Effects of acute ethanol and/or diazepam exposure on immediate and delayed hippocampal metabolite levels in rats anesthetized with isoflurane.

Alcohol and benzodiazepines are psychoactive substances frequently associated in voluntary drug intoxications that share common mechanisms of action, including facilitation of GABAergic transmission. This study aimed to assess the separate and combined effects of ethanol and diazepam acute exposure on hippocampal metabolite levels, as well as on delayed cognitive performance, in rats anesthetized with isoflurane. Adult male Wistar rats received one intraperitoneal injection containing either saline solution ("CTL" group, N = 15), a 5-mg/kg dose of diazepam ("DIA" group, N = 16), a 2-g/kg dose of ethanol ("EtOH" group, N = 18), or a 5-mg/kg dose of diazepam + a 2-g/kg dose of ethanol ("DIA + EtOH" group, N = 24). The levels of brain metabolites in the hippocampal region were assessed using in vivo magnetic resonance spectroscopy (MRS) before and after injection. Behavioral testing, including working memory and visual recognition memory assessment, was performed at week 3, while a new MRS acquisition was conducted 4 weeks after the injection. In the hour following acute exposure, a decrease in glutamate levels was found in the DIA + EtOH group only. Four weeks after injection, a decrease in GABA and glutamate levels and an increase in NAA levels were found in the EtOH group only. No significant between-group differences were found in the behavioral assessment. While the initial decrease in glutamate levels in the DIA + EtOH group suggests an early potentiation effect between ethanol and diazepam, the long-term modifications found only in the EtOH group suggest a possible downregulation of ethanol's effect by diazepam at 4 weeks.

Dose-dependent metabolite changes after ethanol intoxication in rat prefrontal cortex using in vivo magnetic resonance spectroscopy.

Ethanol disrupts the balance between the excitatory (glutamatergic) and inhibitory (GABAergic) neurotransmission systems. We aimed to assess how acute ethanol intoxication in rats affects the levels of GABA, glutamate and other cerebral metabolites after injection of two different doses of ethanol. One in vivo magnetic resonance spectrum of the prefrontal cortex region was acquired before and six spectra were acquired after intraperitoneal injections of saline or ethanol (1 g/kg or 2 g/kg). Brain kinetics after exposure to ethanol were compared to blood ethanol kinetics. GABA levels significantly decreased after injection of 1 g/kg but not 2 g/kg doses of ethanol. Choline levels, which serve as a marker of alterations in membrane composition, significantly decreased after injection of 2 g/kg but not 1 g/kg doses of ethanol. Acute ethanol intoxication appears to result in specific dose-dependent changes in the GABA level and choline level.

Role of cortical microbleeds in cognitive impairment: In vivo behavioral and imaging characterization of a novel murine model.

Cerebral microbleeds (CMBs) could contribute to cognitive impairment in the general population and in patients with dementia. We designed a study to (i) develop a murine model of CMBs, (ii) assess whether CMBs affect cognition in this model and (iii) assess whether this model is sensitive to pharmacological modulation. Male C57Bl6/J mice were stereotactically administered collagenase to induce cortical lesion analysed by MRI at 24 h. CMB-mice were assessed at six weeks post-lesion for cognitive performances (Barnes maze and Touchscreen automated paired-associated learning (PAL) task) and for cerebral metabolism (in vivo PET/CT with fluorodeoxyglucose (FDG)). CMB-model sensitivity to pharmacological modulation was assessed by administering atorvastatin (5 mg/kg/day) over the follow-up period. CMB mice were compared to naïve littermates. Collagenase at 0.8 µU/µl appeared suitable to induce reproducible and reliable CMBs. At six weeks, a decline in learning, spatial and visuospatial memory was significantly observed in CMB-mice. Brain metabolism was impaired in all cortex, striatum and the ipsilateral dentate gyrus. A significant improvement in cognition performances was depicted under atorvastatin. In this novel murine model of CMBs, we validated that CMBs lowered cognitive performances and affected regional metabolism. We also proved that this CMB-model is sensitive to pharmacological modulation.

Topographic distribution of brain iron deposition and small cerebrovascular lesions in amyotrophic lateral sclerosis and in frontotemporal lobar degeneration: a post-mortem 7.0-tesla magnetic resonance imaging study with neuropathological correlates.

Amyotrophic lateral sclerosis (ALS) is associated with frontotemporal lobar degeneration (FTLD) in 15% of the cases. A neuropathological continuity between ALS and FTLD-TDP is suspected. The present post-mortem 7.0-tesla magnetic resonance imaging (MRI) study compares the topographic distribution of iron (Fe) deposition and the incidence of small cerebrovascular lesions in ALS and in FTLD brains. Seventy-eight post-mortem brains underwent 7.0-tesla MRI. The patients consisted of 12 with ALS, 38 with FTLD, and 28 controls. Three ALS brains had minor FTLD features. Three coronal sections of a cerebral hemisphere were submitted to T2 and T2* MRI sequences. The amount of Fe deposition in the deep brain structures and the number of small cerebrovascular lesions was determined in ALS and the subtypes of FTLD compared to control brains, with neuropathological correlates. A significant increase of Fe deposition was observed in the claustrum, caudate nucleus, globus pallidus, thalamus, and subthalamic nucleus of the FTLD-FUS and FTLD-TDP groups, while in the ALS one, the Fe increase was only observed in the caudate and the subthalamic nuclei. White matter changes were only significantly more severe in the FTLD compared to those in ALS and in controls brains. Cortical micro-bleeds were increased in the frontal and temporal lobes of FTLD as well as of ALS brains compared to controls. Cortical micro-infarcts were, on the other hand, more frequent in the control compared to the ALS and FTLD groups. The present study supports the assumption of a neuropathological continuity between ALS and FTLD and illustrates the favourable vascular risk profile in these diseases.

Cerebrovascular Lesions in Mixed Neurodegenerative Dementia: A Neuropathological and Magnetic Resonance Study.

BACKGROUND: In elderly brains of demented patients, Alzheimer and Lewy body pathology (LBP) are frequently associated. Cortical microinfarcts (CoMIs) are more observed in Lewy body disease, even in the absence of cerebral amyloid angiopathy (CAA). The present neuropathological and 7.0-tesla MRI studies investigate whether CoMIs are also more frequent in mixed neurodegenerative dementia syndromes. SUMMARY: Both examinations revealed that CoMIs are increased to different degrees in mixed dementia syndromes according to the severity of the LBP. They were mainly associated with a trend of older age and arterial hypertension in the patients with the most severe LBP. Messages: The increased number of CoMIs in mixed dementia syndromes with LBP is mainly due to the associated cerebrovascular pathology, even in the absence of CAA.

Frequency and topography of small cerebrovascular lesions in vascular and in mixed dementia: a post-mortem 7-tesla magnetic resonance imaging study with neuropathological correlates.

Introduction: Mixed dementia (MixD) refers to a combination of definite Alzheimer's disease (AD) and vascular encephalopathy. The existence of a "pure" type of vascular dementia (VaD) is controversial. There is a need to find magnetic resonance imaging (MRI) characteristics allowing the distinction between VaD and MixD. The present post-mortem 7.0-tesla MRI compares the frequency or severity and the topography of the small cerebrovascular lesions in brains of patients with VaD and with MixD. Material and methods: Based on neuropathological criteria, 14 brains were classified as VaD, 24 as MixD and 11 as controls. Three coronal sections of a cerebral hemisphere and a horizontal section of a cerebellar hemisphere underwent T2 and T2* 7.0-tesla MRI examination. The mean values and topographic distribution of white matter changes (WMCs), lacunar infarcts (LIs), cortical microbleeds (CoMBs) and cortical microinfarcts (CoMIs) were determined and compared between the different groups. Results: Compared to the controls, both VaD and MixD brains had significantly more severe WMCs and increased numbers of CoMBs and CoMIs. Lacunar infarcts predominated only in the VaD cases. On mutual comparison of VaD and MixD brains, CoMBs and CoMIs predominated in the frontal lobe and the cerebellum of VaD, while were mainly present in the occipital lobe of MixD. White matter changes predominated in the temporal lobe of MixD cases. Lacunar infarcts were significantly increased in the corona radiata and putamen of VaD patients. Conclusions: The present post-mortem MRI study shows clear differences in the distribution and the types of cerebrovascular lesions on high-field MRI, confirming that VaD and MixD are different diseases. .

Proton MR Spectroscopy and Diffusion MR Imaging Monitoring to Predict Tumor Response to Interstitial Photodynamic Therapy for Glioblastoma.

Despite recent progress in conventional therapeutic approaches, the vast majority of glioblastoma recur locally, indicating that a more aggressive local therapy is required. Interstitial photodynamic therapy (iPDT) appears as a very promising and complementary approach to conventional therapies. However, an optimal fractionation scheme for iPDT remains the indispensable requirement. To achieve that major goal, we suggested following iPDT tumor response by a non-invasive imaging monitoring. Nude rats bearing intracranial glioblastoma U87MG xenografts were treated by iPDT, just after intravenous injection of AGuIX® nanoparticles, encapsulating PDT and imaging agents. Magnetic Resonance Imaging (MRI) and Magnetic Resonance Spectroscopy (MRS) allowed us an original longitudinal follow-up of post-treatment effects to discriminate early predictive markers. We successfully used conventional MRI, T2 star (T2*), Diffusion Weighted Imaging (DWI) and MRS to extract relevant profiles on tissue cytoarchitectural alterations, local vascular disruption and metabolic information on brain tumor biology, achieving earlier assessment of tumor response. From one day post-iPDT, DWI and MRS allowed us to identify promising markers such as the Apparent Diffusion Coefficient (ADC) values, lipids, choline and myoInositol levels that led us to distinguish iPDT responders from non-responders. All these responses give us warning signs well before the tumor escapes and that the growth would be appreciated.

Lobar intracerebral haematomas: Neuropathological and 7.0-tesla magnetic resonance imaging evaluation.

BACKGROUND AND PURPOSE: The Boston criteria for cerebral amyloid angiopathy (CAA) need validation by neuropathological examination in patients with lobar cerebral haematomas (LCHs). In "vivo" 1.5-tesla magnetic resonance imaging (MRI) is unreliable to detect the age-related signal changes in LCHs. This post-mortem study investigates the validity of the Boston criteria in brains with LCHs and the signal changes during their time course with 7.0-tesla MRI. MATERIALS AND METHODS: Seventeen CAA brains including 26 LCHs were compared to 13 non-CAA brains with 14 LCHs. The evolution of the signal changes with time was examined in 25 LCHs with T2 and T2* 7.0-tesla MRI. RESULTS: In the CAA group LCHs were predominantly located in the parieto-occipital lobes. Also white matter changes were more severe with more cortical microinfarcts and cortical microbleeds. On MRI there was a progressive shift of the intensity of the hyposignal from the haematoma core in the acute stage to the boundaries later on. During the residual stage the hyposignal mildly decreased in the boundaries with an increase of the superficial siderosis and haematoma core collapse. CONCLUSIONS: Our post-mortem study of LCHs confirms the validity of the Boston criteria for CAA. Also 7.0-tesla MRI allows staging the age of the LCHs.

The Topography of Cortical Microinfarcts in Neurodegenerative Diseases and in Vascular Dementia: A Postmortem 7.0-Tesla Magnetic Resonance Imaging Study.

BACKGROUND: Cortical microinfarcts (CoMIs) are considered as barely visible lesions in clinical-neuroradiological correlation studies. On postmortem 7.0-tesla MRI, however, CoMIs of different size are easily detected. SUMMARY: The present MRI study investigates 84 postmortem brains with different neurodegenerative diseases and vascular dementia (VaD) for their topographic distribution and the prevalence of CoMIs. The mean numbers of CoMIs were determined on 6 hemispheric coronal sections and in 22 different gyri with a 7.0-tesla MRI Bruker BioSpin SA. A large coronal section at the level of the mammillary body was also used for neuropathological evaluation. CoMIs were predominantly observed in the prefrontal and postcentral sections of VaD brains. The mean number of CoMIs was significantly increased in the inferior frontal and in the cingulate gyri of VaD brains compared to the controls. No topographic differences were observed in the neurodegenerative diseases. KEY MESSAGES: As the inferior frontal and the cingulated gyri are areas frequently involved in VaD, CoMIs in those strategic locations must have an impact on the evolution of the vascular cognitive decline in those patients.

Topographic distribution of white matter changes and lacunar infarcts in neurodegenerative and vascular dementia syndromes: A post-mortem 7.0-tesla magnetic resonance imaging study.

BACKGROUND: White matter changes and lacunar infarcts are regarded as linked to the same underlying small-vessel pathology. On magnetic resonance imaging, white matter changes are frequently observed, while the number of lacunar infarcts is probably underestimated. The present study post-mortem 7.0-tesla magnetic resonance imaging study compares the severity and the distribution of white matter changes and lacunar infarcts in different neurodegenerative and vascular dementia syndromes in order to determine their impact on the disease evolution. PATIENTS AND METHODS: Eighty-four post-mortem brains consisting of 15 patients with pure Alzheimer's disease and 12 with associated cerebral amyloid angiopathy, 14 patients with frontotemporal lobar degeneration, 7 with Lewy body dementia, 10 with progressive supranuclear palsy, 14 with vascular dementia and 12 control brains were examined. Six hemispheric coronal sections of each brain underwent 7.0-tesla magnetic resonance imaging. Location and severity of white matter changes and lacunar infarcts were evaluated semi-quantitatively in each section separately. RESULTS: White matter changes predominated in the prefrontal and frontal sections of frontotemporal lobar degeneration and in the post-central section of associated cerebral amyloid angiopathy brains, while overall increased in vascular dementia cases. Lacunar infarcts were more frequent in the vascular dementia brains and mainly increased in the centrum semiovale. CONCLUSIONS: White matter changes have a different topographic distribution in neurodegenerative diseases and are most severe and extended in vascular dementia. Lacunar infarcts predominate in the deep white matter of vascular dementia compared to the neurodegenerative diseases. Vascular cognitive impairment is mainly linked to white matter changes due to chronic ischaemia as well as to lacunar infarcts due to small-vessel occlusion.

Detection of Cortical Microbleeds in Postmortem Brains of Patients with Lewy Body Dementia: A 7.0-Tesla Magnetic Resonance Imaging Study with Neuropathological Correlates.

BACKGROUND: It is unclear whether associated cerebrovascular pathology contributes to the clinical spectrum of Lewy body dementia (LBD). SUMMARY: The present postmortem 7.0-tesla MRI study investigates the anatomical distribution of cortical microbleeds (CoMBs) in LBD brains with and without associated Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). CoMBs predominated in the frontal section of the LBD brains and were associated to severe white matter lesions. No differences were observed when LBD brains with and without AD and CAA were compared. KEY MESSAGES: In LBD, there is a specific distribution of CoMBs that is different from that in other neurodegenerative diseases. The increase of frontal CoMBs is not due to the frequently associated AD and CAA features but due to the LBD itself.

Multifunctional ultrasmall nanoplatforms for vascular-targeted interstitial photodynamic therapy of brain tumors guided by real-time MRI.

Photodynamic therapy (PDT) for brain tumors appears to be complementary to conventional treatments. A number of studies show the major role of the vascular effect in the tumor eradication by PDT. For interstitial PDT (iPDT) of brain tumors guided by real-time imaging, multifunctional nanoparticles consisting of a surface-localized tumor vasculature targeting neuropilin-1 (NRP-1) peptide and encapsulated photosensitizer and magnetic resonance imaging (MRI) contrast agents, have been designed. Nanoplatforms confer photosensitivity to cells and demonstrate a molecular affinity to NRP-1. Intravenous injection into rats bearing intracranial glioma exhibited a dynamic contrast-enhanced MRI for angiogenic endothelial cells lining the neovessels mainly located in the peripheral tumor. By using MRI completed by NRP-1 protein expression of the tumor and brain adjacent to tumor tissues, we checked the selectivity of the nanoparticles. This study represents the first in vivo proof of concept of closed-head iPDT guided by real-time MRI using targeted ultrasmall nanoplatforms. From the clinical editor: The authors constructed tumor vascular peptide targeting multifunctional silica-based nanoparticles, with encapsulated gadolinium oxide as MRI contrast agent and chlorin as a photosensitizer, as a proof of concept novel treatment for glioblastoma in an animal model.

The significance of cortical cerebellar microbleeds and microinfarcts in neurodegenerative and cerebrovascular diseases. A post-mortem 7.0-tesla magnetic resonance study with neuropathological correlates.

BACKGROUND: As cortical microbleeds and microinfarcts in neurodegenerative and cerebrovascular diseases have been studied predominantly at the level of the cerebral hemispheres and linked to the presence of cerebral amyloid angiopathy (CAA), we aimed at determining with 7.0-tesla magnetic resonance imaging (MRI) whether the causes and the frequency of cortical cerebellar microbleeds (CCeMBs) and microinfarcts (CCeMIs) are the same. MATERIALS AND METHODS: Hundred and four postmortem brains, composed of 29 with pure Alzheimer's disease (AD), 9 with AD associated to CAA, 10 with frontotemporal lobar degeneration, 9 with amyotrophic lateral sclerosis, 10 with Lewy body disease, 12 with progressive supranuclear palsy, 9 with vascular dementia (VaD), and 16 controls, were examined. On a horizontal section of a cerebellar hemisphere examined with 7.0-tesla MRI, the number CCeMBs and CCeMIs were compared between the different disease groups and the control group. The MRI findings were also compared with the corresponding mean values observed on histological examination of a separate standard horizontal section of a cerebellar hemisphere, used for diagnostic purpose. RESULTS: CCeMBs and CCeMIs were only significantly increased in the VaD group. When comparing the diseased patients with and without CAA mutually and with those with arterial hypertension and severe atherosclerotic cerebrovascular disease, only in the latter an increase of CCeMBs and CCeMIs was observed. There was an excellent correlation between the MRI and the neuropathological findings. CONCLUSIONS: CCeMBs and CCeMIs are mainly due to atherosclerotic cerebrovascular disease and not due to CAA. Their increased presence cannot be included to the Boston diagnostic criteria for CAA.

Dietary CML-enriched protein induces functional arterial aging in a RAGE-dependent manner in mice.

SCOPE: Advanced glycation end-products (AGEs) are endogenously produced and are present in food. N(ε)-carboxymethyllysine (CML) is an endothelial activator via the receptor for AGEs (RAGEs) and is a major dietary AGE. This work investigated the effects of a CML-enriched diet and RAGE involvement in aortic aging in mice. METHODS AND RESULTS: After 9 months of a control diet or CML-enriched diets (50, 100, or 200 µg(CML)/g of food), endothelium-dependent relaxation, RAGE, vascular cell adhesion molecule-1, and sirtuin-1 expression, pulse wave velocity and elastin disruption were measured in aortas of wild-type or RAGE(-/-) male C57BL/6 mice. Compared to the control diet, endothelium-dependent relaxation was reduced in the wild-type mice fed the CML-enriched diet (200 µg(CML)/g) (66.8 ± 12.26 vs. 94.3 ± 2.6%, p < 0.01). RAGE and vascular cell adhesion molecule-1 (p < 0.05) expression were increased in the aortic wall. RAGE(-/-) mice were protected against CML-enriched diet-induced endothelial dysfunction. Compared to control diet, the CML-enriched diet (200 µg(CML)/g) increased the aortic pulse wave velocity (86.6 ± 41.1 vs. 251.4 ± 41.1 cm/s, p < 0.05) in wild-type animals. Elastin disruption was found to a greater extent in the CML-fed mice (p < 0.05). RAGE(-/-) mice fed the CML-enriched diet were protected from aortic stiffening. CONCLUSION: Chronic CML ingestion induced endothelial dysfunction, arterial stiffness and aging in a RAGE-dependent manner.

Long-term risperidone treatment induces visceral adiposity associated with hepatic steatosis in mice: a magnetic resonance approach.

Although atypical antipsychotic drugs (APDs) have led to significant advances in the treatment of psychotic disorders, they still induce metabolic disturbances. We aimed at characterizing the metabolic consequences of a risperidone treatment and at establishing a link with noninvasive MR markers, in order to develop a tool for predicting symptoms of the metabolic syndrome. Fat deposition and liver morphometry were assessed by T1-weighted imaging. Fatty acid composition and fat accumulations in tissues were determined using MR spectroscopy with and without water suppression, respectively. Risperidone treatment induced a weight gain accompanied with metabolic disturbances such as hyperglycemic status, an increase in visceral adipose tissue (VAT), and liver fat depositions. Correlations using Methylene-Water Ratio (MWR) and Polyunsaturated Index (PUI) demonstrated a concomitant increase in the weight gain, VAT and liver fat depositions, and a decrease in the quantity of polyunsaturated fatty acids. These results were consistent with a hepatic steatosis state. We evaluated the ability of MR techniques to detect subtle metabolic disorders induced by APDs. Thus, our model and methodology offer the possibility to investigate APDs side effects in order to improve the health conditions of schizophrenic patients.

Prevalence of small cerebral bleeds in patients with progressive supranuclear palsy: a neuropathological study with 7.0-Tesla magnetic resonance imaging correlates.

INTRODUCTION: Progressive supranuclear palsy (PSP) is a degenerative disease affecting mainly the brain stem, basal ganglia and cerebellum. Associated cerebrovascular lesions, mainly small cerebral bleeds, are frequently observed in some neurodegenerative diseases such as Alzheimer dementia and rare in others such as frontotemporal lobar degeneration. The present post-mortem study investigates the prevalence and distribution of small cerebral bleeds in PSP brains. MATERIAL AND METHODS: Nineteen brains of PSP patients were compared to 12 age-matched controls. The prevalence and distribution of mini-bleeds were investigated on a coronal section of a cerebral hemisphere at the level of the mamillary bodies and on a horizontal section through the pons and cerebellum. In addition, out of these series T2*-weighted gradient-echo 7.0-Tesla magnetic resonance imaging (MRI) of 3 coronal sections of a cerebral hemisphere and of a brain stem and cerebellum was performed in 14 PSP and 11 control brains. RESULTS: Although the total number of mini-bleeds was the same on neuropathological examination of both groups, they prevailed around the dentate nucleus of the cerebellum (p = 0.05) and in the tegmentum pontis (p = 0.05) of the PSP brains. On MRI the small bleeds were also more frequent around the dentate nucleus of the cerebellum (p = 0.02) and in the pons (p = 0.04) of PSP brains. DISCUSSION: In PSP brains, mini-bleeds only prevail in the regions affected by the neurodegenerative process, similarly to what happens in frontotemporal lobar degeneration. They should be considered as the result of increased angiogenesis and microglial activation, leading to associated disturbances of the blood-brain barrier in the most affected regions of PSP. They are not indicative of cerebrovascular disease.

Microbleeds in postmortem brains of patients with Alzheimer disease: a T2*-weighted gradient-echo 7.0 T magnetic resonance imaging study.

This study aims to determine the distribution and to quantify microbleeds (MBs) in postmortem brains of patients with Alzheimer disease (AD) on T2*-weighted gradient-echo 7.0 T magnetic resonance imaging. Twenty-eight AD brains were compared with 5 controls. The AD brains were subdivided further: 18 without and 10 with additional severe cerebral amyloid angiopathy (AD-CAA). The distribution and the number of cortical focal signal intensity losses, representing MBs, were assessed on coronal sections at the frontal, the central, and the occipital level of a cerebral hemisphere. MBs prevailed in the central sections (P=0.005) of AD brains without CAA, whereas in AD-CAA brains, they were more frequent in all coronal sections (P≤0.002). They prevailed in the deep cortical layers of the AD brains and of the controls (P≤0.03). They were significantly increased in all cortical layers of the AD-CAA brains (P≤0.04), compared with the controls. MBs prevalence in brains of AD patients had a different topographic distribution according to the absence or presence of severe CAA.