Operationalizing mild cognitive impairment criteria in small vessel disease: The VMCI-Tuscany Study

Introduction Mild cognitive impairment (MCI) prodromic of vascular dementia is expected to have a multidomain profile. Methods In a sample of cerebral small vessel disease (SVD) patients, we assessed MCI subtypes distributions according to different operationalization of Winblad criteria and compared the neuroimaging features of single versus multidomain MCI. We applied three MCI diagnostic scenarios in which the cutoffs for objective impairment and the number of considered neuropsychological tests varied. Results Passing from a liberal to more conservative diagnostic scenarios, of 153 patients, 5% were no longer classified as MCI, amnestic multidomain frequency decreased, and nonamnestic single domain increased. Considering neuroimaging features, severe medial temporal lobe atrophy was more frequent in multidomain compared with single domain. Discussion Operationalizing MCI criteria changes the relative frequency of MCI subtypes. Nonamnestic single domain MCI may be a previously nonrecognized type of MCI associated with SVD

Vitamin E serum levels are normal in ataxia telangiectasia (Louis-Bar disease).

In order to study the role of vitamin E in the pathogenesis of ataxia telangiectasia, we analysed vitamin E serum levels in five children with this disorder. No differences with respect to controls were found. However, these negative results do not exclude that abnormal vitamin E metabolism may be present at the cellular level

Oxidative-stress-induced apoptosis in PBLs of two patients with Parkinson disease secondary to alpha-synuclein mutation.

Alpha-synuclein has been implicated in the pathology of certain neurodegenerative diseases, including Parkinson disease (PD). Although the precise physiological and pathological role of alpha-synuclein is unclear, overexpression of the protein or its mutants may reduce cell viability. In this study we evaluated the apoptotic response to oxidative stress induced by 2-deoxy-d-ribose (dRib) in peripheral blood lymphocytes (PBLs) of two siblings with Parkinson disease secondary to A53T alpha-synuclein mutation. PBLs exposed to oxidative stress showed a higher percentage of apoptotic cells in PD patients than in controls. However in cells of PD patients, the increase of apoptotic response was lower than in controls, suggesting that cells of PD patients have greater "resistance" to oxidative stress. We conclude that other environmental agents could play a key role in inducing programmed cell death in cells of PD patients with mutant alpha-synuclein

Plasma levels of vitamin E in Parkinson's disease.

We report the analysis of plasma levels of vitamin E that has been found normal in 20 italian patients with Parkinson's disease (PD) confirming the previously reported results from other groups. We discuss the literature data about the possible protective effect of antioxidant agents in the PD and generally in the aging processes

Evaluation of brain apoptosis in a CADASIL postmortem case

OBJECTIVE: To evaluate the role of apoptosis in the pathogenesis of brain lesions in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary microangiopathy leading to cognitive decline and dementia, caused by mutations in the NOTCH3 gene. MATERIALS AND METHODS: Detection of apoptotic nuclei in temporal lobe, brain stem, medulla oblongata, hippocampus and basal ganglia from one young CADASIL patient was performed by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL). RESULTS: Our results showed a great involvement of glial cells in apoptotic cell death in the majority of the brain regions examined; neuronal apoptosis was significantly present only in the brain stem region. CONCLUSIONS: We hypothesized that in the early stages of the disease neuronal involvement of apoptosis is limited to the cells of the brain stem, sparing the cortical area which is involved in neuronal apoptosis and cognitive decline later

Evidence of apoptosis via TUNEL staining in muscle biopsy from patients with mitochondrial encephaloneuromyopathies.

Apoptosis is an evolution-conserved form of cell death essential for development and maintenance of tissue homeostasis. Dysregulation of apoptosis has been implicated in several pathological conditions, including neurodegenerative disorders. The crucial role of mitochondria in regulation of the apoptotic pathway prompted us to investigate the pattern of apoptosis in muscle biopsies from 17 patients with mitochondrial encephaloneuromyopathies caused by mtDNA defects. The results were compared with muscle biopsies from controls and from patients with myopathies without mitochondrial impairment. The terminal deoxynucleotidyl transferase-mediated dUTP nick and labelling (TUNEL) reaction was used as marker of apoptosis. Our findings were very heterogeneous, even between patients with the same mtDNA mutations, suggesting that tissue evaluation of apoptotic process is less useful than in vitro techniques, for investigating the role of apoptosis in mitochondrial pathologies

Oxidative stress-induced apoptosis in two patients with Alagille syndrome.

5noAlagille syndrome (AGS) is an autosomal dominant disorder characterized by cholestasis, cardiac, skeletal and ocular abnormalities. Increasing importance is being given to vascular and central nervous system impairment. AGS is in most cases caused by heterozygous mutations in the Jagged-1 (JAG1) gene encoding a cell-surface ligand of the Notch receptors. The interaction between Notch1 and JAG1 induces proliferation and inhibits apoptosis. We evaluated the role of apoptosis in AGS patients carrying a truncating mutation in exon 7 of JAG1. Peripheral blood lymphocytes (PBLs) from two patients were exposed to 2-deoxy-d-ribose (dRib). Apoptosis was analyzed by flow cytometry, fluorescence microscopy and Western blotting. PBLs from patients showed a significantly higher percentage of apoptosis than controls both in standard culture conditions and after dRib treatment, however we demonstrated a lack of caspase-8 activation in those cells. Our results confirm that JAG1 may play a role in apoptosis regulation. In particular, truncating mutations in JAG1 could lead to Notch signaling inhibition and determine a deregulation of survival and proliferation, favoring apoptosis. Moreover, the lack of caspase-8 activation in AGS patients indicates a possible selective impairment of caspase-8 cleavage suggesting that JAG1 plays a specific role in the regulation of caspase-8 activation.reservedmixedRadi E;Formichi P;Di Maio G;Battisti C;Federico ARadi, Elena; Formichi, Patrizia; DI MAIO, Giuseppe; Battisti, Carla; Federico, Antoni

Vitamin E serum levels and gastric cancer: results from a cohort of patients in Tuscany, Italy.

Alpha-tocopherol has been reported to play an important role against oxidative damage and in the inhibition of cell transforming and mutagenesis. We analysed vitamin E serum levels in 51 cases of patients affected by gastric cancer at different stages of the disease, and in 49 age-matched controls. All patients had normal values of alpha-tocopherol. However, when patients have been grouped according to histotype of gastric lesions, a significant vitamin E increase has been found in diffuse gastric cancer histotype compared to the intestinal histotype. Our results suggest that a correlation between vitamin E serum levels and gastric cancer histotype should be considered

Cerebrolysin administration reduces oxidative-stress induced apoptosis in limphocytes from healthy subjects

Cerebrolysin is the only drug available for clinical use containing active fragments of some important neurotrophic factors obtained from purified porcine brain proteins, which has long been used for the treatment of dementia and stroke sequels. Cerebrolysin has growth factor-like activities and promotes neuronal survival and sprouting, however its molecular mechanism still needs to be determined. It has been shown that Cerebrolysin may interact with proteolytic pathways linked to apoptosis. Administration of Cerebrolysin significantly reduces the number of apoptotic neurons after glutamate exposure. Furthermore, it has been reported that Cerebrolysin inhibits free radicals formation and lipid peroxidation. We in vitro evaluated the protective effects of Cerebrolysin towards spontaneous and induced apoptotic death in cells from human healthy subjects. Peripheral blood lymphocytes (PBLs) from 10 subjects were used as cell model; 2-deoxy-D-ribose (dRib), a highly reducing sugar, was used as paradigm pro-apoptotic stimulus. Apoptosis was analyzed by flow cytometry and fluorescence microscopy. Our results showed that Cerebrolysin significantly reduced the number of apoptotic PBLs after dRib treatment, while it had no significative effects on cells cultured in standard conditions. Our work showed a protective effect of Cerebrolysin on oxidative stress-induced apoptosis and suggested that PBLs can be used as an easy obtainable and handy cell model to verify Cerebrolysin effects in neurodegenerative pathologies. © 2012 The Authors Journal of Cellular and Molecular Medicine © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd