criteria for MCI \[NIA/AA 2011\] specifically: * Concern regarding a change in cognition compared to the person's previous level, by the patient and/or informant * Objective evidence of impairment of one or more cognitive domains, greater than expected for age, and educational background, over time if repeated measures are available. * Preserved independence of functional abilities and minimal to no impairment on complex instrumental functions * Not demented
Alzheimer disease	Transcranial doppler ultrasonography	NIA/AA criteria * Meets the criteria for dementia o The memory impairment and cognitive deficits cause significant impairment functioning, a significant decline from a previous level of functioning, Impairment of at least two cognitive domains * Insidious or gradual onset * Clear history of worsening cognition by report or observation * The initial and most prominent cognitive deficits are evident on history and examination in one of the following domains: * Amnestic: impaired learning and recall of recently learned information * Non amnestic: language/visuospatial/executive dysfunction
Vascular dementia	Transcranial doppler ultrasonography	NINDS-AIREN criteria for VascD, specifically: * Cerebrovascular disease defined by the presence of focal signs on neurological examination consistent with stroke and evidence of cerebrovascular disease on brain imaging. * One or more of: * Onset of dementia within 3 months of a diagnosed stroke * Abrupt deterioration in cognitive function * Fluctuating, stepwise progression of cognitive deficits
Vascular dementia	Blood pressure monitoring	NINDS-AIREN criteria for VascD, specifically: * Cerebrovascular disease defined by the presence of focal signs on neurological examination consistent with stroke and evidence of cerebrovascular disease on brain imaging. * One or more of: * Onset of dementia within 3 months of a diagnosed stroke * Abrupt deterioration in cognitive function * Fluctuating, stepwise progression of cognitive deficits
Vascular dementia	Heart rate monitoring	NINDS-AIREN criteria for VascD, specifically: * Cerebrovascular disease defined by the presence of focal signs on neurological examination consistent with stroke and evidence of cerebrovascular disease on brain imaging. * One or more of: * Onset of dementia within 3 months of a diagnosed stroke * Abrupt deterioration in cognitive function * Fluctuating, stepwise progression of cognitive deficits
Healthy controls	Heart rate monitoring	Healthy Controls-specific Inclusion Criteria 1. No evidence of subjective or objective memory impairment on cognitive testing 2. No major medical co-morbidity (outlined in detail in the exclusion criteria) or medication use that could adversely affect cognition
Alzheimer disease	Blood pressure monitoring	NIA/AA criteria * Meets the criteria for dementia o The memory impairment and cognitive deficits cause significant impairment functioning, a significant decline from a previous level of functioning, Impairment of at least two cognitive domains * Insidious or gradual onset * Clear history of worsening cognition by report or observation * The initial and most prominent cognitive deficits are evident on history and examination in one of the following domains: * Amnestic: impaired learning and recall of recently learned information * Non amnestic: language/visuospatial/executive dysfunction
Healthy controls	End tidal CO2 monitoring	Healthy Controls-specific Inclusion Criteria 1. No evidence of subjective or objective memory impairment on cognitive testing 2. No major medical co-morbidity (outlined in detail in the exclusion criteria) or medication use that could adversely affect cognition
Healthy controls	Addenbrooke's cognitive examination	Healthy Controls-specific Inclusion Criteria 1. No evidence of subjective or objective memory impairment on cognitive testing 2. No major medical co-morbidity (outlined in detail in the exclusion criteria) or medication use that could adversely affect cognition
Alzheimer disease	Heart rate monitoring	NIA/AA criteria * Meets the criteria for dementia o The memory impairment and cognitive deficits cause significant impairment functioning, a significant decline from a previous level of functioning, Impairment of at least two cognitive domains * Insidious or gradual onset * Clear history of worsening cognition by report or observation * The initial and most prominent cognitive deficits are evident on history and examination in one of the following domains: * Amnestic: impaired learning and recall of recently learned information * Non amnestic: language/visuospatial/executive dysfunction
Healthy controls	Blood pressure monitoring	Healthy Controls-specific Inclusion Criteria 1. No evidence of subjective or objective memory impairment on cognitive testing 2. No major medical co-morbidity (outlined in detail in the exclusion criteria) or medication use that could adversely affect cognition

Primary Outcome Measures

Name	Time	Method
Percentage of Recruited Subjects Able to Comply With the Protocol	8 months	The percentage of recruited subjects (HC, MCI patients, VascD patients and AlzD patients) able to comply with the full measurement protocol.

Secondary Outcome Measures

Name	Time	Method
Number of Participants in Which Percentage Change in CBFv Can be Derived	8 months	Overall, the percentage of recruited subjects (healthy controls, MCI patients, VascD patients and AlzD patients) in whom values for the following parameters can be derived: • % change of CBFv at baseline in response to performance of the ACE-III Cognitive Examination
Number of Participants With Rejected Measurements	8 months	The percentage of measurements rejected because of aspects related to data quality during the analysis protocol, with recorded reasons
Number of Participants in Which the Change in the Autoregulation Index (ARI) Can be Derived	8 months	Overall, the percentage of recruited subjects (healthy controls, MCI patients, VascD patients and AlzD patients) in whom values for the following parameters can be derived: • Autoregulation index (using the Tiecks model and from the phase, gain and coherence).

Trial Locations

Locations (2): University Hospitals of Leicester NHS Trust
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Leicester, Leicestershire, United Kingdom
Leicestershire Partnership Trust
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Leicester, Leicestershire, United Kingdom