Assessment of the In Vivo Relationship Between Cerebral Hypometabolism, Tau Deposition, TSPO Expression, and Synaptic Density in a Tauopathy Mouse Model: a Multi-tracer PET Study

Abstract

Cerebral glucose hypometabolism is a typical hallmark of Alzheimer's disease (AD), usually associated with ongoing neurodegeneration and neuronal dysfunction. However, underlying pathological processes are not fully understood and reproducibility in animal models is not well established. The aim of the present study was to investigate the regional interrelation of glucose hypometabolism measured by [¹⁸F]FDG positron emission tomography (PET) with various molecular targets of AD pathophysiology using the PET tracers [¹⁸F]PI-2620 for tau deposition, [¹⁸F]DPA-714 for TSPO expression associated with neuroinflammation, and [¹⁸F]UCB-H for synaptic density in a transgenic tauopathy mouse model. Seven-month-old rTg4510 mice (n = 8) and non-transgenic littermates (n = 8) were examined in a small animal PET scanner with the tracers listed above. Hypometabolism was observed throughout the forebrain of rTg4510 mice. Tau pathology, increased TSPO expression, and synaptic loss were co-localized in the cortex and hippocampus and correlated with hypometabolism. In the thalamus, however, hypometabolism occurred in the absence of tau-related pathology. Thus, cerebral hypometabolism was associated with two regionally distinct forms of molecular pathology: (1) characteristic neuropathology of the Alzheimer-type including synaptic degeneration and neuroinflammation co-localized with tau deposition in the cerebral cortex, and (2) pathological changes in the thalamus in the absence of other markers of AD pathophysiology, possibly reflecting downstream or remote adaptive processes which may affect functional connectivity. Our study demonstrates the feasibility of a multitracer approach to explore complex interactions of distinct AD-pathomechanisms in vivo in a small animal model. The observations demonstrate that multiple, spatially heterogeneous pathomechanisms can contribute to hypometabolism observed in AD mouse models and they motivate future longitudinal studies as well as the investigation of possibly comparable pathomechanisms in human patients.

Keywords: Alzheimer’s disease; Cerebral hypometabolism; Microglial activation; Neuroinflammation; Small animal PET; Synaptic density; Tau.

Fig. 1

Comparison of [¹⁸F]PI-2620 PET, ex vivo autoradiography and histology. Shown are sagittal sections of the same mouse (11 months old), rostral = left. (A) [¹⁸F]PI-2620 PET, start 8 min after tracer injection, 30-min scan duration. Scale bar: 2.5 mm. Color scale: 0–5 SUVR_bg. Tracer accumulation was highest in the olfactory bulb and the frontal cortex. (B) Ex vivo autoradiography of the same animal, start 2 h 15 min after injection, duration 45 min. Smoothing 0.61 mm FWHM. Scale bar: 2.5 mm. Color scale: 0.000–0.0015 cpm. Highest tracer accumulation is visible in the olfactory bulb, frontal cortex, and hippocampus. (C) Histology of the same animal: Thioflavin S staining (green) and PHF1 staining (brown). Scale bars: 30 µm. Tau fibrils are present in the olfactory bulb, frontal cortex, and hippocampus, but absent in the cerebellum. Abbreviations: Cer, cerebellum; FC, frontal cortex; HG, Harderian gland; Hip, hippocampus; OB, olfactory bulb

Fig. 2

Multitracer imaging of rTg4510 mice and non-transgenic littermates (controls). Each row A–D represents a different tracer. Column 1: mean horizontal images of rTg4510 mice (n = 5 to 8). Column 2: mean images of controls (n = 5 to 8). Column 3: voxel-wise comparison between rTg4510 and control mice (t-test, corrected for multiple testing). Red and blue voxels indicate significantly (p < 0.05) higher and lower tracer uptake, respectively, in rTg4510 mice. Column 4: comparison of whole brain tracer uptake (t-test). *t-test, p < 0.05. Scale bar: 5 mm. Abbreviations: Acc, anterior cingulate cortex; Ctx, cortex; FC, frontal cortex; Hip, hippocampus; Hyp, hypothalamus; Ob, olfactory bulb; RS, retrosplenial cortex; SS, somatosensory cortex; Th, thalamus; vFb, ventral forebrain

Fig. 3

Correlation between uptake of different tracers in rTg4510 mice and controls (pooled). Datasets of different tracers were correlated with each other using a Pearson correlation test (significance level p < 0.05, corrected for multiple testing). The resulting correlation maps show for each voxel if the two respective tracers are positively (red) or negatively correlated (blue), or show no relationship at all (gray). The strength of correlation is coded by hue, with light colors reporting strong correlation (R near ± 1) and dark colors indicating weak correlation (R near the significance threshold). The respective significance thresholds are noted on the left side of the color bars, and the brain areas with significant clusters are labeled. [¹⁸F]FDG (glucose metabolism) was correlated with (A) [¹⁸F]UCB-H (synaptic density), (B) [¹⁸F]DPA-714 (TSPO expression), and (C) [¹⁸F]PI-2620 (tau deposition). [¹⁸F]PI-2620 (tau deposition) was correlated with (D) [¹⁸F]UCB-H (synaptic density) and (E) [¹⁸F]DPA-714 (TSPO expression). Scale bar: 5 mm. Abbreviations: Acc, anterior cingulate cortex; Au, auditory cortex; FC, frontal cortex; Hip, hippocampus; Hyp, hypothalamus; Ob, olfactory bulb; PAG, periaqueductal gray; R_TFCE, correlation coefficient; thresholded with a TFCE procedure [38]; RS, retrosplenial cortex; SS, somatosensory cortex; Str, striatum; Th, thalamus; vFb, ventral forebrain; vTh, ventral thalamus