Diffusion tensor imaging of diffuse axonal injury in a rat brain trauma model

Diffusion tensor imaging (DTI) was used to study traumatic brain injury. The impact-acceleration trauma model was used in rats. Here, in addition to diffusivities (mean, axial and radial), fractional anisotropy (FA) was used, in particular, as a parameter to characterize the cerebral tissue early after trauma. DTI was implemented at 7 T using fast spiral k-space sampling and the twice-refocused spin echo radiofrequency sequence for eddy current minimization. The method was carefully validated on different phantom measurements. DTI of a trauma group (n = 5), as well as a sham group (n = 5), was performed at different time points during 6 h following traumatic brain injury. Two cerebral regions, the cortex and corpus callosum, were analyzed carefully. A significant decrease in diffusivity in the trauma group versus the sham group was observed, suggesting the predominance of cellular edema in both cerebral regions. No significant FA change was detected in the cortex. In the corpus callosum of the trauma group, the FA indices were significantly lower. A net discontinuity in fiber reconstructions in the corpus callosum was observed by fiber tracking using DTI. Histological analysis using Hoechst, myelin basic protein and Bielschowsky staining showed fiber disorganization in the corpus callosum in the brains of the trauma group. On the basis of our histology results and the characteristics of the impact-acceleration model responsible for the presence of diffuse axonal injury, the detection of low FA caused by a drastic reduction in axial diffusivity and the presence of fiber disconnections of the DTI track in the corpus callosum were considered to be related to the presence of diffuse axonal injury.     

Diffusion tensor imaging detects axonal injury and demyelination in the spinal cord and cranial nerves of a murine model of globoid cell leukodystrophy

Globoid cell leukodystrophy is an inherited neurodegenerative disorder caused by a deficiency of the lysosomal enzyme galactosylceramidase. In both human patients and the authentic murine Twitcher model, pathological findings include demyelination as well as axonal damage in both the central and peripheral nervous system. Diffusion tensor imaging (DTI) has emerged as a powerful noninvasive technique that is sensitive to these white matter disease processes. Increases in radial diffusivity (λ?) and decreases in axial diffusivity (λ∥) correlate with histopathological evidence of demyelination and axonal damage, respectively. Compared to age‐matched, normal littermates, DTI of optic nerve and trigeminal nerve in end‐stage Twitcher mice displayed a statistically significant increase in λ? and decrease in λ∥, consistent with previously characterized demyelination and axonal damage in these regions. In the Twitcher spinal cord, a statistically significant decrease in λ∥ was identified in both the dorsal and ventrolateral white matter, relative to normal controls. These results were consistent with immunofluorescence evidence of axonal damage in these areas as detected by staining for nonphosphorylated neurofilaments (SMI32). Increase in λ? in Twitcher spinal cord white matter relative to normal controls reached statistical significance in the dorsal columns and approached statistical significance in the ventrolateral region. Correlative reduced levels of myelin basic protein were detected by immunofluorescent staining in both these white matter regions in the Twitcher spinal cord. Fractional anisotropy, a nonspecific but sensitive indicator of white matter disease, was significantly reduced in the optic nerve, trigeminal nerve, and throughout the spinal cord white matter of Twitcher mice, relative to normal controls. This first reported application of spinal cord DTI in the setting of GLD holds potential as a noninvasive, quantitative assay of therapeutic efficacy in future treatment studies. Copyright © 2009 John Wiley & Sons, Ltd.     

Diffusion tensor imaging detects treatment effects of FTY720 in experimental autoimmune encephalomyelitis mice

Fingolimod (FTY720) is an orally available sphingosine‐1‐phosphate (S1P) receptor modulator reducing relapse frequency in patients with relapsing–remitting multiple sclerosis (RRMS). In addition to immunosuppression, neuronal protection by FTY720 has also been suggested, but remains controversial. Axial and radial diffusivities derived from in vivo diffusion tensor imaging (DTI) were employed as noninvasive biomarkers of axonal injury and demyelination to assess axonal protection by FTY720 in experimental autoimmune encephalomyelitis (EAE) mice. EAE was induced through active immunization of C57BL/6 mice using myelin oligodendrocyte glycoprotein peptide 35–55 (MOG_35–55). We evaluated both the prophylactic and therapeutic treatment effect of FTY720 at doses of 3 and 10 mg/kg on EAE mice by daily clinical scoring and end‐point in vivo DTI. Prophylactic administration of FTY720 suppressed the disease onset and prevented axon and myelin damage when compared with EAE mice without treatment. Therapeutic treatment by FTY720 did not prevent EAE onset, but reduced disease severity, improving axial and radial diffusivity towards the control values without statistical significance. Consistent with previous findings, in vivo DTI‐derived axial and radial diffusivity correlated with clinical scores in EAE mice. The results support the use of in vivo DTI as an effective outcome measure for preclinical drug development. Copyright © 2013 John Wiley & Sons, Ltd.     

Axonal injury detected by in vivo diffusion tensor imaging correlates with neurological disability in a mouse model of multiple sclerosis

Recent studies have suggested that axonal damage, and not demyelination, is the primary cause of long-term neurological impairment in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). The axial and radial diffusivities derived from diffusion tensor imaging have shown promise as non-invasive surrogate markers of axonal damage and demyelination, respectively. In this study, in vivo diffusion tensor imaging of the spinal cords from mice with chronic EAE was performed to determine if axial diffusivity correlated with neurological disability in EAE assessed by the commonly used clinical scoring system. Axial diffusivity in the ventrolateral white matter showed a significant negative correlation with EAE clinical score and was significantly lower in mice with severe EAE than in mice with moderate EAE. Furthermore, the greater decreases in axial diffusivity were associated with greater amounts of axonal damage, as confirmed by quantitative staining for non-phosphorylated neurofilaments (SMI32). Radial diffusivity and relative anisotropy could not distinguish between the groups of mice with moderate EAE and those with severe EAE. The results further the notion that axial diffusivity is a non-invasive marker of axonal damage in white matter and could provide the necessary link between pathology and neurological disability.     

Diffusion tensor imaging of white matter in the superior temporal gyrus and temporal stem in autism

Recent MRI studies have indicated that regions of the temporal lobe including the superior temporal gyrus (STG) and the temporal stem (TS) appear to be abnormal in autism. In this study, diffusion tensor imaging (DTI) measurements of white matter in the STG and the TS were compared in 43 autism and 34 control subjects. DTI measures of mean diffusivity, fractional anisotropy, axial diffusivity, and radial diffusivity were compared between groups. In all regions, fractional anisotropy was significantly decreased and both mean diffusivity and radial diffusivity were significantly increased in the autism group. These results suggest that white matter microstructure in autism is abnormal in these temporal lobe regions, which is consistent with theories of aberrant brain connectivity in autism.     

Axonal injury following mild traumatic brain injury is exacerbated by repetitive insult and is linked to the delayed attenuation of NeuN expression without concomitant neuronal death in the mouse

Mild traumatic brain injury (mTBI) affects brain structure and function and can lead to persistent abnormalities. Repetitive mTBI exacerbates the acute phase response to injury. Nonetheless, its long‐term implications remain poorly understood, particularly in the context of traumatic axonal injury (TAI), a player in TBI morbidity via axonal disconnection, synaptic loss and retrograde neuronal perturbation. In contrast to the examination of these processes in the acute phase of injury, the chronic‐phase burden of TAI and/or its implications for retrograde neuronal perturbation or death have received little consideration. To critically assess this issue, murine neocortical tissue was investigated at acute (24‐h postinjury, 24hpi) and chronic time points (28‐days postinjury, 28dpi) after singular or repetitive mTBI induced by central fluid percussion injury (cFPI). Neurons were immunofluorescently labeled for NeuroTrace and NeuN (all neurons), p‐c‐Jun (axotomized neurons) and DRAQ5 (cell nuclei), imaged in 3D and quantified in automated manner. Single mTBI produced axotomy in 10% of neurons at 24hpi and the percentage increased after repetitive injury. The fraction of p‐c‐Jun+ neurons decreased at 28dpi but without neuronal loss (NeuroTrace), suggesting their reorganization and/or repair following TAI. In contrast, NeuN+ neurons decreased with repetitive injury at 24hpi while the corresponding fraction of NeuroTrace+ neurons decreased over 28dpi. Attenuated NeuN expression was linked exclusively to non‐axotomized neurons at 24hpi which extended to the axotomized at 28dpi, revealing a delayed response of the axotomized neurons. Collectively, we demonstrate an increased burden of TAI after repetitive mTBI, which is most striking in the acute phase response to the injury. Our finding of widespread axotomy in large fields of intact neurons contradicts the notion that repetitive mTBI elicits progressive neuronal death, rather, emphasizing the importance of axotomy‐mediated change.     

CLARITY reveals a more protracted temporal course of axon swelling and disconnection than previously described following traumatic brain injury

Diffuse axonal injury (DAI) is an important consequence of traumatic brain injury (TBI). At the moment of trauma, axons rarely disconnect, but undergo cytoskeletal disruption and transport interruption leading to protein accumulation within swellings. The amyloid precursor protein (APP) accumulates rapidly and the standard histological evaluation of axonal pathology relies upon its detection. APP+ swellings first appear as varicosities along intact axons, which can ultimately undergo secondary disconnection to leave a terminal “axon bulb” at the disconnected, proximal end. However, sites of disconnection are difficult to determine with certainty using standard, thin tissue sections, thus limiting the comprehensive evaluation of axon degeneration. The tissue‐clearing technique, CLARITY, permits three‐dimensional visualization of axons that would otherwise be out of plane in standard tissue sections. Here, we examined the morphology and connection status of APP+ swellings using CLARITY at 6 h, 24 h, 1 week and 1 month following the controlled cortical impact (CCI) model of TBI in mice. Remarkably, many APP+ swellings that appeared as terminal bulbs when viewed in standard 8‐µm‐thick regions of tissue were instead revealed to be varicose swellings along intact axons when three dimensions were fully visible. Moreover, the percentage of these potentially viable axon swellings differed with survival from injury and may represent the delayed onset of distinct mechanisms of degeneration. Even at 1‐month post‐CCI, ~10% of apparently terminal bulbs were revealed as connected by CLARITY and are thus potentially salvageable. Intriguingly, the diameter of swellings decreased with survival, including varicosities along intact axons, and may reflect reversal of, or reduced, axonal transport interruption in the chronic setting. These data indicate that APP immunohistochemistry on standard thickness tissue sections overestimates axon disconnection, particularly acutely post‐injury. Evaluating cleared tissue demonstrates a surprisingly delayed process of axon disconnection and thus longer window of therapeutic opportunity than previously appreciated. Intriguingly, a subset of axon swellings may also be capable of recovery.     

Diffusion tensor imaging of renal ischemia reperfusion injury in an experimental model

Renal ischemia reperfusion injury (IRI) is a major cause of acute renal failure. It occurs in various clinical settings such as renal transplantation, shock and vascular surgery. Serum creatinine level has been used as an index for estimating the degree of renal functional loss in renal IRI. However, it only evaluates the global renal function. In this study, diffusion tensor imaging (DTI) was used to characterize renal IRI in an experimental rat model. Spin‐echo echo‐planar DTI with b‐value of 300 s/mm² and 6 diffusion gradient directions was performed at 7 T in 8 Sprague‐Dawley (SD) with 60‐min unilateral renal IRI and 8 normal SD rats. Apparent diffusion coefficient (ADC), directional diffusivities and fractional anisotropy (FA) were measured at the acute stage of IRI. The IR‐injured animals were also examined by diffusion‐weighted imaging with 7 b‐values up to 1000 s/mm² to estimate true diffusion coefficient (D_true) and perfusion fraction (P_fraction) using a bi‐compartmental model. ADC of injured renal cortex (1.69 ± 0.24 × 10^?3 mm²/s) was significantly lower (p < 0.01) than that of contralateral intact cortex (2.03 ± 0.35 × 10^?3 mm²/s). Meanwhile, both ADC and FA of IR‐injured medulla (1.37 ± 0.27 × 10^?3 mm²/s and 0.28 ± 0.04, respectively) were significantly less (p < 0.01) than those of contralateral intact medulla (2.01 ± 0.38 × 10^?3 mm²/s and 0.36 ± 0.04, respectively). The bi‐compartmental model analysis revealed the decrease in D_true and P_fraction in the IR‐injured kidneys. Kidney histology showed widespread cell swelling and erythrocyte congestion in both cortex and medulla, and cell necrosis/apoptosis and cast formation in medulla. These experimental findings demonstrated that DTI can probe both structural and functional information of kidneys following renal IRI. Copyright © 2010 John Wiley & Sons, Ltd.     

Noninvasive detection of brainstem and spinal cord axonal degeneration in an amyotrophic lateral sclerosis mouse model

Degeneration of motor neurons and their associated axons is a hallmark of amyotrophic lateral sclerosis, but reliable noninvasive lesion detection is lacking. In vivo diffusion tensor imaging was performed to evaluate neurodegeneration in the brainstem and cervical spinal cord of wild-type and G93A-SOD1 transgenic mice, an animal model of amyotrophic lateral sclerosis. A statistically significant reduction in the apparent diffusion coefficient was observed in the motor nuclei VII and XII of G93A-SOD1 transgenic mice relative to wild-type mice. No significant difference in diffusion anisotropy was observed in dorsal white or gray matter in cervical and lumbar segments of the spinal cord. In contrast, statistically significant decreases in axial diffusivity (diffusivity parallel to the axis of the spinal cord) and apparent diffusion coefficient were found in the ventrolateral white matter of G93A-SOD1 mice in both the cervical and lumbar spinal cord. The reduction in axial diffusivity, suggestive of axonal injury, in the white matter of the spinal cord of G93A-SOD1 mice was verified by immunostaining with nonphosphorylated neurofilament. The present study demonstrates that in vivo diffusion tensor imaging-derived axial diffusivity may be used to accurately evaluate axonal degeneration in an animal model of amyotrophic lateral sclerosis.     

Diverse changes in microglia morphology and axonal pathology during the course of 1 year after mild traumatic brain injury in pigs

Over 2.8 million people experience mild traumatic brain injury (TBI) in the United States each year, which may lead to long‐term neurological dysfunction. The mechanical forces that are caused by TBI propagate through the brain to produce diffuse axonal injury (DAI) and trigger secondary neuroinflammatory cascades. The cascades may persist from acute to chronic time points after injury, altering the homeostasis of the brain. However, the relationship between the hallmark axonal pathology of diffuse TBI and potential changes in glial cell activation or morphology have not been established in a clinically relevant large animal model at chronic time points. In this study, we assessed the tissue from pigs subjected to rapid head rotation in the coronal plane to generate mild TBI. Neuropathological assessments for axonal pathology, microglial morphological changes, and astrocyte reactivity were conducted in specimens out to 1‐year post‐injury. We detected an increase in overall amyloid precursor protein pathology, as well as periventricular white matter and fimbria/fornix pathology after a single mild TBI. We did not detect the changes in corpus callosum integrity or astrocyte reactivity. However, detailed microglial skeletal analysis revealed changes in morphology, most notably increases in the number of microglial branches, junctions, and endpoints. These subtle changes were most evident in periventricular white matter and certain hippocampal subfields, and were observed out to 1‐year post‐injury in some cases. These ongoing morphological alterations suggest persistent change in neuroimmune homeostasis. Additional studies are needed to characterize the underlying molecular and neurophysiological alterations, as well as potential contributions to neurological deficits.     

The evolution of traumatic brain injury in a rat focal contusion model

Serial MRI facilitates the in vivo analysis of the intra‐ and intersubject evolution of traumatic brain injury lesions. Despite the availability of MRI, the natural history of experimental focal contusion lesions in the controlled cortical impact (CCI) rat model has not been well described. We performed CCI on rats and MRI during the acute to chronic stages of cerebral injury to investigate the time course of changes in the brain. Female Wistar rats underwent CCI of their left motor cortex with a flat impact tip driven by an electromagnetic piston. In vivo MRI was performed at 7 T serially over 6 weeks post‐CCI. The appearances of CCI‐induced lesions and lesion‐associated cortical volumes were variable on MRI, with the percentage change in cortical volume of the CCI ipsilateral side relative to the contralateral side ranging from 18% within 2 h of injury on day 0 to a peak of 35% on day 1, and a trough of –28% by week 5/6, with an average standard deviation of ±14% at any given time point. In contrast, the percentage change in cortical volume of the ipsilateral side relative to the contralateral side in control rats was not significant (1 ± 2%). Hemorrhagic conversion within and surrounding the CCI lesion occurred between days 2 and 9 in 45% of rats, with no hemorrhage noted on the initial scan. Furthermore, hemorrhage and hemosiderin within the lesion were positive for Prussian blue and highly autofluorescent on histological examination. Although some variation in injuries may be technique related, the divergence of similar lesions between initial and final scans demonstrates the inherent biological variability of the CCI rat model. Published 2012. This article is a US Government work and is in the public domain in the USA.     

In vivo diffusion MRI detects early spinal cord axonal pathology in a mouse model of amyotrophic lateral sclerosis

Diffusion magnetic resonance imaging (MRI) exhibits contrast that identifies macro‐ and microstructural changes in neurodegenerative diseases. Previous studies have shown that MR diffusion tensor imaging (DTI) can observe changes in spinal cord white matter in animals and humans affected with symptomatic amyotrophic lateral sclerosis (ALS). The goal of this preclinical work was to investigate the sensitivity of DTI for the detection of signs of tissue damage before symptoms appear. High‐field MRI data were acquired using a 9.4‐T animal scanner to examine the spinal cord of an ALS mouse model at pre‐ and post‐symptomatic stages (days 80 and 120, respectively). The MRI results were validated using yellow fluorescent protein (YFP) via optical microscopy of spinal cord tissue slices collected from the YFP,G93A‐SOD1 mouse strain. DTI maps of diffusion‐weighted imaging (DWI) signal intensity, mean diffusivity (MD), fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD) were computed for axial slices of the lumbar region of the spinal cord. Significant changes were observed in FA (6.7% decrease, p < 0.01), AD (19.5% decrease, p < 0.01) and RD (16.1% increase, p < 0.001) at postnatal day 80 (P80). These differences were correlated with changes in axonal fluorescence intensity and membrane cellular markers. This study demonstrates the value of DTI as a potential tool to detect the underlying pathological progression associated with ALS, and may accelerate the discovery of therapeutic strategies for patients with this disease.     

Brain imaging correlates of verbal working memory in children following traumatic brain injury

Neural correlates of working memory (WM) based on the Sternberg Item Recognition Task (SIRT) were assessed in 40 children with moderate-to-severe traumatic brain injury (TBI) compared to 41 demographically-comparable children with orthopedic injury (OI). Multiple magnetic resonance imaging (MRI) methods assessed structural and functional brain correlates of WM, including volumetric and cortical thickness measures on all children; functional MRI (fMRI) and diffusion tensor imaging (DTI) were performed on a subset of children. Confirming previous findings, children with TBI had decreased cortical thickness and volume as compared to the OI group. Although the findings did not confirm the predicted relation of decreased frontal lobe cortical thickness and volume to SIRT performance, left parietal volume was negatively related to reaction time (RT). In contrast, cortical thickness was positively related to SIRT accuracy and RT in the OI group, particularly in aspects of the frontal and parietal lobes, but these relationships were less robust in the TBI group. We attribute these findings to disrupted fronto-parietal functioning in attention and WM. fMRI results from a subsample demonstrated fronto-temporal activation in the OI group, and parietal activation in the TBI group, and DTI findings reflected multiple differences in white matter tracts that engage fronto-parietal networks. Diminished white matter integrity of the frontal lobes and cingulum bundle as measured by DTI was associated with longer RT on the SIRT. Across modalities, the cingulate emerged as a common structure related to performance after TBI. These results are discussed in terms of how different imaging modalities tap different types of pathologic correlates of brain injury and their relationship with WM.     

Multi‐echo susceptibility‐weighted imaging and histology of open‐field blast‐induced traumatic brain injury in a rat model

Blast‐induced traumatic brain injury is on the rise, predominantly as a result of the use of improvised explosive devices, resulting in undesirable neuropsychological dysfunctions, as demonstrated in both animals and humans. This study investigated the effect of open‐field blast injury on the rat brain using multi‐echo, susceptibility‐weighted imaging (SWI). Multi‐echo SWI provided phase maps with better signal‐to‐noise ratio (SNR) and contrast‐to‐noise ratio (CNR), making it a sensitive technique for brain injury. Male Sprague‐Dawley rats were subjected to a survivable blast of 180 kPa. The visibility of blood vessels of varying sizes improved with multi‐echo SWI. Reduced signal intensity from major vessels post‐blast indicates increased deoxyhaemoglobin. Relative cerebral blood flow was computed from filtered phase SWI images using inferred changes in oxygen saturation from major blood vessels. Cerebral blood flow decreased significantly at day 3 and day 5 post‐blast compared with that pre‐blast. This was substantiated by the upregulation of β‐amyloid precursor protein (β‐APP), a marker of ischaemia, in the neuronal perikaya of the cerebral cortex, as observed by immunofluorescence, and in the cortical tissue by western blot analysis. Our findings indicate the presence of brain ischaemia in post‐blast acute phase of injury with possible recovery subsequently. Our results from cerebrovascular imaging, histology and staining provide an insight into the ischaemic state of the brain post‐blast and may be useful for prognosis and outcome. Copyright © 2015 John Wiley & Sons, Ltd.     

Study of neurometabolic and behavioral alterations in rodent model of mild traumatic brain injury: a pilot study

Mild traumatic brain injury (mTBI) is the most common form of TBI (70–90%) with consequences of anxiety‐like behavioral alterations in approximately 23% of mTBI cases. This study aimed to assess whether mTBI‐induced anxiety‐like behavior is a consequence of neurometabolic alterations. mTBI was induced using a weight drop model to simulate mild human brain injury in rodents. Based on injury induction and dosage of anesthesia, four animal groups were included in this study: (i) injury with anesthesia (IA); (ii) sham1 (injury only, IO); (iii) sham2 (only anesthesia, OA); and (iv) control rats. After mTBI, proton magnetic resonance spectroscopy (¹H‐MRS) and neurobehavioral analysis were performed in these groups. At day 5, reduced taurine (Tau)/total creatine (tCr, creatine and phosphocreatine) levels in cortex were observed in the IA and IO groups relative to the control. These groups showed mTBI‐induced anxiety‐like behavior with normal cognition at day 5 post‐injury. An anxiogenic effect of repeated dosage of anesthesia in OA rats was observed with normal Tau/tCr levels in rat cortex, which requires further examination. In conclusion, this mTBI model closely mimics human concussion injury with anxiety‐like behavior and normal cognition. Reduced cortical Tau levels may provide a putative neurometabolic basis of anxiety‐like behavior following mTBI.     

Assessing neuronal networks: Understanding Alzheimer's disease

Findings derived from neuroimaging of the structural and functional organization of the human brain have led to the widely supported hypothesis that neuronal networks of temporally coordinated brain activity across different regional brain structures underpin cognitive function. Failure of integration within a network leads to cognitive dysfunction. The current discussion on Alzheimer's disease (AD) argues that it presents in part a disconnection syndrome. Studies using functional magnetic resonance imaging, positron emission tomography and electroencephalography demonstrate that synchronicity of brain activity is altered in AD and correlates with cognitive deficits. Moreover, recent advances in diffusion tensor imaging have made it possible to track axonal projections across the brain, revealing substantial regional impairment in fiber-tract integrity in AD. Accumulating evidence points towards a network breakdown reflecting disconnection at both the structural and functional system level. The exact relationship among these multiple mechanistic variables and their contribution to cognitive alterations and ultimately decline is yet unknown. Focused research efforts aimed at the integration of both function and structure hold great promise not only in improving our understanding of cognition but also of its characteristic progressive metamorphosis in complex chronic neurodegenerative disorders such as AD.     

Ablation of the microglial protein DOCK2 reduces amyloid burden in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) neuropathology is characterized by innate immune activation primarily through prostaglandin E2 (PGE₂) signaling. Dedicator of cytokinesis 2 (DOCK2) is a guanyl nucleotide exchange factor expressed exclusively in microglia in the brain and is regulated by PGE₂ receptor EP2. DOCK2 modulates microglia cytokine secretion, phagocytosis, and paracrine neurotoxicity. EP2 ablation in experimental AD results in reduced oxidative damage and amyloid beta (Aβ) burden. This discovery led us to hypothesize that genetic ablation of DOCK2 would replicate the anti-Aβ effects of loss of EP2 in experimental AD. To test this hypothesis, we crossed mice that lacked DOCK2 (DOCK2 −/−), were hemizygous for DOCK2 (DOCK2 +/−), or that expressed two DOCK2 genes (DOCK2 +/+) with APPswe-PS1Δe9 mice (a model of AD). While we found no DOCK2-dependent differences in cortex or in hippocampal microglia density or morphology in APPswe-PS1Δe9 mice, cerebral cortical and hippocampal Aβ plaque area and size were significantly reduced in 10-month-old APPswe-PS1Δe9/DOCK2 −/− mice compared with APPswe-PS1Δe9/DOCK2 +/+ controls. DOCK2 hemizygous APPswe-PS1Δe9 mice had intermediate Aβ plaque levels. Interestingly, soluble Aβ₄₂ was not significantly different among the three genotypes, suggesting the effects were mediated specifically in fibrillar Aβ. In combination with earlier cell culture results, our in vivo results presented here suggest DOCK2 contributes to Aβ plaque burden via regulation of microglial innate immune function and may represent a novel therapeutic target for AD.     

Elucidating the role of 5-HT(1A) and 5-HT(7) receptors on 8-OH-DPAT-induced behavioral recovery after experimental traumatic brain injury

8-OH-DPAT is a 5-HT(1A/7) receptor agonist that enhances behavioral recovery after traumatic brain injury (TBI). This study is a first attempt to decipher whether the benefits induced by 8-OH-DPAT after TBI are mediated by 5-HT(1A) or 5-HT(7) receptors. A single i.p. injection of 8-OH-DPAT (0.5 mg/kg) alone or co-administered with either the 5-HT(1A) or 5-HT(7) receptor antagonists WAY 100635 (0.5 mg/kg) or SB 269970 HCl (2.0 mg/kg), respectively, or vehicle control (1.0 mL/kg) was given 15 min after cortical impact or sham injury. Function was assessed by established motor and cognitive tests. No difference in motor performance was observed among the TBI groups. Spatial acquisition was enhanced, relative to vehicle controls, by 8-OH-DPAT alone and when co-administered with WAY 100635, but not when combined with SB 269970 HCl. These data imply that 5-HT(1A) receptor antagonism does not abate the 8-OH-DPAT-induced cognitive benefits, but 5-HT(7) receptor antagonism does, which suggests that the 8-OH-DPAT-induced benefits in this single administration paradigm may be mediated more by 5-HT(7) versus 5-HT(1A) receptors. Evaluation of a specific 5-HT(7) receptor agonist will further elucidate the contribution of 5-HT(1A) and 5-HT(7) receptors on behavioral recovery conferred by acute 8-OH-DPAT treatment after TBI.     

Biomarkers for major depression and its delineation from neurodegenerative disorders

Major depressive disorders (MDD) are among the most debilitating diseases worldwide and occur with a high prevalence in elderly individuals. Neurodegenerative diseases (in particular Alzheimer's disease, AD) do also show a strong age-dependent increase in incidence and prevalence among the elderly population. A high number of geriatric patients with MDD show cognitive deficits and a very high proportion of AD patients present co-morbid MDD, which poses difficult diagnostic and prognostic questions. Especially in prodromal and in very early stages of AD, it is almost impossible to differentiate between pure MDD and MDD with underlying AD. Here, we give a comprehensive review of the literature on the current state of candidate biomarkers for MDD ("positive MDD markers") and briefly refer to established and validated diagnostic AD biomarkers in order to rule out underlying AD pathophysiology in elderly MDD subjects with cognitive impairments ("negative MDD biomarkers"). In summary, to date there is no evidence for positive diagnostic MDD biomarkers and the only way to delineate MDD from AD is to use "negative MDD" biomarkers. Because of this highly unsatisfactory current state of MDD biomarker research, we propose a research strategy targeting to detect and validate positive MDD biomarkers, which is based on a complex (genetic, molecular and neurophysiological) biological model that incorporates current state of the art knowledge on the pathobiology of MDD. This model delineates common pathways and the intersection between AD and MDD. Applying these concepts to MDD gives hope that positive MDD biomarkers can be successfully identified in the near future.