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

Aktivität Von Zerebralen Netzwerken, Amyloid Und Mikroglia Bei Alterung Und Alzheimer-Krankheit

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.

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?

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