Posterior cortical atrophy of a suspected non-Alzheimer type: a case report.

OBJECTIVE: A case of Posterior Cortical Atrophy syndrome of a suspected non-Alzheimer disease pathology type is presented to illustrate prospective diagnosis and course. METHOD: A 54-year-old woman with vague memory complaints underwent serial neuropsychological assessment, MRI, PET, and CSF screening; data are reviewed. RESULTS: While early diagnosis was confounded by multiple factors, classic visuospatial symptoms were later demonstrated using routine neuropsychological methods. Serial MRI, PET, and CSF screening argued strongly for an alternative underlying pathology to AD. At age 59, her condition had progressed to dementia. CONCLUSIONS: Findings underscore the need for further research on suspected non-amyloid-based pathologies.

The feasibility of establishing a free clinic for uninsured patients with neurologic disorders.

The Dream Center Neurology Clinic (DCNC) is a free specialty clinic associated with the Medical University of South Carolina that provides health care for uninsured patients with neurologic disorders. Routine neurologic care is often neglected by free primary care clinics, leaving indigent and uninsured patients to suffer from treatable neurologic ailments. The DCNC was established by supplementing existing resources from a free primary care facility called the Dream Center. Our strategy of building a high-need specialty service into a preexisting primary care infrastructure may provide a blueprint for neurologists who are eager to address the neurologic needs of the underserved in their local communities. According to local charge estimates, the DCNC has provided roughly $120,000 worth of outpatient neurologic care over the past year. The clinic runs through the collaborative effort of medical students as well as academic and private health care providers. Donated services such as EEG, diagnostic lab work, botulinum toxin, supplies, and imaging are also critical to clinic operations. In addition to providing the uninsured with services that are normally inaccessible to them, the DCNC provides a unique educational opportunity for medical students, residents, and all volunteers who are eager to help and learn.

Creatinine metabolite, HMH (5-hydroxy-1-methylhydantoin; NZ-419), modulates bradykinin-induced changes in vascular smooth muscle cells.

A creatinine metabolite, 5-hydroxy-1-methylhydantoin (HMH: NZ-419), a hydroxyl radical scavenger, has previously been shown to confer renoprotection by inhibiting the progression of chronic kidney disease in rats. In the current study, we demonstrate that HMH modulates the effects of glucose and bradykinin (BK) in vascular smooth muscle cell (VSMC). HMH a novel anti-oxidant drug completely suppressed the expression of B2-kinin receptors (B2KR) in response to high glucose (25 mM) stimulation in VSMC and was also shown to attenuate the effects of BK on VSMC remodeling. HMH inhibited the BK-induced increase in MAPK phosphorylation and attenuated the increase in connective tissue growth factor (CTGF) protein levels in VSMC. These findings suggest that HMH may confer vascular protection against high glucose concentrations and BK-stimulation to ameliorate vascular injury and remodeling through its anti-oxidant properties.

Spinal cord neurosarcoidosis.

BACKGROUND: Spinal cord neurosarcoidosis (SN) is problematic to diagnose because it mimics other inflammatory neurologic diseases. The authors report the clinical features of 29 SN cases. METHODS: They retrospectively reviewed the medical records of 29 histologically proven sarcoidosis patients with spinal cord involvement seen at 3 university medical centers. They collected clinical data including laboratory and radiological findings. Clinical outcomes were assessed retrospectively using the modified Rankin scale. RESULTS: The cohort included high number of African Americans (16/29, 55%). The lung and intrathoracic lymph nodes were the most common confirmatory biopsy sites (18/29, 62%), whereas the spinal cord was a relatively uncommon one (4/29, 14%). The most common presenting symptoms were lower extremity weakness and paresthesias. Thoracic segment was most frequently involved (21/27, 78%). Lesions were mostly intramedullary (22/27, 81%), although nearly half involved the leptomeninges (13/27, 48%). The average size of a lesion spanned 3.9 spine segments (range, 1-9); 17 of 22 (77%) intramedullary patients had ≥3 spine segments involved. Angiotensin-converting enzyme levels in cerebrospinal fluid were elevated in only 2 of 11 (18%) patients. All patients received glucocorticosteroids. Additional immune-modulating agents were used in 24 of 29 (83%) patients. Scores on the modified Rankin scale at the final follow-up visit were improved. CONCLUSIONS: Most SN cases were diagnosed indirectly based on extraneural tissue biopsy. Extended spinal cord lesion (≥3 spine segments) may be useful to distinguish SN from multiple sclerosis. Cerebrospinal fluid analysis was of limited value. Most patients experienced clinical improvement with immunosuppressive treatment, but many required combination therapy.

Isolated neurosarcoidosis: case series in 2 sarcoidosis centers.

BACKGROUND: Neurosarcoidosis occurs in the central or peripheral nervous system and is usually associated with other sarcoidosis organ involvement. However, when sarcoidosis develops exclusively in the nervous system, its diagnosis is problematic. METHODS: Retrospective analysis of patients who were histologically diagnosed with neurosarcoidosis without other organ involvement (isolated neurosarcoidosis) at Medical University of South Carolina and Allegheny General Hospital. For comparison, we also collected data from neurosarcoidosis patients with histologic evidence in an extraneural organ (systemic neurosarcoidosis). RESULTS: Ninety-one cases of neurosarcoidosis were identified with 10 patients having isolated neurosarcoidosis. Common clinical manifestations of the isolated neurosarcoidosis patients were headache (9), paresthesia (5), and cranial neuropathies (4). All isolated neurosarcoidosis patients underwent a biopsy from the central nervous system. The prebiopsy impression included lymphoma (4), tumor (2), and sarcoidosis (2). In all patients, no extranueral sarcoidosis developed during a relatively long follow-up period (mean 58 mo). Compared with the systemic neurosarcoidosis cohort (60), isolated neurosarcoidosis patients had similar demographics and neurological manifestations with a few exceptions including a more common frequency of headache, hemiparesis, and radiculopathy, leptomeningeal involvement on brain MRI, increased cell count in cerebrospinal fluid, and a more favorable clinical outcome (P<0.05). The duration of follow-up and the number of studies performed to evaluate patients for extraneural sarcoidosis were similar in the 2 cohorts. CONCLUSIONS: The clinical and radiologic features of isolated neurosarcoidosis are similar to those of systemic neurosarcoidosis with a few exceptions. The diagnosis of isolated neurosarcoidosis is problematic and often not considered before biopsy of neural tissue.

Low-density lipoprotein induced expression of connective tissue growth factor via transactivation of sphingosine 1-phosphate receptors in mesangial cells.

The pro-fibrotic connective tissue growth factor (CTGF) has been linked to the development and progression of diabetic vascular and renal disease. We recently reported that low-density lipoproteins (LDL) induced expression of CTGF in aortic endothelial cells. However, the molecular mechanisms are not fully defined. Here, we have studied the mechanism by which LDL regulates CTGF expression in renal mesangial cells. In these cells, treatment with pertussis toxin abolished LDL-stimulated activation of ERK1/2 and c-Jun N-terminal kinase (JNK), indicating the involvement of heterotrimeric G proteins in LDL signaling. Treatment with LDL promoted activation and translocation of endogenous sphingosine kinase 1 (SK1) from the cytosol to the plasma membrane concomitant with production of sphingosine-1-phosphate (S1P). Pretreating cells with SK inhibitor, dimethylsphinogsine or down-regulation of SK1 and SK2 revealed that LDL-dependent activation of ERK1/2 and JNK is mediated by SK1. Using a green fluorescent protein-tagged S1P1 receptor as a biological sensor for the generation of physiologically relevant S1P levels, we found that LDL induced S1P receptor activation. Pretreating cells with S1P1/S1P3 receptor antagonist VPC23019 significantly inhibited activation of ERK1/2 and JNK by LDL, suggesting that LDL elicits G protein-dependent activation of ERK1/2 and JNK by stimulating SK1-dependent transactivation of S1P receptors. Furthermore, S1P stimulation induced expression of CTGF in a dose-dependent manner that was markedly inhibited by blocking the ERK1/2 and JNK signaling pathways. LDL-induced CTGF expression was pertussis toxin sensitive and inhibited by dimethylsphinogsine down-regulation of SK1 and VPC23019 treatment. Our data suggest that SK1-dependent S1P receptor transactivation is upstream of ERK1/2 and JNK and that all three steps are required for LDL-regulated expression of CTGF in mesangial cells.

Apoptosis induction by oxidized glycated LDL in human retinal capillary pericytes is independent of activation of MAPK signaling pathways.

BACKGROUND: Pericyte loss is a cardinal feature of early diabetic retinopathy. We previously reported that highly oxidized-glycated low density lipoprotein (HOG-LDL) induces pericyte apoptosis in vitro. In this study, we investigated the role of the mitogen-activated protein kinase (MAPK) signaling pathways in HOG-LDL-induced apoptosis in human pericytes. METHODS: Human retinal capillary pericytes (HRCP) were exposed to native LDL (N-LDL) and HOG-LDL, and apoptosis was measured using flow cytometry. Time- and dose-dependent responses of extracellular signal-regulated kinase (ERK), p38, and Jun N-terminal kinase (JNK) following exposure to N-LDL or HOG-LDL were determined using western blotting. U0126 (ERK inhibitor), SB203580 (p38 inhibitor), and SP600125 (JNK inhibitor) were used to determine the role of MAPK signaling in HOG-LDL-induced apoptosis. RESULTS: HOG-LDL induced apoptosis in HRCP in a dose-dependent manner at concentrations from 5 to 50 mg/l, with a constant effect from 50 to 200 mg/l. When compared to serum-free medium (SFM), this effect of HOG-LDL was found to be significant at all doses above 10 mg/l. In contrast, N-LDL at 200 mg/l did not induce apoptosis compared with SFM. Exposure to N-LDL versus HOG-LDL induced similar phosphorylation of ERK, p38, and JNK, peaking at 5 min, with similar dose-dependent responses up to 25 mg/l that were constant from 25 to 100 mg/l. Blocking of the ERK, p38, and JNK pathways did not inhibit pericyte apoptosis induced by HOG-LDL. CONCLUSIONS: Our data suggest that apoptosis induced by HOG-LDL in HRCP is independent of the activation of MAPK signaling pathways.

Mechanisms of low-density lipoprotein-induced expression of connective tissue growth factor in human aortic endothelial cells.

Hyperlipidemia is a recognized risk factor for atherosclerotic vascular disease. The underlying mechanisms that link lipoproteins and vascular disease are undefined. Connective tissue growth factor (CTGF) is emerging as a key determinant of progressive fibrotic diseases, and its expression is upregulated by diabetes. To define the mechanisms through which low-density lipoproteins (LDL) promote vascular injury, we evaluated whether LDL can modulate the expression of CTGF and collagen IV in human aortic endothelial cells (HAECs). Treatment of HAECs with LDL (50 microg/ml) for 24 h produced a significant increase in the mRNA and the protein levels of CTGF and collagen IV compared with unstimulated controls. To explore the mechanisms by which LDL regulates CTGF and collagen IV expression in HAECs, we determined first if CTGF and collagen IV are downstream targets for regulation by transforming growth factor-beta (TGF-beta). The results demonstrated that TGF-beta produced a concentration-dependent increase in the protein levels of CTGF. To assess whether the induction of CTGF in response to LDL is mediated via autocrine activation of TGF-beta, HAECs were treated with LDL for 24 h in the presence and absence of anti-TGF-beta neutralizing antibodies (anti-TGF-beta NA). The results demonstrated that the increase in CTGF induced by LDL was significantly inhibited by the anti-TGF-beta NA. To investigate the upstream mediators of TGF-beta on activity of CTGF in response to LDL, HAECs were treated with LDL for 24 h in the presence and absence of cell-permeable MAPK inhibitors. Inhibition of p38(mapk) activities did not affect LDL-induced TGF-beta1, CTGF, and collagen IV expression. On the other hand, SP-600125, a specific inhibitor of c-Jun NH(2)-terminal kinase, suppressed LDL-induced TGF-beta, CTGF, and collagen IV expression, and PD-98059, a selective inhibitor of p44/42(mapk), suppressed LDL-induced TGF-beta and CTGF expression. These findings are the first to implicate the MAPK pathway and TGF-beta as key players in LDL signaling, leading to CTGF and collagen IV expression in HAECs. The data also point to a potential mechanistic pathway through which lipoproteins may promote vascular injury.

Evidence for low-density lipoprotein-induced expression of connective tissue growth factor in mesangial cells.

BACKGROUND: Although hyperlipidemia is a risk factor for the progression of renal damage, the relationship between increased plasma lipoproteins and glomerular injury is poorly defined. Connective tissue growth factor (CTGF) is emerging as a key determinant of progressive fibrotic diseases and its expression is up-regulated by diabetes. To define the mechanisms through which low-density lipoproteins (LDLs) promote glomerular injury, we evaluated whether LDL can modulate the expression of CTGF and collagen I. METHODS: The effects of LDL on CTGF and collagen I expression were carried out in rat mesangial cells. RESULTS: Treatment of mesangial cells with LDL for 24 hours produced a significant increase in the protein levels of CTGF and collagen I compared to unstimulated controls. To explore if CTGF and collagen I are downstream targets for regulation by transforming growth factor-beta (TGF-beta), mesangial cells were treated with various concentration of TGF-beta for 24 hours. TGF-beta produced a concentration-dependent increase in the protein levels of CTGF and collagen I. The increase in CTGF and collagen I induced by LDL was significantly inhibited by neutralizing anti-TGF-beta antibodies. Inhibition of p38(mapk) or p42/44(mapk) activities did not affect LDL-induced TGF-beta1, CTGF, and collagen I expression, whereas inhibition of c-Jun NH2-terminal kinase (JNK) suppressed LDL-induced TGF-beta, CTGF, and collagen I expression. CONCLUSION: These findings implicate JNK pathway and TGF-beta1 as key players in LDL signaling leading to CTGF and collagen I expression in mesangial cells. The data also point to a potential mechanistic pathway through which lipoproteins may promote glomerular injury.

Nephropathy in a hypercholesterolemic mouse model with streptozotocin-induced diabetes.

BACKGROUND/AIMS: The contribution of preexisting hypercholesterolemia to diabetic nephropathy remains unclear. We assessed the impact of hypercholesterolemia on diabetic nephropathy using a double knockout (DKO) mouse, null for the low-density lipoprotein receptor (LDLRNDASH;/NDASH;) and the apoB mRNA editing catalytic polypeptide 1 (APOBEC1NDASH;/NDASH;). METHODS: Wild-type (WT) and DKO mice received sham or streptozotocin injections at age 7 weeks, yielding control (WT-C, DKO-C) and diabetic (WT-D, DKO-D) groups. At sacrifice (age 40 weeks), albuminuria was determined by ELISA, and kidney sections were examined by light and electron microscopy. RESULTS: Albuminuria increased in diabetic mice (WT-D: 82.4 +/- 37.2 microg/18 h; DKO-D: 58.0 +/- 45.7 microg/18 h) versusnondiabetic controls (WT-C: 10.2 +/- 7.2 microg/18 h; DKO-C: 8.6 +/- 5.3 microg/18 h) (p LT; 0.0001), but was unaffected by hypercholesterolemia. Light microscopy of kidney sections demonstrated increased collagen levels in glomeruli in WT-D mice, but not in DKO-D mice or either control group. Electron microscopy showed a thickened glomerular basement membrane in WT-D mice only. The proximal tubular basement membrane thickness was increased in both diabetic groups versusnondiabetic controls (p LT; 0.01); in WT-D mice this was attributable to collagen accumulation, but in DKO-D mice it was mainly caused by lipid vacuoles. CONCLUSIONS: In this animal model, preexisting hypercholesterolemia did not exacerbate either glomerular lesions of diabetes (collagen accumulation, basement membrane thickening) or albuminuria, but appeared to mitigate these effects. Furthermore, the combination of hypercholesterolemia and diabetes resulted in a significant lipid accumulation in the tubular basement membrane.