Alzheimer Disease: Di Luca M

Caltagirone C, Bianchetti A, Di Luca M, Mecocci P, Padovani A, Pirfo E, Scapicchio P, Senin U, Trabucchi M, Musicco M, Anonymous00252. · Fondazione IRCCS, Santa Lucia, Università Tor Vergata, Rome, Italy. · Drugs Aging. · Pubmed #16506439 No free full text.

Abstract: A committee of experts from the Italian Association of Psychogeriatrics compiled the following report, which was then approved by a Steering Committee (comprising 20 specialists in neurology, psychiatry or geriatrics) from the Association and by two Alzheimer associations representing patients and families: the Italian Association for Alzheimer's Disease and the Italian Federation for Alzheimer's Disease. The report is based on a comprehensive review of the scientific literature on the treatment of Alzheimer's disease, discusses methodological aspects of dementia management, and details the limitations of current therapies. These guidelines are, in general, consistent with the principles of evidence-based medicine; however, for some controversial or poorly investigated issues, the guidelines integrate scientific evidence with experience and opinions from experts working in the clinical setting. In particular, the clinical experience of experts has been used to define recommendations for starting and interrupting pharmacotherapy, and to critically review evidence about the efficacy of non-pharmacological interventions. The principal pharmacotherapeutic interventions covered in the guidelines are acetylcholinesterase inhibitors (donepezil, galantamine, rivastigmine, and tacrine) and memantine. The main non-pharmacological interventions reviewed are memory training, reality orientation therapy, and combined non-pharmacological interventions. Other issues covered are opportunities for Alzheimer's disease prevention, various modalities of care, and the treatment of comorbidities.

Marcello E, Epis R, Di Luca M. · Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milan, via Balzaretti 9, 20133 Milan, Italy. · Eur J Pharmacol. · Pubmed #18377893 No free full text.

Abstract: Many neurological disorders accompanied by cognitive deficits exhibit abnormal synaptic function. This emerging concept is exemplified by Alzheimer's disease. According to the amyloid hypothesis, Alzheimer's disease is thought to be caused by the progressive accumulation and deposition of neurotoxic Amyloid beta-peptide in amyloid plaques and aggregates in brain. Now new theories are emerging associating synaptic and neuronal loss to Amyloid beta monomers and Amyloid beta oligomers. In particular, Amyloid beta oligomers have been described as the earliest effectors to adversely affect synaptic structure and plasticity. In this way, they compromise aspects of learning and memory, including long-term potentiation. Local inflammatory changes, neurofibrillary degeneration, and neurotransmitter deficits all contribute to the memory impairment, but available evidence suggests that these alterations develop as a consequence of early Amyloid beta accumulation. Even more recently, different studies have focused on the capability of neuronal activity itself to influence Amyloid Precursor Protein (APP) metabolism. Neuronal activity modulates, in fact, the formation and secretion of Amyloid beta peptides. The identification of both the mechanism through which Amyloid beta can modify neuronal activity and the way by which neuronal activity can alter APP metabolism is becoming more and more important. And the challenge for the future is, therefore, to find the linkage between these two processes.

Marcello E, Epis R, Gardoni F, Di Luca M. · Dept. of Pharmacological Sciences and CEND, Centre of Excellence on Neurodegenerative Diseases - University of Milano, via Balzaretti, 9 - 20133 Milano, Italy. · J Nutr Health Aging. · Pubmed #18165847 No free full text.

This publication has no abstract.

Borroni B, Premi E, Di Luca M, Padovani A. · Department of Neurology, and Centre for Ageing Brain and Neurodegenerative Disorders, University of Brescia, Italy. · Curr Med Chem. · Pubmed #17504137 No free full text.

Abstract: Few public health problems have captured the attention of the biomedical and lay communities alike as has Alzheimer Disease (AD). Several questions remain still open in disease management, as the necessity to delineate disease process from "normal ageing". In the last few years, Mild Cognitive Impairment (MCI) has received significant attention, thus it represents the major risk factor for AD. Not all people diagnosed as having MCI, however, will develop AD, hence there is a need to reliably predict progression. To this aim, different biomarkers have been proposed with the attempt to identify MCI people who already have pre-clinical AD. Neuropsychological assessment, peripheral and CSF biomarkers as well as neuroimaging findings (both structural and functional) have reported variable accuracy values, but better results have been obtained by combined biomarker approach. In this review, we summarise the most recent findings on combined biomarkers and their usefulness in clinical practice for the early and preclinical diagnosis of AD.

Borroni B, Di Luca M, Padovani A. · Department of Medical Sciences, University of Brescia, Italy. · Eur J Pharmacol. · Pubmed #16831417 No free full text.

Abstract: A correct clinical diagnosis in the early stage of Alzheimer disease is not only of importance given the current available treatment with acetylcholine esterase inhibitors, but would be the basis for disease-modifying therapy slowing down or arresting the degenerative process. Moreover, in the last years, several efforts have been made to determine if a patient with mild cognitive impairment has incipient Alzheimer disease, i.e. will progress to Alzheimer disease with dementia, or have a benign form of mild cognitive impairment. In this review, the recent published reports regarding progress in early and preclinical Alzheimer disease diagnosis are discussed and the role of peripheral and cerebrospinal fluid biomarkers highlighted. Approaches combining panels of different biomarkers show promise for discovering profiles that are characteristic of Alzheimer disease, even in the pre-symptomatic stage. More work is needed but available novel perspectives offered by recent introduced technologies shed some lights in identifying incipient Alzheimer disease in mild cognitive impairment subjects.

Gardoni F, Di Luca M. · Center of Excellence on Neurodegenerative Diseases and Department of Pharmacological Sciences, University of Milano, via Balzaretti 9, 20133 Milano, Italy. · Eur J Pharmacol. · Pubmed #16831414 No free full text.

Abstract: Excitotoxicity is thought to be a major mechanism in many human disease states such as ischemia, trauma, epilepsy and chronic neurodegenerative disorders. Briefly, synaptic overactivity leads to the excessive release of glutamate that activates postsynaptic cell membrane receptors, which upon activation open their associated ion channel pore to produce ion influx. To date, although molecular basis of glutamate toxicity remain uncertain, there is general agreement that N-methyl-d-aspartate (NMDA) subtype of ionotropic glutamate receptors plays a key role in mediating at least some aspects of glutamate neurotoxicity. On this view, research has focused in the discovery of new compounds able to either reduce glutamate release or activation of postsynaptic NMDA receptors. Although NMDA receptor antagonists prevent excitotoxicity in cellular and animal models, these drugs have limited usefulness clinically. Side effects such as psychosis, nausea, vomiting, memory impairment, and neuronal cell death accompany complete NMDA receptor blockade, dramatizing the crucial role of the NMDA receptor in normal neuronal processes. Recently, however, well-tolerated compounds such as memantine has been shown to be able to block excitotoxic cell death in a clinically tolerated manner. Understanding the biochemical properties of the multitude of NMDA receptor subtypes offers the possibility of developing more effective and clinically useful drugs. The increasing knowledge of the structure and function of this postsynaptic NMDA complex may improve the identification of specific molecular targets whose pharmacological or genetic manipulation might lead to innovative therapies for brain disorders.

Zimmermann M, Gardoni F, Di Luca M. · Centre of Excellence on Neurodegenerative Diseases and Department of Pharmacological Sciences, University of Milan, Italy. · Drugs Aging. · Pubmed #16506440 No free full text.

Abstract: Cerebral deposition of amyloid plaques containing amyloid beta-peptide (Abeta) has traditionally been considered the central feature of Alzheimer's disease (AD). Abeta is derived from amyloid precursor protein (APP), which is cleaved by several different proteases: alpha-, beta- and gamma-secretase. In the past decade, however, the molecular pathogenesis of AD has been shown to involve alterations in several neurotransmitter, inflammatory, oxidative, and hormonal pathways that represent potential targets for AD prevention and treatment. Much research has shown a direct link between cholinergic impairment and altered APP processing as a major pathogenetic event in AD. Three highly probable mechanisms of APP regulation through inhibition of acetylcholinesterase are thus current topics of investigation. Indeed, acetylcholinesterase inhibitors appear to cause selective muscarinic activation of alpha-secretase and to induce the translation of APP mRNA; they may also restrict amyloid fibre assembly. Activation of N-methyl-D-aspartate receptors is considered a probable cause of chronic neurodegeneration in AD, and memantine has been widely used in some countries in AD patients to block cerebral N-methyl-D-aspartate receptors that normally respond to glutamate. Further studies are needed to determine whether antioxidants such as vitamins C and E are effective, through various mechanisms, in patients with mild-to-moderate AD. Additional data are also required for non-steroidal anti-inflammatory drugs, some of which appear to possess experimental effects that may ultimately prove favourable in AD patients. Statins also warrant further investigation, since they have activated alpha-secretase and they reduced Abeta generation and amyloid accumulation in a transgenic mouse model. beta-Secretase would seem to be an ideal target for anti-amyloid therapy in AD, but potential clinical and pharmacological issues, such as ensuring selectivity of inhibition, stability, and ease of blood-brain barrier penetration and cellular uptake, remain to be addressed for beta-secretase inhibitors. gamma-Secretase is not an easy candidate for pharmacological manipulation. Immunotherapeutic strategies have targeted Abeta directly; however, intensive investigation of indirect approaches to the management of AD with immunotherapy is now underway.

Padovani A, Borroni B, Di Luca M. · Department of Neurological Sciences, University of Brescia, 25100 Brescia, Italy. · Adv Clin Chem. · Pubmed #16013669 No free full text.

This publication has no abstract.

Cattabeni F, Colciaghi F, Di Luca M. · Centre of Excellence on Neurodegenerative Diseases and Department of Pharmacological Sciences, University of Milano, via Balzaretti 9, 20133, Milano, Italy. · Prog Neuropsychopharmacol Biol Psychiatry. · Pubmed #15363602 No free full text.

Abstract: Alzheimer disease (AD) is a progressive neurodegenerative disorder characterised by a progressive cognitive and memory decline. From a neuropathological point of view, Alzheimer disease is defined by the presence of characteristic lesions, i.e. mature senile plaques, neurofibrillary tangles and amyloid angiopathy. In particular, accumulation of the amyloid beta-peptide in the brain parenchyma and vasculature is an invariant event in the pathogenesis of both sporadic and familial Alzheimer cases. Amyloid beta-peptide originates from a larger precursor, the Amyloid Precursor Protein (APP) ubiquitously expressed. Among the different peripheral cells expressing APP forms, platelets are particularly interesting since they show concentrations of its isoforms equivalent to those found in brain. Moreover, a number of laboratories independently described alterations in APP metabolism/concentration in platelets of Alzheimer patients when compared to control subjects matched for demographic characteristics. These observations defined the frame of our work aimed to investigate if a correlation between levels of platelet APP forms and Alzheimer disease could be detected. We have reported that patients affected by Alzheimer disease show a differential level of platelet APP forms. This observation has several implications: APP processing abnormalities, believed to be a very early change in Alzheimer disease in neuronal compartment, does occur in extraneuronal tissues, such as platelets, thus suggesting that Alzheimer disease is a systemic disorder; further, our data strongly indicate that a differential level of platelet APP forms can be considered a potential peripheral marker of Alzheimer disease allowing for discrimination between Alzheimer and other types of dementia with good sensitivity and specificity.

Borroni B, Akkawi N, Martini G, Colciaghi F, Prometti P, Rozzini L, Di Luca M, Lenzi GL, Romanelli G, Caimi L, Padovani A. · Clinica Neurologica, Spedali Civili di Brescia, Università degli Studi di Brescia, Piazza Ospedale 1, Brescia 25125, Italy. · J Neurol Sci. · Pubmed #12417382 No free full text.

Abstract: Accumulating evidence from epidemiological and clinical studies suggests that vascular risk factors may be involved in Alzheimer disease (AD). Although the precise contribution of vascular disturbances to the pathogenesis of AD is still unclear, various biochemical and neuropathological data strengthen the view that cerebrovascular deficiencies such as reduced blood supply to the brain and disrupted microvascular integrity in brain parenchyma play a direct or intermediate role in the chain of events ending with a dementia syndrome. The present review focuses on platelet abnormalities and hemostatic alterations in AD. In particular, data from our group, along with current literature, are discussed with regard to the evidence of platelets amyloid precursor protein (APP) processing disturbances in early AD as well as to the recent observations of increased serum levels of thrombomodulin and sE-selectin, which are sensitive markers of endothelial dysfunction. These findings strongly indicate that platelet dysfunction and microvasculature deficiencies occur rather early during the course of AD, thus suggesting a further link between AD-related processes and vascular disorders.

Zimmermann M, Colciaghi F, Cattabeni F, Di Luca M. · Dept of Pharmacological Sciences, University of Milano, Italy. · Cell Mol Biol (Noisy-le-grand). · Pubmed #12396071 No free full text.

Abstract: Ginkgo biloba is registered for the treatment of several diseases and disorders in Europe. In the United States, it is marketed as a dietary supplement; the French and the German agencies consider it to be effective for the treatment of several diseases, and the immense amount of clinical studies concerning Ginkgo biloba makes it worth revising the existing literature about this notable plant. A brief history of the common use of this drug will be followed by a short botanic characterization. The biochemical composition of the original drug, the leaf itself, will be described in detail together with a brief discussion of commercial extracts and the problem of studying Ginkgo biloba clinically to verify the safety and efficacy of its extracts in the treatment of disorders like Alzheimer's diseases. Aspects of molecular mechanisms modifying the efficacy of this drug will be outlined. Several agents like antioxidants, anti-inflammatory drugs, cholinergic agents, estrogens, or neurotrophic factors are in use for the treatment of this neurodegenerative disease, but none can prove fully convincing benefit. In this field, Ginkgo biloba appears as a useful and sensible supplementary medication to treat Alzheimer's disease, as it seems to be a synthesis of all the different profiles of action of the various, commonly used drugs but with less side effects.

Padovani A, Borroni B, Colciaghi F, Pastorino L, Archetti S, Cottini E, Caimi L, Cattabeni F, Di Luca M. · Dipartimento Scienze Mediche e Chirurgiche, Clinica Neurologica-Università degli Studi di Brescia, Piazza Ospedale 1, 25125, Brescia, Italy. · Mech Ageing Dev. · Pubmed #11589917 No free full text.

Abstract: Alzheimer Disease (AD) is characterized by the progressive deposition of beta-amyloid in the parenchyma and cerebral microvasculature. The beta-amyloid peptide derives from the metabolism of a larger precursor, Amyloid Precursor Protein (APP). This protein is present in central nervous system, but it is also expressed in peripheral tissues such as circulating cells. An alteration of the APP forms pattern in platelets has been recently reported in AD patients when compared to platelets both of control subjects or non AD patients (NADD). The accuracy of the assay to identify AD is high and decreased levels are found throughout the course of AD with a significant association with severity of symptoms. Moreover, a recent study has demonstrated that AD patients on donepezil (5 mg daily) for 4 weeks displayed two-fold increase in their APPr baseline levels up to normal range. Thus, platelet APP ratio (APPr) holds the potential to be a clinical marker, which might be of helpful and adjunctive value in the diagnosis of AD and in tracking the course of illness, also in the early stages when pharmacological treatment has the greatest potential of being effective.

Di Luca M, Colciaghi F, Pastorino L, Borroni B, Padovani A, Cattabeni F. · Institute of Pharmacological Sciences, University of Milano, via Balzaretti, 9-20133, Milan, Italy. · Eur J Pharmacol. · Pubmed #11033334 No free full text.

Abstract: Alzheimer disease is a progressive neurodegenerative disease, characterised by a progressive cognitive and memory decline. From a neuropathological point of view, Alzheimer disease is defined by the presence of characteristic lesions, i.e. mature senile plaques, neurofibrillary tangles (NFTs) and amyloid angiopathy. In particular, accumulation of the amyloid beta-peptide in the brain parenchyma and vasculature is an invariant event in the pathogenesis of both sporadic and familial Alzheimer cases. Amyloid beta-peptide originates from a larger precursor, the amyloid precursor protein (APP) ubiquitously expressed. Among the different peripheral cells expressing APP forms, platelets are particularly interesting since they show concentrations of its isoforms equivalent to those found in brain. Moreover, a number of laboratories independently described alterations in APP metabolism/concentration in platelets of Alzheimer patients when compared to control subjects matched for demographic characteristics. These observations defined the frame of our work aimed to investigate if a correlation between levels of platelet APP forms and Alzheimer disease could be detected. We have reported that patients affected by Alzheimer disease show a differential level of platelet APP forms. This observation has several implications: APP processing abnormalities, believed to be a very early change in Alzheimer disease in neuronal compartment, do occur in extraneuronal tissues, such as platelets, thus, suggesting that Alzheimer disease is a systemic disorder; further, our data strongly indicate that a differential level of platelet APP isoforms can be considered a potential peripheral marker of Alzheimer disease allowing for discrimination between Alzheimer and other types of dementia.

Borroni B, Pettenati C, Bordonali T, Akkawi N, Di Luca M, Padovani A. · Department of Medical Sciences, Neurological Clinic, University of Brescia, P.za Spedali Civili, 1, 25100 Brescia, Italy. · Neurosci Lett. · Pubmed #12770699 No free full text.

Abstract: The clinical, genetic or biological variables which regulate long-term efficacy of cholinesterase inhibitors (ChEIs) in Alzheimer disease (AD) are still unknown and it is not possible to predict who will benefit from the treatment. In this study we showed that high cholesterol levels correlated with faster decline at 1-year follow-up in AD patients on ChEIs. These findings suggest that serum cholesterol is a modulating factor of treatment response and additional therapies aimed at reducing treatable high cholesterol levels may represent an alternative strategy to improve ChEIs efficacy and slow down disease progression over time.

Borroni B, Colciaghi F, Pastorino L, Pettenati C, Cottini E, Rozzini L, Monastero R, Lenzi GL, Cattabeni F, Di Luca M, Padovani A. · Department of Neurology, University of Brescia, Italy. · Arch Neurol. · Pubmed #11255448 links to  free full text

Abstract: BACKGROUND: Amyloid precursor protein (APP) forms with apparent molecular weights of 130, 110, and 106 kd are present in human platelets. It has been demonstrated that Alzheimer disease (AD) is specifically associated with a decreased APP forms ratio in platelets. OBJECTIVE: To investigate whether acetylcholinesterase (AChE) inhibitor treatment modifies the ratio of platelet APP forms in patients with AD. PATIENTS AND METHODS: From a large sample of patients with probable AD, 30 with mild to moderate AD were selected. Each patient underwent a clinical evaluation including the Mini-Mental State Examination (MMSE) and platelet APP forms analysis at baseline and after 30 days. During this interval, 20 of 30 patients with AD were treated with donepezil hydrochloride (5 mg/d), a piperidine phosphate-based cholinesterase inhibitor. Platelets were subjected to Western blot analysis using monoclonal antibody (22C11). The ratio between the immunoreactivity of the higher-molecular-weight APP form (130 kd) and the lower forms (106 and 110 kd) was measured. RESULTS: All patients taking donepezil completed the 30 days of treatment without adverse effects. The platelet APP forms ratio at baseline did not differ between the 2 AD groups (mean +/- SD optical density ratio: untreated AD, 0.47 +/- 0.12; treated AD, 0.38 +/- 0.18), whereas a significant difference was found at follow-up (mean +/- SD optical density ratio: untreated AD, 0.45 +/- 0.17; treated AD, 0.77 +/- 0.29; P<.001). A significant improvement in MMSE scores in treated AD patients was observed from baseline (16.9 +/- 3.8) to 30 days (18.9 +/- 4.42) (P<.009, 30 days vs baseline), but no significant correlation was found in treated AD patients between MMSE score improvement and APP forms/ratio increase (P =.09). CONCLUSIONS: Administration of AChE inhibitors increases the ratio of APP forms in platelets of patients with AD, suggesting a potential effect of AChE inhibitors on APP trafficking or processing in a peripheral cell.

Borroni B, Malinverno M, Gardoni F, Alberici A, Parnetti L, Premi E, Bonuccelli U, Grassi M, Perani D, Calabresi P, Di Luca M, Padovani A. · Centre for Aging Brain and Dementia, Department of Neurology, University of Brescia, Italy. · Neurology. · Pubmed #18971445 No free full text.

Abstract: OBJECTIVE: In CSF, extended (55 kDa) and truncated (33 kDa) tau forms have been previously recognized, and the tau 33 kDa/55 kDa ratio has been found significantly reduced in progressive supranuclear palsy (PSP) vs in other neurodegenerative disorders. The aim of this study was to evaluate the diagnostic value of the CSF tau form ratio as a biomarker of PSP and to correlate the structural anatomic changes as measured by means of voxel-based morphometry (VBM) to CSF tau form ratio decrease. METHODS: A total of 166 subjects were included in the study (21 PSP, 20 corticobasal degeneration syndrome, 44 frontotemporal dementia, 29 Alzheimer disease, 10 Parkinson disease, 15 dementia with Lewy bodies, and 27 individuals without any neurodegenerative disorder). Each patient underwent a standardized clinical and neuropsychological evaluation. In CSF, a semiquantitative immunoprecipitation was developed to evaluate CSF tau 33 kDa/55 kDa ratio. MRI assessment and VBM analysis was carried out. RESULTS: Tau form ratio was significantly reduced in patients with PSP (0.504 +/- 0.284) when compared to age-matched controls (0.989 +/- 0.343), and to patients with other neurodegenerative conditions (range = 0.899-1.215). The area under the curve (AUC) of the receiver operating characteristic analysis in PSP vs other subgroups ranged from 0.863 to 0.937 (PSP vs others, AUC = 0.897, p < 0.0001). VBM study showed that CSF tau form ratio decrease correlated significantly with brainstem atrophy. CONCLUSIONS: Truncated tau production, which selectively affects brainstem neuron susceptibility, can be considered a specific and reliable marker for PSP. Tau form ratio was the lowest in progressive supranuclear palsy with no overlap with any other neurodegenerative illness.

Epis R, Marcello E, Gardoni F, Longhi A, Calvani M, Iannuccelli M, Cattabeni F, Canonico PL, Di Luca M. · Department of Pharmacological Sciences and Center of Excellence on Neurodegenerative Diseases, University of Milan, Milan, Italy. · Eur J Pharmacol. · Pubmed #18801359 No free full text.

Abstract: Alzheimer Disease is the most common chronic neurodegenerative disorder associated with aging. Nevertheless, its pharmacological therapy is still an unresolved issue. In double-blind controlled studies, acetyl-L-carnitine (ALC) demonstrated beneficial effects on Alzheimer's disease. However, the mechanisms behind its neuroprotective ability remain to be fully established. In this study, the effect of acetyl-L-carnitine on amyloid precursor protein (APP) metabolism was investigated by in vitro models, both in a neuroblastoma cell line and in primary hippocampal cultures. We found that ALC treatment stimulates alpha-secretase activity and physiological APP metabolism. In particular, ALC favors the delivery of ADAM10 (a disintegrin and metalloproteinase 10, the most accredited candidate for alpha-secretase) to the post-synaptic compartment, and consequently positively modulates its enzymatic activity towards APP. Our findings suggest that the benefits of ALC reported in previous clinical studies are underscored by the specific biological mechanism of this compound on APP metabolism. In fact, ALC can directly influence the primary event in Alzheimer's disease pathogenesis, i.e. the Amyloid beta cascade, promoting alpha-secretase activity and directly affecting the release of the non amyloidogenic metabolite.

Borroni B, Gardoni F, Parnetti L, Magno L, Malinverno M, Saggese E, Calabresi P, Spillantini MG, Padovani A, Di Luca M. · Department of Neurology, University of Brescia, Italy. · Neurobiol Aging. · Pubmed #17709155 No free full text.

Abstract: Cerebrospinal fluid (CSF) total Tau levels vary widely in neurodegenerative disorders, thus being not useful in their discrimination over Alzheimer disease. No CSF marker for progressive supranuclear palsy (PSP) is currently available. The aim of this study was to characterise and measure Tau forms in order to verify the differential patterns among neurodegenerative disorders. Seventy-eight patients with neurodegenerative disorders and 26 controls were included in the study. Each patient underwent a standardised clinical and neuropsychological evaluation, MRI, and CSF total-Tau and phospho-Tau dosage. In CSF and cerebral cortex, a quantitative immunoprecipitation was developed. An extended (55 kDa), and a truncated (33 kDa) forms of Tau were recognised. CSF samples were assayed, the optical density of the two Tau forms was measured, and the ratio calculated (Tau ratio, 33 kDa/55 kDa forms). Tau ratio 33 kDa/55 kDa was significantly decreased in patients with PSP (0.46+/-0.16) when compared to controls, including healthy subjects (1.16+/-0.46, P=0.002) and Alzheimer disease (1.38+/-0.68, P<0.001), and when compared to frontotemporal dementia (0.98+/-0.30, P=0.008) or corticobasal degeneration syndrome (0.98+/-0.48, P=0.02). Moreover, in PSP patients Tau form ratio was lower than in other neurodegenerative extrapyramidal disorders, such as Parkinson disease (1.16+/-0.26, P=0.002) and dementia with lewy bodies (1.44+/-0.48, P<0.001). Tau ratio 33 kDa/55 kDa did not correlate either with demographic characteristics, cognitive performances or with motor impairment severity. Truncated Tau production shows a different pattern in PSP compared to other neurodegenerative disorders, supporting the view of disease-specific pathological pathways. These findings are promising in suggesting the identification of a marker for PSP diagnosis in clinical practice.

Borroni B, Perani D, Archetti S, Agosti C, Paghera B, Bellelli G, Di Luca M, Padovani A. · Centre for Aging Brain and Neurodegenerative Disorders, Department of Neurology, University of Brescia, Italy. · BMC Neurol. · Pubmed #16930470 links to  free full text

Abstract: BACKGROUND: It has been recently demonstrated that in Frontotemporal Lobar Degeneration (FTLD) memory deficits at presentation are commoner than previously thought. Apolipoprotein E (ApoE) genotype, the major genetic risk factor in sporadic late-onset Alzheimer Disease (AD), modulates cerebral perfusion in late middle-age cognitively normal subjects. ApoE epsilon4 homozygous have reduced glucose metabolism in the same regions involved in AD.The aim of this study was to determine whether ApoE genotype might play a key-role in influencing the cerebral functional pattern as well as the degree of memory deficits in FTLD patients. METHODS: Fifty-two unrelated FTLD patients entered the study and underwent a somatic and neurological evaluation, laboratory examinations, a brain structural imaging study, and a brain functional Single Photon Emission Tomography study. ApoE genotype was determined. RESULTS: ApoE genotype influenced both clinical and functional features in FTLD. ApoE epsilon4-carriers were more impaired in long-term memory function (ApoE epsilon4 vs. ApoE non epsilon4, 6.3 +/- 3.9 vs. 10.1 +/- 4.2, p = 0.004) and more hypoperfused in uncus and parahippocampal regions (x,y,z = 38,-6,-20, T = 2.82, cluster size = 100 voxels; -32,-12,-28, T= 2.77, cluster size = 40 voxels). CONCLUSION: The present findings support the view that ApoE genotype might be considered a disease-modifying factor in FTLD, thus contributing to define a specific clinical presentation, and might be of relevance for pharmacological approaches.

Borroni B, Grassi M, Agosti C, Archetti S, Costanzi C, Cornali C, Caltagirone C, Caimi L, Di Luca M, Padovani A. · Centre for Ageing Brain and Dementia, Department of Neurology, University of Brescia, Brescia, Italy. · Am J Geriatr Psychiatry. · Pubmed #16582043 No free full text.

Abstract: OBJECTIVE: The objective of this study was to investigate the cumulative effect of the genes likely involved in Alzheimer disease (AD)-related psychosis and their interaction with disease stage and environmental factors. METHODS: Two hundred thirty-four patients with AD underwent clinical and neuropsychologic examination, behavioral and psychiatric disturbances evaluation, and were subsequently divided into two subgroups according to the presence (AD-P) or the absence (AD-nP) of psychotic symptoms. Cathecol-O-methyltransferase (COMT), serotonin gene-linked promoter region (5-HTTLPR), and Apolipoprotein E (ApoE) genotypes were performed. RESULTS: COMT*H (H/H or H/liter; odds ratio [OR]: 2.4; 95% confidence interval [CI]: 1.13-5.11) and 5-HTTLPR*S (S/S or S/liter, OR: 2.14; 95% CI: 1.13-4.07) were associated with AD-P. A gene dose effect was observed; in fact, carriers of both polymorphisms showed a fivefold risk for psychosis compared with patients bearing no polymorphisms. An interaction between these two genetic variations with disease stage and ischemic cardiomyopathy was found, the latter influencing AD-P risk only if "at-risk" genetic polymorphisms were present. The combined trend effect of COMT*H plus 5-HTTLPR*S and advance disease stage on AD-P risk was approximately 200% greater than that predicted by assuming additive effects, whereas the one obtained by COMT*H plus 5-HTTLPR*S and ischemic cardiomyopathy was 50% greater. ApoE genotype did not influence AD-P risk. CONCLUSIONS: These findings claim for a synergic effect of COMT*H and 5-HTTLPR*S polymorphisms on the risk of psychosis in AD and for their interaction with disease stage and ischemic cardiomyopathy. This study suggests that considering both the genetic background and the environmental correlates might provide new insight for understanding psychosis mechanisms related to AD.

Borroni B, Anchisi D, Paghera B, Vicini B, Kerrouche N, Garibotto V, Terzi A, Vignolo LA, Di Luca M, Giubbini R, Padovani A, Perani D. · Department of Neurological Sciences, Neurologic Clinic, University of Brescia, P.za Spedali Civili 1, 25100 Brescia, Italy. · Neurobiol Aging. · Pubmed #16298237 No free full text.

Abstract: Identifying pre-clinical Alzheimer's disease (AD) in subjects with mild cognitive impairment (MCI) is a major issue in clinical diagnosis. Establishing a combination of predictive markers from different fields of research might help in increasing the diagnostic accuracy. Aim of this study was to evaluate the potential role of 99mTc-ECD single photon emission computed tomography (SPECT) and memory scores in predicting conversion to AD in MCI subjects. Thirty-one MCI subjects underwent a clinical and neuropsychological examination, and a regional cerebral blood flow (rCBF) SPECT scan at baseline. Subjects had been followed periodically through 2 years in order to monitor the progression of cognitive symptoms. Canonical variate analysis of principal components was able to separate all subjects who converted to AD from those who remained stable, the former being characterized by a specific hypometabolic pattern, involving the parietal and temporal lobes, precuneus, and posterior cingulate cortex. Canonical correlation analysis of combined baseline memory deficits and rCBF SPECT images identified pre-clinical AD with a sensitivity and specificity of 77.8%. The pattern of hypoperfusion 99mTc-ECD SPECT and the severity of memory deficits predict the risk of progression to probable AD dementia in MCI subjects.

Borroni B, Grassi M, Agosti C, Costanzi C, Archetti S, Franzoni S, Caltagirone C, Di Luca M, Caimi L, Padovani A. · Center for Aging Brain and Dementia, Department of Neurology, University of Brescia, Italy. · Neurobiol Aging. · Pubmed #16257094 No free full text.

Abstract: Several studies have been conducted to understand the genetic correlates of Alzheimer disease (AD)-related behavioral and psychological symptoms in dementia (BPSD). However, given that BPSD rarely occur in isolation, it has been suggested that targeting BPSD individually is too narrow of an approach if one wants to accurately define all the associated risk factors. To date, we know of no work on genetic polymorphisms related to behavioral endophenotypes in AD. The present study sought to evaluate the relationship between such behavioral endophenotypes in AD and genetic variations in dopamine- or serotonin-related genes, such as catechol-O-methyltransferase (COMT) or 5-HTT gene-linked promoter region (5-HTTLPR), and apolipoprotein E (APOE). Among 232 AD patients who underwent clinical and neuropsychological examination, a behavioral and psychiatric evaluation, and genotyping at COMT, 5-HTTPLR, and APOE; 66.4% showed more than one behavioral symptom. By Principal Component Analysis of Neuropsychiatric Inventory (NPI) symptoms four endophenotypes were identified, these were termed "psychosis", "moods", "apathy", and "frontal". Modeling NPI symptom-endophenotype-genotype relationships, and taking into account possible confounds (i.e. demographic characteristics, comorbidities, concomitant pharmacological treatments, and disease severity) by latent variable models, COMT and 5-HTTLPR genetic variations correlated with "frontal" and "psychosis" endophenotypes. APOE genotype did not correlate with any endophenotype. These findings suggest that the possibility of identifying distinct phenotypes on a genetic basis among AD patients exists, and suggest that clustering of BPSD into endophenotypes might provide a new strategy for guiding future research on this issue.

Di Luca M, Grossi E, Borroni B, Zimmermann M, Marcello E, Colciaghi F, Gardoni F, Intraligi M, Padovani A, Buscema M. · Centre of Excellence for Neurodegenerative Disorders, Department of Pharmacological Sciences, University of Milan, Italy. · J Transl Med. · Pubmed #16048651 links to  free full text

Abstract: BACKGROUND: Previous studies have shown that in platelets of mild Alzheimer Disease (AD) patients there are alterations of specific APP forms, paralleled by alteration in expression level of both ADAM 10 and BACE when compared to control subjects. Due to the poor linear relation among each key-element of beta-amyloid cascade and the target diagnosis, the use of systems able to afford non linear tasks, like artificial neural networks (ANNs), should allow a better discriminating capacity in comparison with classical statistics. OBJECTIVE: To evaluate the accuracy of ANNs in AD diagnosis. METHODS: 37 mild-AD patients and 25 control subjects were enrolled, and APP, ADM10 and BACE measures were performed. Fifteen different models of feed-forward and complex-recurrent ANNs (provided by Semeion Research Centre), based on different learning laws (back propagation, sine-net, bi-modal) were compared with the linear discriminant analysis (LDA). RESULTS: The best ANN model correctly identified mild AD patients in the 94% of cases and the control subjects in the 92%. The corresponding diagnostic performance obtained with LDA was 90% and 73%. CONCLUSION: This preliminary study suggests that the processing of biochemical tests related to beta-amyloid cascade with ANNs allows a very good discrimination of AD in early stages, higher than that obtainable with classical statistics methods.

Borroni B, Perani D, Broli M, Colciaghi F, Garibotto V, Paghera B, Agosti C, Giubbini R, Di Luca M, Padovani A. · Clinica Neurologica, Università degli Studi di Brescia, Pza Spedali Civili, 1, 25100 Brescia, Italy. · J Neurol. · Pubmed #15965586 No free full text.

Abstract: Platelet Amyloid Precursor Protein ratio of different abnormal forms and 99mTc-ECD SPECT perfusion analysis were evaluated in Mild Cognitive Impairment (MCI) subjects who progressed to Alzheimer Disease (AD) and in stable MCI. We report that their combined evaluation increases the discriminative power of the analysis in identifying presymptomatic AD. The positive predictive value of these combined markers in identifying progressive MCI was 0.87, and the negative predictive value was 0.90. This observation suggests that the interplay of different markers should be considered for enhancing diagnostic accuracy of pre-clinical AD.

Zimmermann M, Borroni B, Cattabeni F, Padovani A, Di Luca M. · Centre of Excellence on Neurodegenerative Diseases and Department of Pharmacological Sciences, University of Milan, via Balzaretti 9, 20133 Milan, Italy. · Neurobiol Dis. · Pubmed #15837579 No free full text.

Abstract: Platelets mirror pathogenic alterations in the central nervous system of Alzheimer disease (AD) patients: an alteration of the Amyloid Precursor Protein (APP) forms pattern and decreased alpha-secretase activity--the non-amyloidogenic APP processing enzyme--were demonstrated. Platelets were analysed at baseline and after 30 days of cholinesterase inhibitor (ChEI) treatment (T30). ADAM10 levels, alpha- and beta-secretase activity were assessed measuring ADAM10 immunoreactivity, sAPPalpha release and the membrane-attached C-terminal fragments produced by beta- and alpha-secretase cleavage, that is, CTF99 and CTF83, respectively. ChEIs treatment rescues impaired APP metabolism increasing significantly ADAM10 levels (T30 vs. T0, P < 0.05), alpha-secretase activity (T30 vs. T0, P < 0.05) and reducing beta-secretase cleavage (T30 vs. T0, P < 0.05). Restoration of the balance between the mutually exclusive alpha- and beta-secretase pathway in APP processing caused by short-term ChEIs treatment potentially represents a key event in AD therapy linking in vivo cholinergic effect to APP metabolism. The use of platelets may represent a useful tool to follow molecular aspects of pharmacological response in AD patients.