A case of posterior cortical atrophy with vertical neglect.

Posterior cortical atrophy (PCA) is a syndrome caused by a neurodegenerative disease that often presents with visuospatial deficits, and can be debilitating. PCA is often characterized by elements of Balint's syndrome and dyslexia. The most common underlying pathology has been found to be Alzheimer's disease. Signs of horizontal neglect are frequently associated with PCA, but the presence of vertical (or altitudinal) neglect has not yet been reported in a patient with PCA or other forms of neurodegenerative dementia. In this paper, we present a patient with PCA who on vertical line bisection and cancellation tests revealed upper altitudinal spatial neglect. Detection of this abnormality may have important implications for diagnosis, therapeutic interventions, and patient safety.

Subclinical cerebrovascular disease inversely associates with learning ability: The NOMAS.

OBJECTIVE: Memory has been examined in subjects with imaging markers of cerebrovascular disease, but learning has been less well studied. We examined the relationship among subclinical cerebrovascular disease, cerebral volumes, and verbal learning in an ethnically and racially diverse community sample. METHODS: A clinically stroke-free subset of Northern Manhattan Study participants underwent cognitive testing and brain MRI with quantification of white matter hyperintensity volume (WMHV) and total cerebral volume (TCV) using semiautomated segmentation. We used generalized linear regression and mixed models to examine the association between imaging findings and verbal learning. RESULTS: There were 1,272 participants (61% women, mean age 70 ± 9 years). Participants with greater WMHV and smaller TCV remembered fewer total words on a list-learning task (ß = -0.83 per SD change in WMHV, 95% confidence interval [CI] = -1.22 to -0.45, p < 0.0001; and ß = 0.48 per SD change in TCV, 95% CI = 0.05 to 0.90, p = 0.03, respectively). Subclinical brain infarction (SBI) was not associated with total words learned (ß = -0.04, 95% CI = -1.08 to 1.00, p = 0.94). Those with greater WMHV had increased odds of a flatter learning slope. After excluding participants with SBI, the association between total words learned and WMHV remained significant. All measurements were adjusted for age, education, race/ethnicity, medical insurance status, and the presence of SBI. CONCLUSIONS: White matter hyperintensities, a marker of cerebral small vessel disease, may have an impact on learning slope. This suggests that verbal learning performance can be incorporated into neuropsychological measures for vascular cognitive impairment and that cerebrovascular disease discovered on imaging affects the ability to learn new information.

Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative cause of dementia and is responsible for significant individual morbidity and mortality, and economic impact on the health care system. Neurodegeneration (including neuronal atrophy and/or loss) are attributed to extraneuronal toxic amyloid oligomers and proteins, intraneuronal neurofibrillary tangles consisting of hyperphosphorylated tau, region-specific diminished cerebral glucose metabolism, synaptic dysfunction, and mitochondrial dysfunction. Several of these pathologic changes may occur decades before symptom onset, leaving ample time for implementing prevention strategies that target the earliest stages of the disease. In recent years, a myriad of modifiable and nonmodifiable risk factors have been elucidated. We describe the latest criteria for the diagnosis of AD, including earliest diagnostic stage of preclinical AD, which has the highest potential for research, including diagnosis and disease modification. We discuss both FDA-approved pharmacologic treatments, as well as nonpharmacologic strategies for AD therapeutics, including prevention via evidence-based, low-risk interventions. Genotype is an important consideration in managing patients on the AD continuum, as presence of the APOE ε4 allele may influence response to treatment. We present the most current evidence relating to pharmacogenomics, nutrigenomics, and distinctive nutritional requirements targeted toward AD.

Effect of hypercholesterolemia on myocardial necrosis and apoptosis in the setting of ischemia-reperfusion.

BACKGROUND: Hypercholesterolemia is prevalent in patients who experience myocardial ischemia-reperfusion injury (IR). We investigate the impact of dietary-induced hypercholesterolemia on the myocardium in the setting of acute IR. METHODS AND RESULTS: In normocholesterolemic (NC, n=7) and hypercholesterolemic (HC, n=7) Yucatan male pigs, the left anterior descending coronary artery was occluded for 60 minutes, followed by reperfusion for 120 minutes. Hemodynamic values were recorded, and TTC staining was used to assess necrosis. Oxidative stress was measured. Specific cell death and survival signaling pathways were assessed by Western blot and TUNEL staining. Infarct size was 45% greater in HC versus NC (42% versus 61%, P<0.05), whereas the area at risk (AAR) was similar in both groups (P=0.61). Whereas global LV function (+dP/dt, P<0.05) was higher during entire period of IR in HC versus NC, regional function deteriorated more following reperfusion in HC (P<0.05). Ischemia increased indices of myocardial oxidative stress such as protein oxidation (P<0.05), lipid peroxidation (P<0.05), and nitrotyrosylation in HC versus NC, as well as the expression of phospho-eNOS (P<0.05). The expression of myeloperoxidase, p38 MAPK, and phospho-p38 MAPK was higher in HC versus NC (all P<05). Ischemia caused higher expression of the proapoptotic protein PARP (P<0.05), and lower expression of the prosurvival proteins Bcl2 (P<0.05), phospho-Akt, (P<0.05), and phospho-PKCepsilon (P<0.05) in the HC versus NC. TUNEL-positive cell count was 3.8-fold (P<0.05) higher in the AAR of HC versus NC. CONCLUSIONS: This study demonstrates that experimental hypercholesterolemia is associated with increased myocardial oxidative stress and inflammation, attenuation of cell survival pathways, and induction of apoptosis in the ischemic territory, which together may account for the expansion of myocardial necrosis in the setting of acute IR.

Effect of hydrogen sulfide in a porcine model of myocardial ischemia-reperfusion: comparison of different administration regimens and characterization of the cellular mechanisms of protection.

OBJECTIVE: We investigate the impact of different regimens of parenteral hydrogen sulfide (H2S) administration on myocardium during ischemia-reperfusion (IR) and the molecular pathways involved in its cytoprotective effects. METHODS: Eighteen male Yorkshire pigs underwent 60 minutes of mid-left anterior descending coronary artery occlusion followed by 120 minutes of reperfusion. Pigs received either placebo (control, n = 6) or H2S as a bolus (bolus group, n = 6, 0.2 mg/kg over 10 seconds at the start of reperfusion) or as an infusion (infusion group, n = 6, 2 mg.kg.h initiated at the onset of ischemia and continued into the reperfusion period). Myocardial function was monitored throughout the experiment. The area at risk and myocardial necrosis was determined by Monastral blue/triphenyl tetrazolium chloride staining. Apoptosis and the expression pattern of various intracellular effector pathways were investigated in the ischemic territory. Coronary microvascular reactivity to endothelium-dependent and endothelium-independent factors was measured. RESULTS: H2S infusion but not bolus administration markedly reduce myocardial infarct size (P < 0.05) and improve regional left ventricular function, as well as endothelium-dependent and endothelium-independent microvascular reactivity (P < 0.05). The expression of B-cell lymphoma 2 (P = 0.059), heat shock protein 27 and alphaB-crystallin (P < 0.05) were lower in H2S-treated groups. Infusion of H2S caused higher expression of phospho-glycogen synthase kinase-3 beta isoform(P < 0.05) and lower expression of mammalian target of rapamycin and apoptosis-inducing factor (P < 0.05). Bolus of H2S caused higher expression of phospho-p44/42 MAPK extracellular signal-regulated kinase and lower expression of Beclin-1 (P < 0.05). The expression of caspase 3 and cleaved caspase 3 were lower (P < 0.05), whereas the expression of phospho-Bad(Ser136) was higher in the bolus group versus control and infusion groups (P < 0.05). The terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cell count was lower in both H2S-treated groups compared with the control (P < 0.05). CONCLUSIONS: This study demonstrates that infusion of H2S is superior to a bolus alone in reducing myocardial necrosis after IR injury, even though some markers of apoptosis and autophagy were affected in both H2S-treated groups. Thus, the current results indicate that infusion of H2S throughout IR may offer better myocardial protection from IR injury.

Effect of thrombin fragment (TP508) on myocardial ischemia-reperfusion injury in hypercholesterolemic pigs.

Myocardial ischemia-reperfusion (IR) injury occurs frequently in the setting of hypercholesterolemia. We investigated the potential efficacy of a novel thrombin fragment (TP508) on IR injury in a hypercholesterolemic porcine model. Twenty-one hypercholesterolemic male Yucatan pigs underwent 60 min of mid-left anterior descending coronary artery occlusion followed by 120 min of reperfusion. Pigs received either placebo (control, n = 7) or TP508 in two doses (TP508 low dose, n = 7, as bolus of 0.5 mg/kg 50 min into ischemia and an infusion of 1.25 mg.kg(-1).h(-1) during reperfusion period or TP508 high dose, n = 7, a double dose of TP508 low-dose group). Myocardial function was monitored throughout the experiment. The area at risk and myocardial necrosis were determined by Monastryl blue/triphenyl tetrazolium chloride staining. Apoptosis in the ischemic territory was assessed. Coronary microvascular reactivity to endothelium-dependent and -independent factors was measured. Myocardial necrosis was lower in both TP508-treated groups vs. control (P < 0.05). Regional left ventricular function was improved only in the TP508 high-dose group (P < 0.05). Endothelium-dependent coronary microvascular reactivity was greater in both TP508-treated groups (P < 0.05) vs. control. The expression of proteins favoring cell survival, 90-kDa heat shock protein and phospho-Bad (Ser112) was higher in the TP508 high-dose group (P < 0.05). The expression of the cell death signaling proteins, cleaved caspase-3 (P < 0.05), apoptosis-inducing factor (P < 0.05), and poly-ADP ribose polymerase (P = 0.07) was lower in the TP508 low-dose group vs. TP508 high-dose and control. The terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling positive cell count was lower in both TP508 groups compared with the control (P < 0.05). This study demonstrates that, in hypercholesterolemic pigs, TP508 decreases myocardial necrosis and apoptosis after IR. Thus TP508 may offer a novel approach in protecting the myocardium from IR injury.

Hypercholesterolemia is associated with hyperactive cardiac mTORC1 and mTORC2 signaling.

Nutritional excess and hyperlipidemia increase the heart's susceptibility to ischemic injury. Mammalian target of rapamycin (mTOR) controls the cellular response to nutritional status and may play a role in ischemic injury. To explore the effect of hypercholesterolemia on cardiac mTOR signaling, we assessed mTOR signaling in hypercholesterolemic swine (HC) that are also susceptible to increased cardiac ischemia-reperfusion injury. Yucatan pigs were fed a high-fat/high-cholesterol diet for 4 weeks to induce hypercholesterolemia, and mTOR signaling was measured by immunoblotting and immunofluorescence in the non-ischemic left ventricular area. Total myocardial mTOR and raptor levels were markedly increased in the HC group compared to the normocholesterolemic group, and directly correlated with serum cholesterol levels. mTOR exhibited intense perinuclear staining in myocytes only in the HC group. Hypercholesterolemia was associated with hyperactive signaling upstream and downstream of both mTOR complexes, including myocardial Akt, S6K1, 4EBP1, S6 and PKC-alpha, increased levels of cardiac hypertrophy markers, and a trend toward lower levels of myocardial autophagy. Hypercholesterolemia can now be added to the growing list of conditions associated with aberrant mTOR signaling. Hypercholesterolemia produces a unique profile of alterations in cardiac mTOR signaling, which is a potential target in cardiac diseases associated with hypercholesterolemia and nutritional excess.