Regional tau pathology is associated with loss of synapses and reduced synaptic activity: A combined [18F]flortaucipir, [11C]UCB‐J and magnetoencephalography study: Neuroimaging: Imaging the human synapse in AD.

Background: The mechanisms contributing to synaptic loss in Alzheimer's disease (AD) are poorly understood and may be associated with tau pathology. In this combined positron emission tomography (PET) and magnetoencephalography (MEG) study, we therefore investigated associations between tau ([18F]flortaucipir PET), synaptic density (synaptic vesicle 2A [11C]UCB‐J PET) and synaptic function (MEG) in AD. Method: Seven amyloid‐positive AD subjects (age 64.3±8.2; 3/7 female; MMSE 24.1±1.8) were included from the Amsterdam Dementia Cohort. All subjects underwent dynamic 130‐min [18F]flortaucipir and 60‐min [11C]UCB‐J PET with arterial sampling. Six subjects underwent 10‐min eyes‐closed 306‐channel MEG. [18F]flortaucipir binding potential (BPND) was determined with receptor parametric mapping (reference region: cerebellar gray matter) with partial volume correction (Hypr‐IDM‐Hypr). [11C]UCB‐J distribution volume ratio (DVR, plasma input‐derived) was obtained using the centrum semi‐ovale as reference region. [18F]flortaucipir BPND, [11C]UCB‐J DVR and MEG spectral measures (total power (0.5‐48Hz), peak frequency, and relative delta (0.5‐4Hz), theta (4‐8Hz), alpha (8‐13Hz) power) were calculated in 12 bilateral a priori defined temporal, parietal, frontal and occipital region‐of‐interests (ROIs). We used generalized estimating equations (GEE), correcting for multiple ROIs per subject, to investigate associations between [18F]flortaucipir, [11C]UCB‐J and spectral MEG. GEE analyses with MEG were performed separately per brain lobe. Additionally, within‐subject regional correlations (Spearman) between [18F]flortaucipir and [11C]UCB‐J were performed. Result: Higher [18F]flortaucipir BPND was associated with lower [11C]UCB‐J DVR (β=‐0.35, p<0.001) (Figure 1A,B). Within subjects, negative associations were observed when neocortical tau was high, while positive associations were observed when neocortical tau was low (Figure 1C). Additionally, higher [18F]flortaucipir was strongly associated with oscillatory slowing, reflected by negative associations with peak frequency and alpha power, and positive associations with delta or theta power (Table 1). In contrast, lower [11C]UCB‐J binding was associated with lower peak frequency and alpha power, and higher delta power, most clearly in the occipital lobe (Table 1). Conclusion: Across subjects, higher regional tau pathology was associated with synaptic loss, while within subjects, this association depended on subjects' neocortical tau levels. Moreover, higher tau pathology and synaptic loss were associated with oscillatory slowing. This suggests that tau is associated with synaptic loss and reduced synaptic activity, yet that a tau‐threshold may need to be reached before regional synaptic loss occurs. [ABSTRACT FROM AUTHOR]