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?
Study Type
OBSERVATIONAL
Enrollment
140
MRI data acquisition was performed on a 3 Tesla MRI scanner with parallel transmission and reception technology (Skyra Magnetom, Siemens Healthcare, Erlangen, Germany). Imaging is performed with a maximum gradient strength of 45mT/m and a maximum slew rate of 200 T/m/s and a 64-element head coil.
A 20-channel resting EEG (Brain Products, Gilching, Germany) is recorded as part of routine clinical diagnostics in the Department of Psychiatry and Psychotherapy at the LMU to rule out focal neurophysiological pathologies. Within the scope of the present study, an extended examination will be carried out, which includes a 64-channel EEG, including a passive visual paradigm. After completion of the clinical evaluation, the neurophysiological changes in resting activity will be scientifically analyzed in comparison to the MRI and PET data.
Aβ1-42 and 1-40, total tau protein and phosphorylated tau protein 181 (p-Tau), apolipoprotein E (APOE), soluble TREM2 protein, neurofilament light chain and glial fibrillary protein (GFAP) will be determined.
According to an established and standardized protocol, PET scans are performed with the TSPO receptor ligand \[18F\]-GE-180, \[18F\]flutemetamol for assessment of fibrillar Aβ 162 accumulation and the Tau ligand \[18F\]-PI-2620. In brief, \[18F\]GE-180 TSPO PET images (mean dose: 177 ± 17 MBq) with an emission window of 60-80 min after injection will be acquired to measure the activation of glial cells. \[18F\]Flutemetamol Aβ PET images (average dose: 182 ± 11 MBq) are acquired with an emission window of 90-110 min after injection to assess fibrillar Aβ accumulation. Dynamic \[18F\]PI-2620 tau PET (average dose: 186 ± 14 MBq) with an emission window of 0-60 minutes after injection are performed for quantification of tau aggregation. Static images of the late phase (20-40 min) are reconstructed. These images are used for further processing and analysis.
Trained psychologists at the Memory Clinic of the LMU Hospital administered the CDR, CERAD-NB and Mini-Mental State Examination (MMSE). The CERAD-NB battery was used to generate a total score for the six subscales: semantic fluency (animals/60 s), modified Boston naming test, lexical items, construction practice, lexical items retrieval, and lexical items discrimination, with higher scores indicating better performance.
association of cerebral connectivity with microglia activation patterns
association between functional/structural connectivity and TSPO SUVR
Time frame: until 06/2024
Individual regional associations between Aβ-, tau- and neurodegeneration with microglial activation
association of regional amyloid and tau with microglial activation (measured by TSPO-PET)
Time frame: until 06/2024
validation of blood-based biomarkers in the differentiation of AD, SCI and CBS cases
comparison of AD-related biomarkers (pTau181, Abeta1-42/1-40), plasma apolipoprotein E and inflammatory biomarkers (GFAP, NfL)
Time frame: until 06/2024
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.