Sophia Sundararajan

PPARγ as a therapeutic target in central nervous system diseases

Diseases of the central nervous system present a challenge for the development of new therapeutic agents. Nuclear receptors are ligand-activated transcription factors that have proven to be valuable targets for development of new drugs owing to their ability to directly regulate gene expression. The nuclear receptor, peroxisome proliferator-activated receptor γ (PPARγ), has been investigated for its action in ameliorating the development and progression of a number of CNS diseases. PPARγ agonists exhibit potent anti-inflammatory effects and appear to have direct neuroprotective actions. PPARγ agonists have been shown to be efficacious in animal models of Alzheimers disease, stroke, multiple sclerosis, Parkinsons disease and amyotrophic lateral sclerosis. The availability of FDA-approved agonists of this receptor will facilitate the rapid translation of these findings into clinical trials for a number of CNS diseases.

Reperfusion brain injury Focus on cellular bioenergetics

Energy production for the maintenance of brain function fails rapidly with the onset of ischemia and is reinstituted with timely reperfusion. The key bioenergetic organelle, the mitochondrion, is strongly affected by a cascade of events occurring with ischemia and reperfusion. Enhanced production of reactive oxygen species, disruption of calcium homeostasis, and an inflammatory response are induced by reperfusion and have a profound effect on cellular bioenergetics in reversible stroke. The impact of perturbed bioenergetics on cellular homeostasis/function during and after ischemia are discussed. Because mitochondrial function can be compromised by derangements at more than one of the susceptible sites on this organelle, we propose that a combination therapy is needed for the restoration and maintenance of cellular bioenergetics after reperfusion.

Gravity-dependent nystagmus and inner-ear dysfunction suggest anterior and posterior inferior cerebellar artery infarct

Cerebellar lesions may present with gravity-dependent nystagmus, where the direction and velocity of the drifts change with alterations in head position. Two patients had acute onset of hearing loss, vertigo, oscillopsia, nausea, and vomiting. Examination revealed gravity-dependent nystagmus, unilateral hypoactive vestibulo-ocular reflex (VOR), and hearing loss ipsilateral to the VOR hypofunction. Traditionally, the hypoactive VOR and hearing loss suggest inner-ear dysfunction. Vertigo, nausea, vomiting, and nystagmus may suggest peripheral or central vestibulopathy. The gravity-dependent modulation of nystagmus, however, localizes to the posterior cerebellar vermis. Magnetic resonance imaging in our patients revealed acute cerebellar infarct affecting posterior cerebellar vermis, in the vascular distribution of the posterior inferior cerebellar artery (PICA). This lesion explains the gravity-dependent nystagmus, nausea, and vomiting. Acute onset of unilateral hearing loss and VOR hypofunction could be the manifestation of inner-ear ischemic injury secondary to the anterior inferior cerebellar artery (AICA) compromise. In cases of combined AICA and PICA infarction, the symptoms of peripheral vestibulopathy might masquerade the central vestibular syndrome and harbor a cerebellar stroke. However, the gravity-dependent nystagmus allows prompt identification of acute cerebellar infarct.

A Targeted Self-Management Approach for Reducing Stroke Risk Factors in African American Men Who Have Had a Stroke or Transient Ischemic Attack:

Purpose: This study compared a novel self-management (TargetEd MAnageMent Intervention [TEAM]) versus treatment as usual (TAU) to reduce stroke risk in African American (AA) men. Design: Six-month prospective randomized controlled trial with outcomes evaluated at baseline, 3 months, and 6 months. Setting: Academic health center. Participants: Thirty-eight (age < 65) AA men who had a stroke or transient ischemic attack and a Barthel index score of >60 were randomly assigned to TEAM (n = 19) or TAU (n = 19). Intervention: Self-management training, delivered in 1 individual and 4 group sessions (over 3 months). Measures: Blood pressure, glycosylated hemoglobin (HbA1c), lipids, medication adherence, weight, and standardized measures of health behaviors (diet, exercise, smoking, substances), depression, and quality of life. Qualitative assessments evaluated the perspectives of TEAM participants. Analysis: T tests for paired differences and nonparametric tests. Thematic content qualitative analysis. Results: Mean age was 52.1 (standard deviation [SD] = 7.4) and mean body mass index was 31.4 (SD = 7.4). Compared to TAU, TEAM participants had significantly lower mean systolic blood pressure by 24 weeks, and there was also improvement in HbA1c and high-density lipoprotein cholesterol (P = .03). Other biomarker and health behaviors were similar between groups. Qualitative results suggested improved awareness of risk factors as well as positive effects of group support.

Dynamic Angiographic Nature of Cerebral Mycotic Aneurysms in Patients With Infective Endocarditis.

A 41-year-old male with nonischemic cardiomyopathy and left ventricular assist device on coumadin presented with constitutional symptoms for 1 week. Blood cultures were drawn. The next day, he developed severe headache (Hunt–Hess grade II), and noncontrast head computed tomography (CT) showed Fisher grade II subarachnoid hemorrhage over bilateral frontal convexities. International Normalized Ratio was 9. The blood cultures grew methicillin-resistant Staphylococcus aureus within a day. He was diagnosed with an infected left ventricular assist device and started on intravenous vancomycin. Brain CT angiography was negative for any vessel abnormality. Cerebral angiography on post bleed day 1 showed areas of subocclusive emboli in the left M3 segment of the middle cerebral artery (MCA) and left pericallosal artery, but did not reveal any identifiable source for subarachnoid hemorrhage. On post bleed day 2, the patient developed left frontal seizures that eventually progressed to status epilepticus. Repeat CT head showed a new intraparenchymal hemorrhage within the left frontal operculum, measuring 1.8 cm in diameter. Repeat cerebral angiography on post bleed day 2 revealed a new left M3 fusiform mycotic aneurysm (MA) in the exact location of the previously seen left M3 segment embolus. The pericallosal branch embolus had progressed to near vessel occlusion rather than aneurysm formation. The patient’s family withdrew care because of his poor cardiac and neurological status (Figure 1).nnnnFigure 1. nInitial cerebral angiogram ( A ) showing subocclusive filling defects in the left pericallosal (black arrows) and M3 middle cerebral artery branch (white arrow) arteries. Follow-up angiography shows near occlusion of the left pericallosal branch ( B ), and fusiform mycotic aneurysmal dilatation of the previous left M3 lesion ( C and D ).nnnnA 31-year-old female with history of Tetrology of Fallot that had been repaired when she was a child, and previous infective endocarditis secondary to intravenous drug abuse requiring aortic valve replacement, …

Acute onset of upbeat nystagmus, exotropia, and internuclear ophthalmoplegia—A tell-tale of ponto-mesencephalic infarct

Two patients were assessed for acute onset of diplopia. Clinical examination revealed upbeat nystagmus, exotropia, and internuclear ophthalmoplegia (INO). Both patients had vascular risk factors; acute ischemic stroke affecting ponto-mesencephalic junction was suspected. Magnetic resonance imaging confirmed strategic location of the acute infarct affecting the medial longitudinal fasciculus, adjacent occulomotor nuclei, and paramedian tract. We propose that constellation of acute onset of upbeat nystagmus, INO, and exotropia in patients with vascular risk factors might be unequivocal manifestation of the ponto-mesencephalic stroke.

Stroke in the Young Patent Foramen Ovale and Pregnancy

A 27-year-old right-handed woman who was 2 weeks postpartum awoke with left-sided weakness and dysarthria. In the emergency room, her National Institutes of Health stroke scale was 4 with points received for a left-sided hemiparesis. Computed tomography of the brain was negative for hemorrhage and she was given aspirin 325 mg. Magnetic resonance imaging showed an ischemic stroke in the centrum semiovale. Magnetic resonance angiography of the head and neck showed no intracranial or extracranial atherosclerosis. Transthoracic echocardiography revealed a patent foramen ovale (PFO) with right to left shunt (Figure). Echocardiography was otherwise unremarkable. She had a low-density lipoprotein level of 153 mg/dL. A hypercoagulable workup (Factor V Leiden, methylenetetrahydrofolate reductase mutations 677C>T and 1298A>C, prothrombin factor II, antinuclear antibody, extractable nuclear antigens, anticardiolipin antibody, β2-glycoprotein, C-reactive protein, homocysteine, protein C and S, and protein electrophoresis with immunofixation) was unremarkable. She was started on aspirin and a statin. Anticoagulation was not considered because of persistent vaginal bleeding. The mechanism of the stroke was felt to be either small vessel disease or paradoxical embolism. She was discharged home with physical therapy.nnnnFigure. nOur patient’s transthoracic echocardiogram demonstrating agitated saline bubbles crossing from the left atrium to the right atrium within 5 cardiac cycles of injection ( A ) and subsequent bubbles seen in the left ventricle on next cardiac cycle ( B ).nnnnOne week later she complained of pain in the left lower extremity with calf tenderness. A venous duplex ultrasound was negative for deep vein thrombosis (DVT). However, 2 weeks later the left calf became swollen and a repeat ultrasound showed acute DVT involving the distal femoral, popliteal, and posterior tibial veins. She was admitted to the hospital and treated with intravenous heparin followed by oral warfarin. An intrauterine device was placed for birth control. She came to her follow-up appointment with questions …

Angioinvasive aspergillosis of the central nervous system.

Aspergillosis is usually seen in immunocompromised patients, but it may also occur in immunocompetent individuals. Invasion of intravascular aspergillus fungus hyphae in the central nervous system (CNS) causes multiple embolic infarcts. These organisms then erode the blood vessel, leading to hemorrhagic transformation, purulent necrosis, and lesion expansion without edema. Aspergillosis in the CNS has a peculiar radiological presentation. Exemplary MRI features suggestive of CNS aspergillosis are described here in a 50-year-old immunocompromised woman who was evaluated for altered awareness (Figure 1). The arrows in Figure 1A depict focal hyperintensity in diffusion-weighted imaging (DWI) and the hypointense correlation on apparent diffusion coefficient (ADC). Larger lesions had a core with a hypointense signal on DWI and a bright signal on ADC (Figure 1A, open arrows). The lesions were isointense on T1, but hyperintense on a fluid-attenuated inversion recovery sequence (Figure 1A, arrow). There was no contrast enhancement, edema, or midline shift. These findings suggested acute infarction with a purulent core, which is a possible manifestation of aspergillosis. Similar lesions affected multiple brain regions as noted in the MRI performed on day one (Figure 1B, top panel). The lesions were more abundant on day four, and the preexisting lesions expanded in size (Figure 1B, bottom panel). This constellation of MRI findings is typical for CNS aspergillosis. Autopsy confirmed disseminated aspergillosis of the brain, lung, and thyroid (Figure 1C). A differential diagnosis for such presentation includes metastatic tumors, multiple infarcts resulting from septic bacterial emboli, or embolic shower from a cardiac thrombus. Rapid progression, as seen in our patient, is not typical for metastatic tumors, but sometimes it is difficult to differentiate abscess resulting from aspergillosis from that resulting from a neoplastic process. Ischemic infarcts from cardiogenic emboli may increase in number and involve spatially independent locations, but they do not increase in size, except in cases in which ischemic penumbra is converted to a complete infarct. Hemorrhagic conversion of an ischemic lesion resulting from septic bacterial emboli is also possible, but malignant expansion as seen in aspergillosis is less likely.

Peroxisome Proliferator-Activated Receptor Gamma Agonists

Inflammatory processes play a central role in a number of diseases afflicting the nervous system. There is considerable controversy over whether inflammatory mechanisms are the cause or consequence of neurodegenerative changes. Moreover, if inflammatory changes are secondary to more primary neuropathological changes, do they exacerbate neuronal dysfunction and promote cell death? In some neurological diseases, the inflammatory cells are the primary effectors of the pathology; for example, in multiple sclerosis, T cells direct macrophage-mediated loss of myelin. In other diseases such as stroke, peripheral leukocytes are recruited to the lesion site along with the parallel activation of the endogenous microglia. These cells act in concert to mount a robust pro-inflammatory response that greatly expands and exacerbates the primary infarct. Traumatic brain injury is also associated with inflammatory cell infiltration and induction of a local inflammatory response. More recently, human immunodeficiency virus (HIV) and CreutzfeldtJakob disease have been shown to have an inflammatory component arising secondary to the primary neuropathological process. The involvement of an inflammatory component in the etiology of Alzheimer’s disease (AD) has recently received considerable attention (1). Indeed, the only demonstrated effective therapy for AD patients is long-term treatment with nonsteroidal anti-inflammatory drugs (NSAIDs). The mechanistic basis of the efficacy of NSAIDs in AD remains unclear. However, the recent recognition that NSAIDs can bind to and activate the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) has offered an explanation for the efficacy of these drugs in AD and has opened new therapeutic approaches to this disease. Indeed, the newly appreciated anti-inflammatory actions of PPARγ agonists may allow novel therapies for other central nervous system (CNS) indications with an inflammatory component.

Inflammatory Mechanisms in Alzheimer’s Disease: β-Amyloid-Stimulated Proinflammatory Responses are Blocked by PPARγ Agonists

The pathogenesis of Alzheimer’s disease (AD) involves inflammatory processes as evidenced by the presence of abundant reactive microglia and their secretory products in the brain. Moreover, individuals on long-term nonsteroidal anti-inflammatory drug (NSAID) treatments exhibit a dramatic (60%) reduction of risk for AD, reduced symptomatic severity, and delayed progression of the disease. An unappreciated target of NSAIDs action is the transcription factor, peroxisome proliferator activated receptor gamma (PPARγ), whose transcriptional actions are activated upon binding of these drugs, its natural lipid ligands and drugs of the thiazolidinedione class. PPARγ binds to the promoter elements of a number of proinflammatory genes and regulates their expression. Exposure of microglia or monocytes to fibrillar forms of Aβ results in the activation of complex tyrosine kinase-based signaling cascades resulting in a broad range of proinflammatory responses. We report that exposure of monocytes and microglia to PPARγ agonists inhibited the Aβ-stimulated synthesis of the cytokines TNFα and IL-6, and blocked the induction of cyclooxygenase-2 expression. PPARγ agonists blocked the Aβ-mediated secretion of microglial proinflammatory products responsible for neurotoxicity and astrogliosis. Moreover, PPARγ agonists suppressed the Aβ stimulated expression of the complement receptor MAC1 by microglia and blocked macrophage differentiation. These data provide evidence that PPARγ plays a critical role regulating the inflammatory responses of microglia and monocytes to Aβ.