Diabetes Mellitus Impairs Cognitive Function in Middle-Aged Rats and Neurological Recovery in Middle-Aged Rats After Stroke.

BACKGROUND AND PURPOSE: Diabetes mellitus (DM) is a common metabolic disease among the middle-aged and older population, which leads to an increase of stroke incidence and poor stroke recovery. The present study was designed to investigate the impact of DM on brain damage and on ischemic brain repair after stroke in aging animals. METHODS: DM was induced in middle-aged rats (13 months) by administration of nicotinamide and streptozotocin. Rats with confirmed hyperglycemia status 30 days after nicotinamide-streptozotocin injection and age-matched non-DM rats were subjected to embolic middle cerebral artery occlusion. RESULTS: Middle-aged rats subjected to nicotinamide-streptozotocin injection became hyperglycemic and developed cognitive deficits 2 months after induction of DM. Histopathologic analysis revealed that there was sporadic vascular disruption, including cerebral microvascular thrombosis, blood-brain barrier leakage, and loss of paravascular aquaporin-4 in the hippocampi. Importantly, middle-aged DM rats subjected to stroke had exacerbated sensorimotor and cognitive deficits compared with age-matched non-DM ischemic rats during stroke recovery. Compared with age-matched non-DM ischemic rats, DM ischemic rats exhibited aggravated neurovascular disruption in the bilateral hippocampi and white matter, suppressed stroke-induced neurogenesis and oligodendrogenesis, and impaired dendritic/spine plasticity. However, DM did not enlarge infarct volume. CONCLUSIONS: Our data suggest that DM exacerbates neurovascular damage and hinders brain repair processes, which likely contribute to the impairment of stroke recovery.

Complications of ventricular entry during craniotomy for brain tumor resection.

OBJECTIVE Recent studies have demonstrated that periventricular tumor location is associated with poorer survival and that tumor location near the ventricle limits the extent of resection. This finding may relate to the perception that ventricular entry leads to further complications and thus surgeons may choose to perform less aggressive resection in these areas. However, there is little support for this view in the literature. This study seeks to determine whether ventricular entry is associated with more complications during craniotomy for brain tumor resection. METHODS A retrospective analysis of patients who underwent craniotomy for tumor resection at Henry Ford Hospital between January 2010 and November 2012 was conducted. A total of 183 cases were reviewed with attention to operative entry into the ventricular system, postoperative use of an external ventricular drain (EVD), subdural hematoma, hydrocephalus, and symptomatic intraventricular hemorrhage (IVH). RESULTS Patients in whom the ventricles were entered had significantly higher rates of any complication (46% vs 21%). Complications included development of subdural hygroma, subdural hematoma, intraventricular hemorrhage, subgaleal collection, wound infection, urinary tract infection/deep venous thrombosis, hydrocephalus, and ventriculoperitoneal (VP) shunt placement. Specifically, these patients had significantly higher rates of EVD placement (23% vs 1%, p < 0.001), hydrocephalus (6% vs 0%, p = 0.03), IVH (14% vs 0%, p < 0.001), infection (15% vs 5%, p = 0.04), and subgaleal collection (20% vs 4%, p < 0.001). It was also observed that VP shunt placement was only seen in cases of ventricular entry (11% vs 0%, p = 0.001) with 3 of 4 of these patients having a large ventricular entry (defined here as entry greater than a pinhole [< 3 mm] entry). Furthermore, in a subset of glioblastoma patients with and without ventricular entry, Kaplan-Meier estimates for survival demonstrated a median survival time of 329 days for ventricular entry compared with 522 days for patients with no ventricular entry (HR 1.13, 95% CI 0.65-1.96; p = 0.67). CONCLUSIONS There are more complications associated with ventricular entry during brain tumor resection than in nonviolated ventricular systems. Better strategies for management of periventricular tumor resection should be actively sought to improve resection and survival for these patients.

Impairment of the glymphatic system after diabetes.

The glymphatic system has recently been shown to clear brain extracellular solutes and abnormalities in glymphatic clearance system may contribute to both initiation and progression of neurological diseases. Despite that diabetes is known as a risk factor for vascular diseases, little is known how diabetes affects the glymphatic system. The current study is the first investigation of the effect of diabetes on the glymphatic system and the link between alteration of glymphatic clearance and cognitive impairment in Type-2 diabetes mellitus rats. MRI analysis revealed that clearance of cerebrospinal fluid contrast agent Gd-DTPA from the interstitial space was slowed by a factor of three in the hippocampus of Type-2 diabetes mellitus rats compared to the non-DM rats and confirmed by florescence imaging analysis. Cognitive deficits detected by behavioral tests were highly and inversely correlated to the retention of Gd-DTPA contrast and fluorescent tracer in the hippocampus of Type-2 diabetes mellitus rats. Type-2 diabetes mellitus suppresses clearance of interstitial fluid in the hippocampus and hypothalamus, suggesting that an impairment of the glymphatic system contributes to Type-2 diabetes mellitus-induced cognitive deficits. Whole brain MRI provides a sensitive, non-invasive tool to quantitatively evaluate cerebrospinal fluid and interstitial fluid exchange in Type-2 diabetes mellitus and possibly in other neurological disorders, with potential clinical application.

Class IIa histone deacetylases affect neuronal remodeling and functional outcome after stroke.

We have previously demonstrated that stroke induces nuclear shuttling of class IIa histone deacetylase 4 (HDAC4). Stroke-induced nuclear shuttling of HDAC4 is positively and significantly correlated with improved indices of neuronal remodeling in the peri-infarct cortex. In this study, using a rat model for middle cerebral artery occlusion (MCAO), we tested the effects of selective inhibition of class IIa HDACs on functional recovery and neuronal remodeling when administered 24hr after stroke. Adult male Wistar rats (n = 15-17/group) were subjected to 2 h MCAO and orally gavaged with MC1568 (a selective class IIa HDAC inhibitor), SAHA (a non-selective HDAC inhibitor), or vehicle-control for 7 days starting 24 h after MCAO. A battery of behavioral tests was performed. Lesion volume measurement and immunohistochemistry were performed 28 days after MCAO. We found that stroke increased total HDAC activity in the ipsilateral hemisphere compared to the contralateral hemisphere. Stroke-increased HDAC activity was significantly decreased by the administration of SAHA as well as by MC1568. However, SAHA significantly improved functional outcome compared to vehicle control, whereas selective class IIa inhibition with MC1568 increased mortality and lesion volume and did not improve functional outcome. In addition, MC1568 decreased microtubule associated protein 2 (MAP2, dendrites), phosphorylated neurofilament heavy chain (pNFH, axons) and myelin basic protein (MBP, myelination) immunoreactivity in the peri-infarct cortex. Quantitative RT-PCR of cortical neurons isolated by laser capture microdissection revealed that MC1568, but not SAHA, downregulated CREB and c-fos expression. Additionally, MC1568 decreased the expression of phosphorylated CREB (active) in neurons. Taken together, these findings demonstrate that selective inhibition of class IIa HDACs impairs neuronal remodeling and neurological outcome. Inactivation of CREB and c-fos by MC1568 likely contributes to this detrimental effect.