Activity of Cerebral Networks, Amyloid and Microglia in Aging and Alzheimer's Disease

Active, not recruiting

• Conditions: Alzheimer Disease; Corticobasal Syndrome
• Interventions: Diagnostic Test: magnetic resonance imaging; Other: electroencephalography; Diagnostic Test: blood and CSF biomarker; Diagnostic Test: positron emission tomography; Diagnostic Test: neuropsychological test

• Registration Number: NCT06224920
• Lead Sponsor: Ludwig-Maximilians - University of Munich

Brief Summary

The temporal sequence of microglial activation, changes in functional and structural connectivity and the progression of neurocognitive deficits has not been conclusively clarified. To date, there have been no studies of the topographical and pathogenetic relationship between microglial activation and network degeneration. The main aim of the present study is to investigate the relationships between functional, structural MRI connectivity and microglial activation at different stages of AD in a multimodal approach. Genetic predisposition and biomarkers in blood and cerebrospinal fluid will also be taken into account in order to close the explanatory gap in pathogenesis between the known molecular pathological changes and their effects at system level in an integrative approach.

Detailed Description

The main aim of the present study is to investigate correlations between functional and structural MRI connectivity and microglial activation in PET at different stages of AD. Some previous studies have described that especially the brain regions affected by AD-related alterations show increased microglial activity. How these relationships known at the anatomical level relate to changes in functional connectivity is still largely unclear. The multimodal analysis of functional connectivity in the resting networks and the investigation of inflammatory effects using microglia PET may be able to reveal previously unknown neuropathological connections between different stages of AD. Since a direct toxicity effect of Aβ on surrounding neurons can also be assumed, the topography of fibrillar Aβ deposits is also recorded using PET. To date, there are no studies investigating changes in functional and structural connectivity with microglia-associated inflammatory changes and Aβ at different disease stages.

1. evaluation of the correlation of microglial activation determined in PET with the degeneration of functional networks depending on the stage of the disease.

1. Is microglial activation or Aβ deposition the cause of changes in functional networks?

2. What is the overlap between microglia- and Aβ-induced network degeneration (modulation of synaptic pruning vs. neurotoxic effect of ß-amyloid)

3. How reliable is functional connectivity as a biomarker for AD stratification at different disease stages?

4. What is the temporal and topographical spread of AD pathologies along the hub regions of the resting networks and can a pattern of spread indicative of a specific molecular mechanism be identified?

5. Does the extent (quantitative and regional) of microglial activation correlate with existing amyloid and tau deposits, as well as network changes? How does microglial activation change in relation to the progression of tau deposits?

2. correlation of inflammatory changes in a multimodal comparison with changes in structural connectivity, metabolic alterations, biomarker abnormalities and changes at the neurotransmitter level.

1. Is there an image morphologic correlate of soluble TREM2 receptor concentration in cerebrospinal fluid at different disease stages?

2. What role does oxidative stress (glutathione changes) play in the pathogenesis of AD and is there a connection to other disease-related changes at the multimodal level?

3. are there certain correlations between genetic factors (especially carriers vs. non-carriers of apolipoprotein E, APOE, risk allele ε4 as the strongest genetic risk factor of sporadic AD) and structural or functional connectivity changes depending on the disease stage that can be derived from the multimodal data analysis? a. What is the temporal relationship between microglial activation and Aβ deposits or functional and structural network alterations?

Study Timeline

• Study Start: 2017-01-01
• Status Verified: 2024-01
• Primary Completion: 2024-01-16
• Study First Submitted: 2024-01-16
• Study First Submitted QC: 2024-01-16
• Last Update Submitted: 2024-01-16
• Study First Posted: 2024-01-25
• Last Update Posted: 2024-01-25
• Study Completion: 2024-03-31

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 140

Inclusion Criteria

• Informed consent for the additional examinations, written declaration of consent
• Constant pharmacotherapy in a period of one week before the MRI/EEG/PET examination

Exclusion Criteria

• Existence of legal guardianship/restricted capacity to consent
• Other severe concomitant psychiatric illnesses, e.g. schizophrenia, bipolar affective disorder
• Clinically relevant depressive symptoms (Beck Depression Inventory, BDI, score > 17/GDS > 5)
• Acute suicidal tendencies
• Drug, medication or alcohol abuse at the time of the study
• Severe traumatic brain injury (> 2nd degree TBI) in the medical history or 1st degree within the last 3 months.
• Evidence of structural damage to the basal ganglia or brainstem
• Severe neurological diseases (such as disc prolapse in the last 6 months, sensory, motor or autonomic polyneuropathies)
• Severe internal diseases (such as manifest arterial hypertension, severe heart disease, pacemaker, respiratory insufficiency)
• Any electronic implants (e.g. pacemakers) or other MRI and/or PET contraindications
• Malignant diseases of any kind in the last 5 years, severe active infectious diseases, chronic and systemic skin diseases
• Bone diseases (such as Paget's disease, osteoporosis with spontaneous fractures, recent fractures)
• Other circumstances which, in the opinion of the investigator, speak against the patient's participation in this study
• Occupational or other radiation exposure >15 mSv/a

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Alzheimer´s disease spectrum	blood and CSF biomarker	MCI-AD patients Evidence of minor cognitive impairment with essentially preserved everyday competence and evidence of reduced Aβ42 concentration in the cerebrospinal fluid. Score in the CERAD word list 1.5 SD below the normal range. Patients with AD-dementia Evidence of pronounced cognitive impairment and relevant impairment of everyday life and evidence of reduced Aβ42 concentration in the cerebrospinal fluid (diagnostic criteria (NIA-AA fulfilled)).
Alzheimer´s disease spectrum	electroencephalography	MCI-AD patients Evidence of minor cognitive impairment with essentially preserved everyday competence and evidence of reduced Aβ42 concentration in the cerebrospinal fluid. Score in the CERAD word list 1.5 SD below the normal range. Patients with AD-dementia Evidence of pronounced cognitive impairment and relevant impairment of everyday life and evidence of reduced Aβ42 concentration in the cerebrospinal fluid (diagnostic criteria (NIA-AA fulfilled)).
corticobasal syndrome due to probable 4 repeat taupathy	blood and CSF biomarker	Evidence of the typical clinical picture of an atypical Parkinson's syndrome with onset of symptoms \> 1 year. No evidence of reduced Aβ42 concentration in the cerebrospinal fluid. Fulfillment of the revised Armstrong criteria for probable CBS or the Movement Disorder's Society criteria for suggestive/possible PSP-CBS.
Alzheimer´s disease spectrum	positron emission tomography	MCI-AD patients Evidence of minor cognitive impairment with essentially preserved everyday competence and evidence of reduced Aβ42 concentration in the cerebrospinal fluid. Score in the CERAD word list 1.5 SD below the normal range. Patients with AD-dementia Evidence of pronounced cognitive impairment and relevant impairment of everyday life and evidence of reduced Aβ42 concentration in the cerebrospinal fluid (diagnostic criteria (NIA-AA fulfilled)).
corticobasal syndrome due to probable 4 repeat taupathy	magnetic resonance imaging	Evidence of the typical clinical picture of an atypical Parkinson's syndrome with onset of symptoms \> 1 year. No evidence of reduced Aβ42 concentration in the cerebrospinal fluid. Fulfillment of the revised Armstrong criteria for probable CBS or the Movement Disorder's Society criteria for suggestive/possible PSP-CBS.
corticobasal syndrome due to probable 4 repeat taupathy	electroencephalography	Evidence of the typical clinical picture of an atypical Parkinson's syndrome with onset of symptoms \> 1 year. No evidence of reduced Aβ42 concentration in the cerebrospinal fluid. Fulfillment of the revised Armstrong criteria for probable CBS or the Movement Disorder's Society criteria for suggestive/possible PSP-CBS.
corticobasal syndrome due to probable 4 repeat taupathy	neuropsychological test	Evidence of the typical clinical picture of an atypical Parkinson's syndrome with onset of symptoms \> 1 year. No evidence of reduced Aβ42 concentration in the cerebrospinal fluid. Fulfillment of the revised Armstrong criteria for probable CBS or the Movement Disorder's Society criteria for suggestive/possible PSP-CBS.
Alzheimer´s disease spectrum	magnetic resonance imaging	MCI-AD patients Evidence of minor cognitive impairment with essentially preserved everyday competence and evidence of reduced Aβ42 concentration in the cerebrospinal fluid. Score in the CERAD word list 1.5 SD below the normal range. Patients with AD-dementia Evidence of pronounced cognitive impairment and relevant impairment of everyday life and evidence of reduced Aβ42 concentration in the cerebrospinal fluid (diagnostic criteria (NIA-AA fulfilled)).
Alzheimer´s disease spectrum	neuropsychological test	MCI-AD patients Evidence of minor cognitive impairment with essentially preserved everyday competence and evidence of reduced Aβ42 concentration in the cerebrospinal fluid. Score in the CERAD word list 1.5 SD below the normal range. Patients with AD-dementia Evidence of pronounced cognitive impairment and relevant impairment of everyday life and evidence of reduced Aβ42 concentration in the cerebrospinal fluid (diagnostic criteria (NIA-AA fulfilled)).
subjective congnitive decline	electroencephalography	Subjective memory impairment, with age-appropriate unremarkable neurocognitive test battery (CERAD) and no evidence of reduced Aβ42 concentration or increased total tau or phospho-tau concentration in the cerebrospinal fluid. Subjective cognitive deterioration over a period of 6 months to 5 years.
subjective congnitive decline	positron emission tomography	Subjective memory impairment, with age-appropriate unremarkable neurocognitive test battery (CERAD) and no evidence of reduced Aβ42 concentration or increased total tau or phospho-tau concentration in the cerebrospinal fluid. Subjective cognitive deterioration over a period of 6 months to 5 years.
corticobasal syndrome due to probable 4 repeat taupathy	positron emission tomography	Evidence of the typical clinical picture of an atypical Parkinson's syndrome with onset of symptoms \> 1 year. No evidence of reduced Aβ42 concentration in the cerebrospinal fluid. Fulfillment of the revised Armstrong criteria for probable CBS or the Movement Disorder's Society criteria for suggestive/possible PSP-CBS.
subjective congnitive decline	blood and CSF biomarker	Subjective memory impairment, with age-appropriate unremarkable neurocognitive test battery (CERAD) and no evidence of reduced Aβ42 concentration or increased total tau or phospho-tau concentration in the cerebrospinal fluid. Subjective cognitive deterioration over a period of 6 months to 5 years.
subjective congnitive decline	neuropsychological test	Subjective memory impairment, with age-appropriate unremarkable neurocognitive test battery (CERAD) and no evidence of reduced Aβ42 concentration or increased total tau or phospho-tau concentration in the cerebrospinal fluid. Subjective cognitive deterioration over a period of 6 months to 5 years.
subjective congnitive decline	magnetic resonance imaging	Subjective memory impairment, with age-appropriate unremarkable neurocognitive test battery (CERAD) and no evidence of reduced Aβ42 concentration or increased total tau or phospho-tau concentration in the cerebrospinal fluid. Subjective cognitive deterioration over a period of 6 months to 5 years.

Primary Outcome Measures

Name	Time	Method
association of cerebral connectivity with microglia activation patterns	until 06/2024	association between functional/structural connectivity and TSPO SUVR
Individual regional associations between Aβ-, tau- and neurodegeneration with microglial activation	until 06/2024	association of regional amyloid and tau with microglial activation (measured by TSPO-PET)
validation of blood-based biomarkers in the differentiation of AD, SCI and CBS cases	until 06/2024	comparison of AD-related biomarkers (pTau181, Abeta1-42/1-40), plasma apolipoprotein E and inflammatory biomarkers (GFAP, NfL)