No abstract

Hypersynchrony of FC may be used as a new noninvasive read out of early AD and can be recovered by anti-Aβ treatment, encouraging preventive treatment strategies in familial AD.

The development and characterization of new improved animal models is pivotal in Alzheimer's Disease (AD) research, since valid models enable the identification of early pathological processes, which are often not accessible in patients, as well as subsequent target discovery and evaluation. The TgF344-AD rat model of AD, bearing mutant human amyloid precursor protein (APPswe) and Presenilin 1 (PSEN1ΔE9) genes, has been described to manifest the full spectrum of AD pathology similar to human AD, i.e. progressive cerebral amyloidosis, tauopathy, neuronal loss and agedependent cognitive decline. Here, AD-related pathology in female TgF344-AD rats was examined longitudinally between 6 and 18 months by means of complementary translational MRI techniques: resting state functional MRI (rsfMRI) to evaluate functional connectivity (FC) and diffusion tensor imaging (DTI) to assess the microstructural integrity. Additionally, an evaluation of macroscopic changes (3D anatomical MRI) and an image-guided validation of ex vivo pathology were performed. We identified slightly decreased FC at 6 months followed by severe and widespread hypoconnectivity at 10 months of age as the earliest detectable pathological MRI hallmark. This initial effect was followed by age-dependent progressive microstructural deficits in parallel with age-dependent ex vivo AD pathology, without signs of macroscopic alterations such as hippocampal atrophy. This longitudinal MRI study in the TgF344-AD rat model of AD revealed early rsfMRI and DTI abnormalities as seen in human AD patients. The characterization of AD pathology in this rat model using non-invasive MRI techniques further highlights the translational value of this model, as well as its use for potential treatment evaluation.

There is currently a lack of prognostic biomarkers to predict the different sequelae following traumatic brain injury (TBI). The present study investigated the hypothesis that subacute neuroinflammation and microstructural changes correlate with chronic TBI deficits. Rats were subjected to controlled cortical impact (CCI) injury, sham surgery, or skin incision (naïve). CCI-injured (n = 18) and sham-operated rats (n = 6) underwent positron emission tomography (PET) imaging with the translocator protein 18 kDa (TSPO) radioligand [F]PBR111 and diffusion tensor imaging (DTI) in the subacute phase (≤3 weeks post-injury) to quantify inflammation and microstructural alterations. CCI-injured, sham-operated, and naïve rats (n = 8) underwent behavioral testing in the chronic phase (5.5-10 months post-injury): open field and sucrose preference tests, two one-week video-electroencephalogram (vEEG) monitoring periods, pentylenetetrazole (PTZ) seizure susceptibility tests, and a Morris water maze (MWM) test. In vivo imaging revealed pronounced neuroinflammation, decreased fractional anisotropy, and increased diffusivity in perilesional cortex and ipsilesional hippocampus of CCI-injured rats. Behavioral analysis revealed disinhibition, anhedonia, increased seizure susceptibility, and impaired learning in CCI-injured rats. Subacute TSPO expression and changes in DTI metrics significantly correlated with several chronic deficits (Pearson's |r| = 0.50-0.90). Certain specific PET and DTI parameters had good sensitivity and specificity (area under the receiver operator characteristic [ROC] curve = 0.85-1.00) to distinguish between TBI animals with and without particular behavioral deficits. Depending on the investigated behavioral deficit, PET or DTI data alone, or the combination, could very well predict the variability in functional outcome data (adjusted R = 0.54-1.00). Taken together, both TSPO PET and DTI seem promising prognostic biomarkers to predict different chronic TBI sequelae.

studies from other species 12,13 , we have freely released all data and the generated code.