Sónia Costa

Genetic and biochemical markers in patients with Alzheimer's disease support a concerted systemic iron homeostasis dysregulation

Alzheimers disease (AD) is the most common form of dementia in the elderly individuals, resulting from a complex interaction between environmental and genetic factors. Impaired brain iron homeostasis has been recognized as an important mechanism underlying the pathogenesis of this disease. Nevertheless, the knowledge gathered so far at the systemic level is clearly insufficient. Herein, we used an integrative approach to study iron metabolism in the periphery, at both genotypic and phenotypic levels, in a sample of 116 patients with AD and 89 healthy control subjects. To assess the potential impact of iron metabolism on the risk of developing AD, genetic analyses were performed along with the evaluation of the iron status profile in peripheral blood by biochemical and gene expression studies. The results obtained showed a significant decrease of serum iron, ferritin, and transferrin concentrations in patients compared with the control subjects. Also, a significant decrease of ferroportin (SLC40A1) and both transferrin receptors TFRC and TFR2 transcripts was found in peripheral blood mononuclear cells from patients. At the genetic level, significant associations with AD were found for single nucleotide polymorphisms in TF, TFR2, ACO1, and SLC40A1 genes. Apolipoprotein E gene, a well-known risk factor for AD, was also found significantly associated with the disease in this study. Taken together, we hypothesize that the alterations on systemic iron status observed in patients could reflect an iron homeostasis dysregulation, particularly in cellular iron efflux. The intracellular iron accumulation would lead to a rise in oxidative damage, contributing to AD pathophysiology.

Rapidly progressive corticobasal degeneration syndrome.

Introduction: Corticobasal syndrome (CBS) has a heterogeneous clinical presentation with no specific pathologic substratum. Its accurate diagnosis is a challenge for neurologists; in order to establish CBS definitively, postmortem confirmation is required. Some clinical and radiological features can help to distinguish it from other neurodegenerative conditions, such as Creutzfeldt-Jakob disease (CJD). Clinical Case: A 74-year-old woman presented with language impairment, difficulty in walking and poor attentiveness that had begun 10 days before. Other symptoms, such as asymmetrical extra-pyramidal dysfunction, limb dystonia and ‘alien limb’ phenomena, were established over the next 2 months, with rapid progression. Death occurred 3 months after symptom onset. Laboratory results were normal. Initially, imaging only showed restricted diffusion with bilateral parieto-occipital gyri involvement on DWI-MRI, with unspecific EEG changes. An autopsy was performed. Brain neuropathology confirmed sporadic CJD (sCJD). Conclusions: CBS is a heterogeneous clinical syndrome whose differential diagnosis is extensive. CJD can occasionally present with clinical characteristics resembling CBS. MRI detection of abnormalities in some sequences (FLAIR, DWI), as previously reported, has high diagnostic utility for sCJD diagnosis – especially in early stages – when other tests can still appear normal. Abnormalities on DWI sequencing may not correlate with neuropathological findings, suggesting a functional basis to explain the changes found.

Transient Spinal Cord Ischemia as Presenting Manifestation of Polycythemia Vera

Spinal arterial vascularization is supplied by a large anastomotic net, making spinal ischemic events far less common than ischemic cerebral strokes. Polycythemia vera, due to blood hyperviscosity and activated platelet aggregation, is associated with a higher risk of arterial and venous thrombotic events. We report a patient with spinal cord transient ischemic attacks, a rarely presenting manifestation, and polycythemia vera, which highlights the thrombotic potential of this disease, and the requirement of exhaustive diagnostic workout of a spinal ischemic event.

Decrease in APP and CP mRNA expression supports impairment of iron export in Alzheimer's disease patients.

Alzheimers disease (AD) is a neurodegenerative disorder of still unknown etiology and the leading cause of dementia worldwide. Besides its main neuropathological hallmarks, a dysfunctional homeostasis of transition metals has been reported to play a pivotal role in the pathogenesis of this disease. Dysregulation of iron (Fe) metabolism in AD has been suggested, particularly at the level of cellular iron efflux. Herein, we intended to further clarify the molecular mechanisms underlying Fe homeostasis in AD. In order to achieve this goal, the expression of specific Fe metabolism-related genes directly involved in Fe regulation and export was assessed in peripheral blood mononuclear cells (PBMCs) from 73AD patients and 74 controls by quantitative PCR. The results obtained showed a significant decrease in the expression of aconitase 1 (ACO1; P=0.007); ceruloplasmin (CP; P<0.001) and amyloid-beta precursor protein (APP; P=0.006) genes in AD patients compared with healthy volunteers. These observations point out to a significant downregulation in the expression of genes associated with ferroportin-mediated cellular Fe export in PBMCs from AD patients, when compared to controls. Taken together, these findings support previous studies suggesting impairment of Fe homeostasis in AD, which may lead to cellular Fe retention and oxidative stress, a typical feature of this disease.

23-year-old man with a superficial cortical brain tumor.

A 23-year-old male presented with a tonic-clonic generalized seizure. Neuroradiological examination revealed a superficial cystic mass with a mural nodule in the right fronto-parietal lobe. Histological and immunohistochemical examination were consistent with a pigmented (melanin producing) desmoplastic ganglioglioma.These tumors have been first described in childhood, one of them displaying melanin deposits. Only twenty cases of non-infantile desmoplastic gangliogliomas have been reported in the literature, none of them pigmented. According to the clinical and histomorphology (including the desmoplastic component) features, the differential diagnosis should include the ganglioglioma, the xanthoastrocytoma pleomorphic (both tumors also with pigmented forms) and the superficial desmoplastic infantile astrocytoma.

Treatment of Adult Meningitis and Complications

The most common and often most severe forms of meningitis are due to infections, including bacteria, viruses, fungi, and parasites. Noninfectious causes of meningitis include primary inflammatory syndromes such as vasculitis and connective tissue disease, neoplasms of solid tumor and hematologic forms, and chemical irritants including certain medications, subarachnoid blood, and biologic matter spilling into CSF from tumors.

Neurofibromatosis - Diagnostic Assessment

Descriptions of individuals supposed to have neurofibromatosis have been discovered in manuscripts dating from 1000 AD (Zanca, 1980). However, it was not until 1881 that Von Recklinghausen coined the term ‘‘neurofibroma’’ when he observed that this benign tumour arose from the peripheral nerve sheath. His colleagues honored his contribution by naming the condition Von Recklinghausen’s disease. However, the different forms of neurofibromatosis were not separated and delineated until the latter part of the twentieth century (Ferner et al., 2007a). Neurofibromatosis is one of the called “neurocutaneous disorders” or “phakomatoses”, genetic diseases that involve both skin and the nervous system. They share some features: hereditary transmission, involvement of organs of ectodermal origin and a tendency to develop certain types of central and peripheral nervous system tumours. Advances in clinical genetics allowed to separate neurofibromatosis in two diseases, each caused by a different gene, although recognition still requires an appreciation of the cutaneous and systemic symptoms. (Ferner 2007a, 2010)

Leukoencephalopathy and microhemorrhages

Background: While the Alzheimer’s disease Assessment Scale-Cognitive Subscale (ADAS-Cog) is commonly used to measure cognitive decline in probable Alzheimer’s disease (pAD) and mild cognitive impairment (MCI) patients, rates of decline vary. We previously introduced a single index, Hypometabolic Convergence Index (HCI), to characterize the extent to which the pattern and magnitude of cerebral hypometabolism in a person’s fluorodeoxyglucose-positron emission tomography (FDGPET) image corresponds to that in pAD patients. Here, we used data from ADNI to examine the extent to which 1) a person’s baseline HCI predicts cognitive decline using the ADAS-Cog, Mini-Mental State Exam (MMSE), Clinical Dementia Rating-sum of boxes (CDR-SB) and Auditory-Verbal Learning Test (AVLT-Total), and 2) the HCI could be used to enrich clinical trials for clinical decline and reduce the number of patients needed to detect a treatment’s clinical effects. Methods: Baseline HCIs were computed for 120 MCI and 54 mild AD patients who had up to 24-month data. We first characterized the extent to which HCIs correlated with 12-month and 24-month clinical declines.We then estimated the sample sizes needed to detect an AD-slowing treatment’s effects on ADAS-Cog before/after enrichment for those patients with HCIs greater than the predetermined threshold of 13.82 for pAD and 8.19 for MCI (Chen et al., 2011, Neuroimage) with 80% power, 0.05 type-I error and a 25% treatment effect. Results: In pAD, HCIs correlated (p < 1⁄4 0.05) with subsequent ADAS-Cog, MMSE, CDR-SB and AVLT-Total 12month(24-month) decline (r 1⁄4 0.42(0.47), -0.35(-0.55), 0.28(0.29), -0.40(-0.43), respectively). InMCI, HCI also correlated with subsequent decline at 12-month(24-month) (r 1⁄4 0.33(0.32), -0.43(-0.50), 0.29(0.37), -0.17(-0.32), respectively). HCI enrichment is estimated to reduce the number of pAD patients needed per treatment arm to detect an AD-slowing treatment’s effect on ADAS-Cog from 406 to 243 in a 12-month trial and from 168 to 137 in a 24-month trial. Similarly, it is estimated to reduce the number ofMCI patients from 1,718 to 749 in a 12-month trial and from 926 to 374 in a 24-month trial. Conclusions: Baseline HCIs could be used to predict subsequent clinical declines in pAD andMCI patients and to reduce the number of patients needed to detect an AD-slowing treatment’s effects in randomized clinical trials.