Giuseppe Sorrentino

Biological Mechanisms of Physical Activity in Preventing Cognitive Decline

In order to guarantee better conditions for competition, the nervous system has developed not only mechanisms controlling muscle effectors, but also retrograde systems that, starting from peripheral structures, may influence brain functions. Under such perspective, physical activity could play an important role in influencing cognitive brain functions including learning and memory. The results of epidemiological studies (cross-sectional, prospective and retrospective) support a positive relationship between cognition and physical activities. Recent meta-analysis confirmed a significant effect of exercise on cognitive functions. However, the biological mechanisms that underlie such beneficial effects are still to be completely elucidated. They include supramolecular mechanisms (e.g. neurogenesis, synaptogenesis, and angiogenesis) which, in turn, are controlled by molecular mechanisms, such as BDNF, IGF-1, hormone and second messengers.

Neurodegeneration and Alzheimer's disease: the lesson from tauopathies.

The Amyloid Cascade Hypothesis suggests that the decisive event in Alzheimers disease (AD) is the deposition of fibrils of β-amyloid protein (Aβ). The main objection to this hypothesis is the weak correlation between plaque load and severity of dementia. The good correlation between synaptic loss and dementia suggests that AD may be regarded as a synaptic failure. The toxicity of Aβ depends on its state of aggregation. The most important implication derived from the studies of tau gene mutations in a familial form of frontotemporal dementia (FTDP-17) is that the mutation itself is sufficient to cause neuronal loss. Several recent data suggest that apoptotic mechanisms may represent the missing link between Aβ deposition and proteolysis of tau, an early event in the pathogenic sequence of AD. Collectively, these observations suggest a model of AD whereby overproduction or reduced clearance of Aβ initiates a cascade of events that lead to neuronal loss directly or through post-translational modification of tau.

Late appearance of acanthocytes during the course of chorea-acanthocytosis

A case of chorea-acanthocytosis (CA) syndrome is described. The presence of acanthocytes has usually been considered an important diagnostic marker of CA. However, it is not specific and other neurological diseases have to be considered. In the present report we rule out other diagnostic possibilities and show that the acanthocytes in the peripheral blood smears can appear even later during the course of the disease.

The dark sides of amyloid in Alzheimer’s disease pathogenesis

Although widely explored, the pathogenesis of Alzheimers disease (AD) has yet to be cleared. Over the past twenty years the so call amyloid cascade hypothesis represented the main research paradigm in AD pathogenesis. In spite of its large consensus, the proposed role of β‐amyloid (Aβ) remain to be elucidated. Many evidences are starting to cast doubt on Aβ as the primary causative factor in AD. For instance, Aβ is deposited in the brain following many different kinds of injury. Also, concentration of Aβ needed to induce toxicity in vitro are never reached in vivo. In this review we propose an amyloid‐independent interpretation of several AD pathogenic features, such as synaptic plasticity, endo‐lysosomal trafficking, cell cycle regulation and neuronal survival.

Phospholipases as mediators of amyloid beta peptide neurotoxicity: an early event contributing to neurodegeneration characteristic of Alzheimer's disease

There is a consensus that by some still to be defined mechanism amyloid beta peptide, which accumulates in Alzheimers disease brain tissue, contributes to the characteristic neurodegeneration. We suggest that one of these mechanisms for amyloid beta peptide is the ability to activate cellular phospholipases. Excessive phospholipid hydrolysis would produce a variety of lipidic second messengers. These catabolites would then evoke unnecessary stereotypic responses. This indiscriminate activation of the phospholipases could be responsible for the increased amounts of phospholipid catabolites found in Alzheimers disease brain tissue. Failure to maintain regeneration of the membrane components would result in a loss of essential cellular neuronal processes.

Hearing Impairment in Parkinson's Disease: Expanding the Nonmotor Phenotype

The objective of this study was to evaluate hearing impairment in patients affected by Parkinsons disease compared with hearing scores observed in normal age‐ and sex‐matched controls. One hundred eighteen consecutive patients with a clinical diagnosis of Parkinsons disease were screened. Severity of motor symptoms and staging were measured with the Unified Parkinsons Disease Rating Scale (section III) and the Hoehn and Yahr scale. Audiometric evaluation consisted of a comprehensive audiologic case history and questionnaire, visual otoscopic examination, acoustic immittance measures (tympanogram and acoustic reflexes), pure tone audiometry, and measurement of brain stem auditory‐evoked potentials. Healthy age‐ and sex‐matched subjects were selected as the control group. One hundred six of 118 patients were enrolled. Pure tone audiometry revealed age‐dependent high‐frequency hearing loss in patients with Parkinsons disease compared with both normative values and values for healthy age‐ and sex‐matched controls (75/106 [71%], χ2 = 5.959, P = .02; 92/106 [86.8%] vs 60/106 [56.6%], χ2 = 23.804, P < .001, respectively). Pure tone audiometry scores correlated with Hoehn and Yahr scale scores (P < .05). Brain stem auditory‐evoked potentials were normal in all patients. Our patients with Parkinsons disease showed age‐dependent peripheral, unilateral, or bilateral hearing impairment. Whether these auditory deficits are intrinsic to Parkinsons disease or secondary to a more complex impaired processing of sensorial inputs occurring over the course of illness remains to be determined. Because α‐synuclein is located predominately in the efferent neuronal system within the inner ear, it could affect susceptibility to noise‐induced hearing loss or presbycusis. It is feasible that the natural aging process combined with neurodegenerative changes intrinsic to Parkinsons disease might interfere with cochlear transduction mechanisms, thus anticipating presbycusis.

Guidelines for the diagnosis of dementia and Alzheimer's disease

SIN DOCUMENT*The Dementia Study Group is co-ordinated by Sandro Sorbi andincludes: Margherita Alberoni, Milan; Pasquale Alfieri, SommaVesuviana (NA); Serena Amici, Perugia; Daniele Antana, Rome;Ildebrando Appollonio, Monza (MI); Stefano Avanzi,Castelgoffredo (MN); Antonella Bartoli, Pescara; BrunoBergamasco, Turin; Laura Bracco, Florence; Amalia Bruni,Lamezia Terme (CZ); Orso Bugiani, Milan; Paolo Caffarra, Parma;Carlo Caltagirone, Rome; Antonio Carolei, L’Aquila; Anna RosaCasini, Rome; Luciana Ciannella, Benevento; Antonietta Citterio,Pavia; Antonio Daniele, Rome; Graziella D’Achille, Isernia;Giuseppe Del Curatolo, Grosseto; Grazia Dell’Agnello, Pisa;Daniele Durante, Parma; Elisabetta Farina, Milan; Patrizia Ferrero,Turin; Paolo Forleo, Florence; Guido Gainotti, Rome; PaoloGabriele, Cassino (FR); Emanuela Galante, Castelgoffredo (MN);Virgilio Gallai, Perugia; Roberto Gallassi, Bologna; MaddalenaGasparini, Milan; Bernardino Ghetti, Indianapolis (USA); GiorgioGiaccone, Milan; Floriano Girotti, Milan; Luigi Grimaldi, Milanand Caltanisetta; Serenella Grioli, Catania; Bianca MariaGuarnieri, Pescara; Stefano Grottoli, Fossombrone (PS); FrancescoIemolo, Ragusa; Stefania Latorraca, Florence; Francesco Le Pira,Catania; Gian Luigi Lenzi, Rome; Sebastiano Lorusso, Rimini;Claudio Mariani, Milan; Gabriella Marcon, Udine; VincenzoMascia, Carbonia (CA); Simonetta Mearelli, L’Aquila; MariaMorante, Senigallia (AN); Michela Morbin, Milan; MassimoMusicco, Segrate (MI); Ettore Nardelli, Verona; Paolo Nichelli,Modena; Alessandro Padovani, Brescia; Marco Paganini, Florence;Roberta Pantieri, Bologna; Pietro Parisen, Vicenza; LucillaParnetti, Perugia; Bruno Passerella, Brindisi; Carla Pettenati, Rho(MI); Silvia Piacentini, Florence; Federico Piccoli, Palermo; CarloPiccolini, Perugia; Gilberto Pizzolato, Padova; LeandroProvinciali, Ancona; Nicola Pugliese, Salerno; Francesco Redi,Arezzo; Rosa Maria Ruggieri, Palermo; Umberto Ruggiero,Naples; Marco Saetta, Siracusa; Rudolf Schoenuber, Bolzano;Maria Caterina Silveri, Rome; Sandro Sorbi, Florence; GiuseppeSorrentino, Naples; Patrizia Sucapane, L’Aquila; Andrea Stracciari,Bologna; Massimo Tabaton, Genova; Fabrizio Tagliavini, Milan;Vito Toso, Vicenza; Francesco Valluzzi, Putignano Noci (BA)S. Sorbi ( )Department of Neurological and Psychiatric SciencesUniversity of FlorenceViale Morgagni 85, I-50131 Florence, Italy

Phospholipid metabolism in Alzheimer's disease and in a human cholinergic cell

There is evidence available suggesting that membrane alterations occur in Alzheimers disease including the metabolism of membrane phospholipids. We have quantitated in vitro the phospholipase D activity of homogenates from Alzheimers disease brain tissue. There was a significant increase of this enzyme activity as compared to controls. Amyloid beta protein is the predominant protein of the characteristic senile plaques found in Alzheimers disease. Treatment of LA-N-2 cells, a human cholinergic neuroblastoma clone, with amyloid beta protein results in an activation of phospholipases A, C and D.

Gait patterns in parkinsonian patients with or without mild cognitive impairment

Although in recent years the relationship between cognition and gait in Parkinsons disease (PD) has received increasing attention, the specific connections between gait patterns and cognitive features are not fully understood. The objective of this study was to describe the gait patterns in patients affected by PD with or without mild cognitive impairment (MCI+ and MCI−, respectively). We also sought to find an association between gait patterns and specific cognitive profiles. Using a gait analysis system, we compared the gait patterns among MCI+ patients (n = 19), MCI− patients (n − 24), and age‐ and sex‐matched healthy subjects (HS; n = 20) under the following conditions: (1) normal gait, (2) motor dual task, and (3) cognitive dual task. In PD patients, gait parameters were evaluated in both the off and on states. Memory, executive, and visuospatial domains were assessed using an extensive neuropsychological battery. Compared with MCI− PD and HS, MCI+ PD patients displayed reduced step length and swing time and impairment of measures of dynamic stability; these dysfunctions were only partially reversed by levodopa. We also found that dual‐task conditions affected several walking parameters in MCI+ PD in the off and on states relative to MCI− PD and HS. Factor analysis revealed 2 independent factors, namely, pace and stability. The latter was strongly and directly correlated to the visuospatial domain. In conclusion, dysfunctions on specific gait parameters, which were poorly responsive to levodopa and highly sensitive to dual‐task conditions, were associated with MCI in PD patients. Importantly, visuospatial impairment was strongly associated with the development of instability and more generally with the progression of PD.

Activation of LA-N-2 Cell Phospholipase D by Amyloid Beta Protein (25-35)

Amyloid β protein is the major protein component of neuritic plaques found in the brain of Alzheimers disease. The activation of phospholipase D by amyloid beta protein (25–35), quisqualate and phorbol 12, 13-dibutyrate was investigated in LA-N-2 cells by measuring phosphatidylethanol formation. The activation of phospholipase D by quisqualate and AβP (25–35) was calcium-independent. The AβP (25–35) and quisqualate activation of phospholipase D appeared to be mediated through a pertussis toxin-sensitive GTP-binding protein. Phospholipase D activation by AβP (25–35), quisqualate and phorbol dibutyrate was not blunted by the protein kinase C inhibitors, staurosporine, H-7 and RO-31-8220. However, it was abolished by overnight exposure to phorbol dibutyrate. This activation of phospholipase D was prevented by the tyrosine kinase inhibitor, genistein but not by tyrophostin A. Several excitatory amino acid antagonists were tested for their ability to prevent the phospholipase D activation by quisqualate and AβP (25–35). Only NBQX was effective with an IC50 of 75 μM for AβP (25–35) and quisqualate. Activation of phospholipase D by AβP or quisqualate was absent in LA-N-2 cells previously desensitized by quisqualate or AβP (25–35), but the activation by phorbol dibutyrate was unaltered. The responsiveness to AβP and quisqualate in previously desensitized cells reappeared subsequent to a period of resensitization. The observations with the antagonist NBQX, and the desensitization and resensitization experiments, are consistent with a receptor occupancy mediated activation of phospholipase D by quisqualate and by AβP (25–35).