Publications by authors named "Alessandra Bizzarro"

29 Publications

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Top-Down Proteomics of Human Saliva Highlights Anti-inflammatory, Antioxidant, and Antimicrobial Defense Responses in Alzheimer Disease.

Front Neurosci 2021 26;15:668852. Epub 2021 May 26.

Dipartimento di Scienze della Vita e dell'Ambiente, Università di Cagliari, Cagliari, Italy.

Alzheimer disease (AD) is the most prevalent neurodegenerative disease in the elderly, characterized by accumulation in the brain of misfolded proteins, inflammation, and oxidative damage leading to neuronal cell death. By considering the viewpoint that AD onset and worsening may be influenced by environmental factors causing infection, oxidative stress, and inflammatory reaction, we investigated the changes of the salivary proteome in a population of patients with respect to that in healthy controls (HCs). Indeed, the possible use of saliva as a diagnostic tool has been explored in several oral and systemic diseases. Moreover, the oral cavity continuously established adaptative and protective processes toward exogenous stimuli. In the present study, qualitative/quantitative variations of 56 salivary proteoforms, including post-translationally modified derivatives, have been analyzed by RP-HPLC-ESI-IT-MS and MS/MS analyses, and immunological methods were applied to validate MS results. The salivary protein profile of AD patients was characterized by significantly higher levels of some multifaceted proteins and peptides that were either specific to the oral cavity or also expressed in other body districts: (i) peptides involved in the homeostasis of the oral cavity; (ii) proteins acting as ROS/RNS scavengers and with a neuroprotective role, such as S100A8, S100A9, and their glutathionylated and nitrosylated proteoforms; cystatin B and glutathionylated and dimeric derivatives; (iii) proteins with antimicrobial activity, such as α-defensins, cystatins A and B, histatin 1, statherin, and thymosin β4, this last with a neuroprotective role at the level of microglia. These results suggested that, in response to injured conditions, Alzheimer patients established defensive mechanisms detectable at the oral level. Data are available via ProteomeXchange with identifier PXD021538.
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http://dx.doi.org/10.3389/fnins.2021.668852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189262PMC
May 2021

Role of CLU, PICALM, and TNK1 Genotypes in Aging With and Without Alzheimer's Disease.

Mol Neurobiol 2018 May 19;55(5):4333-4344. Epub 2017 Jun 19.

Complex Structure of Geriatrics, Research Laboratory, Department of Medical Sciences, I.R.C.C.S. Casa Sollievo della Sofferenza, Viale Cappuccini 1, 71013, San Giovanni Rotondo, Foggia, Italy.

Healthy and impaired cognitive aging may be associated to different prevalences of single-nucleotide polymorphisms (SNPs). In a multicenter case-control association study, we studied the SNPs rs11136000 (clusterin, CLU), rs541458 (phosphatidylinositol binding clatrin assembly protein, PICALM), and rs1554948 (transcription factor A, and tyrosine kinase, non-receptor, 1, TNK1) according to the three age groups 50-65 years (group 1), 66-80 years (group 2), and 80+ years (group 3) in 569 older subjects without cognitive impairment (NoCI) and 520 Alzheimer's disease (AD) patients. In NoCI subjects, a regression analysis suggested a relationship between age and TNK1 genotypes, with the TNK1-A/A genotype frequency that increased with higher age, and resulting in a different distribution of the TNK1-A allele. In AD patients, a regression analysis suggested a relationship between age and PICALM genotypes and TNK1 genotypes, with the PICALM-T/C and TNK1-A/A genotype frequencies that decreased with increasing age. A resulting difference in the distribution of PICALM-C allele and TNK1-A allele was also observed. The TNK1-A allele was overrepresented in NoCI subjects than in AD patients in age groups 2 and 3. These results confirmed after adjustment for apolipoprotein E polymorphism, which suggested a different role of PICALM and TNK1 in healthy and impaired cognitive aging. More studies, however, are needed to confirm the observed associations.
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http://dx.doi.org/10.1007/s12035-017-0547-xDOI Listing
May 2018

Patient with rapidly evolving neurological disease with neuropathological lesions of Creutzfeldt-Jakob disease, Lewy body dementia, chronic subcortical vascular encephalopathy and meningothelial meningioma.

Neuropathology 2017 Apr 16;37(2):110-115. Epub 2016 Sep 16.

Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanità, Rome, Italy.

We report a case of rapidly evolving neurological disease in a patient with neuropathological lesions of Creutzfeldt-Jakob disease (CJD), Lewy body dementia (LBD), chronic subcortical vascular encephalopathy and meningothelial meningioma. The coexistence of severe multiple pathologies in a single patient strengthens the need to perform accurate clinical differential diagnoses in rapidly progressive dementias.
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http://dx.doi.org/10.1111/neup.12343DOI Listing
April 2017

An atypical case of acute disseminated encephalomyelitis associated with cytomegalovirus infection.

Mult Scler Relat Disord 2016 Jan 10;5:70-2. Epub 2015 Nov 10.

Institute of Neurology, Department of Geriatrics, Neurosciences and Orthopedic, Catholic University, Rome, Italy.

We present the case of a young man admitted to our hospital for persistent headache associated with fever, retrorbitary pain and vomiting, who rapidly developed encephalopathy with drowsiness, paraplegia, hypoesthesia with a D6 sensory level and urinary retention. Brain and spinal cord MRI revealed findings compatible with acute disseminated encephalomyelitis (ADEM) and microbiological tests documented a cytomegalovirus (CMV) infection. CMV infection is extraordinarily associated with ADEM, but must be included in microbiological tests, because early diagnosis and treatment ameliorate the neurological outcome.
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http://dx.doi.org/10.1016/j.msard.2015.11.003DOI Listing
January 2016

Neural substrates of the 'low-level' system for speech articulation: Evidence from primary opercular syndrome.

J Neuropsychol 2017 09 7;11(3):450-457. Epub 2016 Feb 7.

Department of Neuroimaging, Catholic University, Rome, Italy.

We describe a patient with progressive disorder of speech, without language impairment (opercular syndrome). Morphometric analysis confirmed asymmetric volume reduction of the precentral areas (>left). Diffusion imaging showed significant white matter changes in the left frontal lobe, with specific involvement of the left corticobulbar tract and connections between supplementary/pre-supplementary motor areas and the frontal operculum (frontal aslant tract). We suggest that the organization of expressive language includes a 'low level' motor system principally distributed in the left hemisphere that shows specific susceptibility to neurodegeneration, distinct from neural systems subtending praxic, and cognitive aspects of language.
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http://dx.doi.org/10.1111/jnp.12099DOI Listing
September 2017

Sleep palsy involving different nerves: Role of ultrasound.

Muscle Nerve 2016 Apr 20;53(4):656-7. Epub 2016 Jan 20.

Department of Geriatrics, Neurosciences and Orthopaedics, Catholic University of the Sacred Heart, Rome, Italy.

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http://dx.doi.org/10.1002/mus.25005DOI Listing
April 2016

Cognitive and behavioral determinants of psychotic symptoms in Alzheimer's disease.

Dement Geriatr Cogn Disord 2015 7;39(3-4):194-206. Epub 2015 Jan 7.

Research Center for Neuropsychology, Institute of Neurology, Catholic University, Rome, Italy.

Aims: To investigate the relationship between psychotic symptoms and cognitive impairment in Alzheimer's disease (AD).

Methods: A total of 108 subjects affected by AD were subdivided into subjects without delusions (ND), subjects with paranoid delusions (PD), subjects with delusional misidentifications (DM), subjects with both DM and PD (DM+PD), subjects with visual hallucinations (v-HALL), and subjects without visual hallucinations (N-HALL).

Results: PD and ND subjects performed similarly on neuropsychological tests, while DM patients performed significantly worse than PD and ND patients. v-HALL patients performed worse than N-HALL patients on memory, visuospatial, and executive functions. As for behavioral features, DM and v-HALL subjects reported higher scores on the abnormal motor behavior subscale of the neuropsychiatric inventory (NPI); PD subjects reported higher scores on the disinhibition subscale of the NPI. The severity of PD was predicted by the severity of disinhibition (B = 0.514; p = 0.016) but not by neuropsychological performances. The severity of DM was predicted by age (B = 0.099; p = 0.048) and MMSE (B = -0.233; p = 0.001). The severity of v-HALL was predicted by age (B = 0.052; p = 0.037) and scores on an immediate visual memory task (B = -0.135; p = 0.007).

Conclusions: The occurrence of PD may require the relative sparing of cognitive functions and be favored by frontal lobe dysfunction, while DM is associated with the overall level of cognitive impairment. Finally, v-HALL are associated with the impairment of visuospatial abilities.
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http://dx.doi.org/10.1159/000369161DOI Listing
August 2015

R208H-129VV haplotype in the prion protein gene: phenotype and neuroimaging of a patient with genetic Creutzfeldt-Jakob disease.

J Neurol 2013 Oct 25;260(10):2650-2. Epub 2013 Aug 25.

Dipartimento di Gerontologia, Neuroscienze ed Ortopedia, Istituto di Neurologia, Università Cattolica del Sacro Cuore, Policlinico A.Gemelli, Largo A. Gemelli 8, 00168, Rome, Italy.

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http://dx.doi.org/10.1007/s00415-013-7078-9DOI Listing
October 2013

Cerebellar degeneration associated with mGluR1 autoantibodies as a paraneoplastic manifestation of prostate adenocarcinoma.

J Neuroimmunol 2013 Oct 3;263(1-2):155-8. Epub 2013 Aug 3.

Institute of Neurology, Department of Neuroscience, Catholic University, Rome, Italy. Electronic address:

Subacute cerebellar degeneration associated with metabotropic glutamate receptor type 1 (mGluR1) autoantibodies is an uncommon syndrome known to be part of the spectrum of paraneoplastic cerebellar degenerations associated with neuronal autoantibodies. We describe a patient with prostate adenocarcinoma who developed a subacute cerebellar ataxia. Autoantibodies specific to mGluR1 were detected in patient's serum and cerebrospinal fluid (CSF). Immunohistochemistry analyses of patient's prostate adenocarcinoma revealed abundant mGluR1 expression in luminal acinar epithelial cells and binding of patient's IgGs to tumoral mGluR1. These findings suggest that cerebellar degeneration associated with mGluR1 antibodies can be a paraneoplastic accompaniment of prostate adenocarcinoma.
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http://dx.doi.org/10.1016/j.jneuroim.2013.07.015DOI Listing
October 2013

The serotonin transporter gene locus in late-life major depressive disorder.

Am J Geriatr Psychiatry 2013 Jan 2;21(1):67-77. Epub 2013 Jan 2.

Geriatric Unit & Gerontology-Geriatric Research Laboratory, Department of Medical Sciences, Institute of Care and Scientific Research Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.

Objective: Polymorphism C in the solute carrier family 6 (neurotransmitter transporter, serotonin), member 4 (SLC6A4) gene has been variously associated with major depressive disorder (MDD). To the best of our knowledge, no data were reported regarding a role of SLC6A4 in late-life MDD. The aim of this study was to explore the possible involvement of the SLC6A4 locus in patients with late-life MDD by means of a haplotype-tagged approach.

Design: Case-control study.

Setting: Older patients attending a geriatric unit.

Participants: A total of 218 patients with late-life MDD (61 men and 157 women) age 65 to 92 years (76.29 ± 6.53 years) and 363 depression-free healthy subjects (156 men and 207 women) age 41 to 65 years (48.33 ± 5.94 years).

Measurements: Genotyping and haplotype estimation of the three markers rs4795541, rs140701, and rs3813034 spanning a 39-kb block the SLC6A4 locus. Diagnoses of late-life MDD, mild cognitive impairment, Alzheimer disease, vascular dementia, and other dementing diseases were made using current clinical criteria.

Results: No significant differences were observed in allele or genotype distribution for the three SLC6A4 markers across the study groups. Because the comparison group could not be matched for age, a sensitivity analysis for the misclassification of controls was performed according to different scenarios. For each simulated scenario, the same nonsignificant result was observed. However, the results are limited to late-life MDD that is specifically not associated with cognitive impairment, and there was limited power for detecting very small effect sizes.

Conclusions: Our findings suggested that the SLC6A4 locus play a minor role, if any, in the pathogenesis of late-life MDD. Also, tempering our conclusions, we were unable to account for population stratification, recurrence or chronicity of depression, nor the influence of coexisting medical, cognitive, and psychosocial stressors.
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http://dx.doi.org/10.1016/j.jagp.2012.10.012DOI Listing
January 2013

Possible relationship between Al/ferritin complex and Alzheimer's disease.

Clin Biochem 2013 Jan 24;46(1-2):89-93. Epub 2012 Oct 24.

Laboratory of Clinical Biochemistry - Policlinico Agostino Gemelli, Catholic University, Rome, Italy.

Objectives: Ferritin is the main iron-storage protein capable of containing thousands of iron atoms. However, ferritin can bind in vitro other atoms such as aluminum and it has been shown that also in vivo atoms other than iron, as aluminum and zinc, are present in large amounts in ferritin. Since aluminum appears to be involved in the development of Alzheimer's disease, in the present study the specific content of aluminum in ferritin of Alzheimer's patients was analyzed and compared with other control groups.

Design And Methods: The content of Fe, Al and Zn of blood ferritin was measured by mass spectrometry in patients with Alzheimer's disease and compared with other clinical and control groups.

Results: The results obtained confirm the hypothesis of a functional role of ferritin as a regulatory protein of toxic metals and clearly indicate that ferritin from Alzheimer's patients has a content of aluminum higher than that of controls.

Conclusions: The specific aluminum content of ferritin seems to be related to different disease stages of Alzheimer's disease. This result confirms the hypothesis of aluminum as a possible factor inducing the Alzheimer's disease and opens the ways to possible new diagnostic tests.
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http://dx.doi.org/10.1016/j.clinbiochem.2012.10.023DOI Listing
January 2013

Replication of association of CHRNA4 rare variants with sporadic amyotrophic lateral sclerosis: the Italian multicentre study.

Amyotroph Lateral Scler 2012 Oct 8;13(6):580-4. Epub 2012 Aug 8.

Istituto di Neurologia, Università Cattolica del Sacro Cuore, Roma, Italy.

Neuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels widely expressed throughout the mammalian brain, including bulbar and spinal motor neurons. They are involved in neuroprotection and in control of release of many neurotransmitters, including glutamate. Previous data raised the hypothesis that rare variants in the region coding the intracellular loop subunits of nAChRs might represent one of several genetic risk factors for SALS. The aim of present study was to replicate the study in an independent cohort of ALS patients. We analysed 718 sporadic ALS patients from five Italian ALS centres and 1300 ethnically matched controls. We focused primarily on CHRNA4, encoding α4 subunit, since most mutations were previously detected in this gene. We observed a significant association between CHRNA4 mutations and ALS (OR 2.91; 95% CI 1.4080-6.0453; p = 0.0056). Most mutations detected in patients were not present in the dbSNP134 and in 3500 ethnically matched control chromosomes and affected evolutionary conserved amino acid residues. In conclusion, the present data confirm that CHRNA4 variants are overrepresented in SALS strengthening the hypothesis can they act as predisposing genetic factors for SALS.
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http://dx.doi.org/10.3109/17482968.2012.704926DOI Listing
October 2012

TOMM40, APOE, and APOC1 in primary progressive aphasia and frontotemporal dementia.

J Alzheimers Dis 2012 ;31(4):731-40

Gerontology and Geriatrics Research Laboratory, I.R.C.C.S. Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.

The aim of this study was to investigate the apolipoprotein E (APOE) chromosomal region in frontotemporal lobar degeneration (FTLD), and in particular in primary progressive aphasia (PPA) and the behavioral variant frontotemporal dementia (bvFTD). To this aim, we selected three single-nucleotide polymorphisms (SNPs) rs2075650 and rs157590 (TOMM40), and rs1064725 (APOC1), representative of the linkage disequilibrium (LD) blocks at the 19q13-q13.2 chromosomal region. The SNPs rs429358 and rs7412 forming the APOE polymorphism were also included in the study. The analysis was made in 282 patients with a clinical diagnosis of sporadic FTLD, namely 207 bvFTD and 75 PPA, and 296 cognitively healthy control subjects. LD (r2 = 0.35) between TOMM40 (rs2075650) and APOC1 (rs1064725) was observed in PPA, but not in controls and in bvFTD. Inside this region of 26.9 kb, LD (r2 ≥ 0.50) between TOMM40 (rs2075650) and APOE (rs429358) was observed in bvFTD and in controls, but not in PPA. Inside this region of 16.3 kb, LD (r2 = 0.14) between TOMM40 (rs157590) and APOE (rs429358) was observed in PPA, but not in bvFTD and in controls. Although the genetics of PPA and bvFTD needs further investigation, our results suggested the presence of a different genetic background underlying PPA and bvFTD at the 19q13-q13.2 chromosomal region.
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http://dx.doi.org/10.3233/JAD-2012-120403DOI Listing
July 2013

EPA and DHA differentially affect in vitro inflammatory cytokine release by peripheral blood mononuclear cells from Alzheimer's patients.

Curr Alzheimer Res 2012 Oct;9(8):913-23

Institute of General Pathology, Università Cattolica S. Cuore, L.go F. Vito 1, 00168 Rome, Italy.

It has been hypothesized that pro-inflammatory cytokines may play a pathogenic role in Alzheimer's disease (AD), and that n-3 polyunsaturated fatty acids may be protective against the development and progression of this disease. A reduced release of inflammatory cytokines by lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs) from AD patients dietary supplemented with a mixture of eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) was recently reported. On this basis, we investigated the possible differential effects of the two purified fatty acids on inflammatory cytokine release, a subject still not explored, even though of great pharmacological interest. We treated in vitro phytohaemagglutinin (PHA)- or LPS-stimulated PBMCs from AD patients and age-matched healthy controls (HCs) with purified EPA or DHA. Higher pro- to anti-inflammatory cytokine ratios, indicative of a pro-inflammatory profile, were observed in PHA-stimulated PBMCs from AD patients in basal conditions. The addition of both EPA and DHA markedly reduced the cytokine release, with DHA showing always a more prominent effect than EPA. However, whereas DHA reduced only the high IL-1β/IL-10 ratio, EPA was able to reduce also the IL-6/IL-10 ratio. In stimulated PMBCs from HCs the reducing effect on cytokine release was not always observed, or observed at a lower degree. In conclusion, whereas DHA appeared more powerful in inhibiting each single inflammatory cytokine, the proinflammatory profile of the AD patients' cells was better reverted by EPA to a profile more similar to that found in HCs. A combination of both the fatty acids, seems to be still the best solution.
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http://dx.doi.org/10.2174/156720512803251147DOI Listing
October 2012

Effectiveness of a high-throughput genetic analysis in the identification of responders/non-responders to CYP2D6-metabolized drugs.

Clin Lab 2011 ;57(11-12):887-93

Laboratory of Clinical Chemistry, Department of Clinical Pathology, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy.

Background: Recent studies investigating the single cytochrome P450 (CYP) 2D6 allele *2A reported an association with the response to drug treatments. More genetic data can be obtained, however, by high-throughput based-technologies. Aim of this study is the high-throughput analysis of the CYP2D6 polymorphisms to evaluate its effectiveness in the identification of patient responders/non-responders to CYP2D6-metabolized drugs.

Methods: An attempt to compare our results with those previously obtained with the standard analysis of CYP2D6 allele *2A was also made. Sixty blood samples from patients treated with CYP2D6-metabolized drugs previously genotyped for the allele CYP2D6*2A, were analyzed for the CYP2D6 polymorphisms with the AutoGenomics INFINITI CYP4502D6-I assay on the AutoGenomics INFINITI analyzer.

Results: A higher frequency of mutated alleles in responder than in non-responder patients (75.38 % vs 43.48 %; p = 0.015) was observed. Thus, the presence of a mutated allele of CYP2D6 was associated with a response to CYP2D6-metabolized drugs (OR = 4.044 (1.348 - 12.154). No difference was observed in the distribution of allele *2A (p = 0.320).

Conclusions: The high-throughput genetic analysis of the CYP2D6 polymorphisms better discriminate responders/non-responders with respect to the standard analysis of the CYP2D6 allele *2A. A high-throughput genetic assay of the CYP2D6 may be useful to identify patients with different clinical responses to CYP2D6-metabolized drugs.
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February 2012

The APOE gene locus in frontotemporal dementia and primary progressive aphasia.

Arch Neurol 2011 May;68(5):622-8

BiolD, Geriatric Unit and Gerontology-Geriatrics Research Laboratory, Department of Medical Sciences, I.R.C.C.S. Casa Sollievo della Sofferenza, Viale Cappuccini 1, San Giovanni Rotondo.

Objective: To investigate the role of the apolipoprotein E (APOE) locus in frontotemporal dementia (FTD) and primary progressive aphasia (PPA).

Design: Case-control study.

Setting: Neurology clinic, Rome, Italy.

Patients: Eighty-six patients with a clinical diagnosis of sporadic FTD, including 32 patients with a clinical diagnosis of PPA, and 99 nondemented cognitively intact control subjects.

Main Outcome Measures: Genotype analysis of the 3 single-nucleotide polymorphisms rs449647, rs769446, and rs405509 in the promoter region of the APOE gene and of the 2 single-nucleotide polymorphisms rs429358 and rs7412 forming the common apoE polymorphism.

Results: Significant associations with FTD were observed for genotypes rs449647 A/T (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0-4.5), rs769446 T/C (OR, 4.4; 95% CI, 1.9-10.2), and APOE ε3/ε4 (OR, 4.1; 95% CI, 1.6-10.9). Significant associations with PPA were also observed for genotypes APOE ε3/ε4 (OR, 22.5; 95% CI, 1.2-229.4) and ε4/ε4 (OR, 7.5; 95% CI, 2.6-21.6). Significant associations with FTD were observed for haplotypes A-C-G-C-C (OR, 5.6; 95% CI, 1.4-21.5) and T-T-T-C-C (OR, 5.2; 95% CI, 1.1-24.0). Significant associations with PPA were also observed for haplotypes A-T-T-T-C (OR, 0.4; 95% CI, 0.2-0.9) and A-T-T-C-C (OR, 5.2; 95% CI, 1.4-19.3).

Conclusion: Although the physiological role of apoE in FTD and PPA needs further investigations, our results suggest an involvement of the APOE gene locus in the genetics of FTD and PPA.
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http://dx.doi.org/10.1001/archneurol.2011.90DOI Listing
May 2011

Role of cytochrome P4502D6 functional polymorphisms in the efficacy of donepezil in patients with Alzheimer's disease.

Pharmacogenet Genomics 2011 Apr;21(4):225-30

Geriatric Unit & Gerontology-Geriatrics Research Laboratory, Department of Medical Sciences, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy.

Objective: Cytochrome P450 (CYP) 2D6 enzyme is the major responsible for the metabolism of donepezil, an inhibitor of acetyl cholinesterase currently used for the symptomatic treatment of mild-to-moderate Alzheimer's disease (AD). Functional polymorphisms in the CYP2D6 gene may affect enzyme activity and thus, the metabolism of donepezil. The aim of this study was to evaluate the effect of 16 functional polymorphisms in the CYP2D6 gene on the clinical response to donepezil treatment in patients with mild-to-moderate AD.

Methods: In this multicenter prospective cohort study we evaluated 57 unrelated Caucasians clinically diagnosed as AD according to the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association Work Group criteria. Patients were treated with donepezil (5-10 mg/daily) for 6 months. The response to donepezil treatment was evaluated at 6-month follow-up according to the National Institute for Health and Clinical Excellence requirements. The identification of 16 clinically relevant CYP2D6 gene variants was performed by a high-throughput genetic analysis.

Results: Thirty-eight of 57 patients (67%) were responders and 19 patients (33%) were nonresponders to donepezil treatment. A significantly higher frequency of gene variants conferring decreased or absent enzyme activity was observed in responder than in nonresponder patients (73.68% vs. 36.84%; P=0.005). The presence of gene variants conferring decreased or absent activity of the CYP2D6 enzyme was significantly associated with a clinical response to donepezil treatment (odds ratio=6.286; 95% confidence interval=1.828-21.667).

Conclusions: Functional polymorphisms in the CYP2D6 gene can influence the clinical efficacy of donepezil. The analysis of CYP2D6 genotypes may be useful in identifying subgroups of AD patients with different clinical response to donepezil treatment.
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http://dx.doi.org/10.1097/FPC.0b013e32833f984cDOI Listing
April 2011

An atypical phenotype of CJD associated with the E200K mutation in the prion protein gene.

Neurol Sci 2010 Dec 21;31(6):837-9. Epub 2010 Aug 21.

Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy.

E200K mutation of the prion protein gene (PRNP) presented with a variety of phenotypes. A 55-year-old woman complaining of slowly progressive walking difficulties came to our observation. She showed a severe progressive ataxo-spastic syndrome but a mild cognitive impairment only. Repeated EEGs showed a diffuse slowing of the rhythm without specificity. Brain MRI revealed by FLAIR showed widespread multiple hyperintensities in the whole cerebral cortex, caudate and putamen nuclei, and in the pulvinar and medial thalamus bilaterally. These signal abnormalities were best detected by DWI with restricted diffusion on ADC map. The clinical diagnosis of possible genetic Creutzfeldt-Jakob disease (CJD) has been confirmed by PRNP gene analysis which revealed the presence of a E200K mutation. This report confirms the heterogeneity of phenotypes in E200K mutated familial CJD with the occurrence of a new phenotype not previously described.
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http://dx.doi.org/10.1007/s10072-010-0388-0DOI Listing
December 2010

Polymorphism C in the serotonin transporter gene in depression-free elderly patients with vascular dementia.

Dement Geriatr Cogn Disord 2010 26;29(5):424-31. Epub 2010 May 26.

Geriatric Unit and Gerontology-Geriatrics Research Laboratory, Department of Medical Sciences, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy. dseripa @ operapadrepio.it

Background: Genotypes of the solute carrier family 6 (neurotransmitter transporter, serotonin) member 4 (SLC6A4) have been variously associated with depression, obsessive-compulsive disorder, memory impairment, and anxiety. Less clear are data regarding their association with severe dementia, in particular with vascular dementia (VaD).

Aims: To evaluate the possible involvement of different SLC6A4 genotypes/haplotypes in VaD.

Methods: The analysis of the 3 markers rs3813034, rs140701 and rs4795541 spanning the SLC6A4 locus was made in 541 consecutive patients clinically diagnosed as having VaD (n = 372) or no cognitive impairment (n = 169) attending a geriatric ward. A community-dwelling sample of 353 healthy subjects, as a reference for the genetic frequencies in the recruitment area, was also included in the study. All patients and subjects were free from any symptoms of depression, obsessive-compulsive disorder and anxiety. A complete neuroimaging documentation was available for all patients.

Results: No important differences were observed in genotype distribution across the study groups. Similarly, no important differences were observed in haplotype distribution when a 3-point analysis was made.

Conclusion: Our findings suggest that polymorphism C in the promoter region of the SLC6A4 gene plays a minor role, if any, in the pathogenesis of VaD.
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http://dx.doi.org/10.1159/000275670DOI Listing
September 2010

BuChE K variant is decreased in Alzheimer's disease not in fronto-temporal dementia.

J Neural Transm (Vienna) 2010 Mar;117(3):377-83

Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy.

Alzheimer's disease (AD) is characterized by a significant reduction in AcetylCholinesterase and an increase in ButyrylCholinesterase (BuChE) activity. The existence of polymorphic regions on the BuChE gene has been previously described; the most frequently found polymorphism is the so-called K variant, which leads to a 30% decreased enzymatic activity. Different studies reported a positive association between K variant and AD, strongest among late-onset AD and Apolipoprotein E (APOE) e4 carriers. We analyzed APOE and BuChE polymorphisms in 167 AD and 59 fronto-temporal dementia (FTD) patients compared with 129 healthy controls (HC). We reported a significantly lower frequency of the BuChE K variant in AD compared with HC and FTD and a significant increased frequency of the K variant in FTD. These results are in agreement with the known increase of the BuChE activity in AD and support the evidence of different molecular pathways involved in the pathogenesis of AD and FTD.
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http://dx.doi.org/10.1007/s00702-009-0358-yDOI Listing
March 2010

The complex interaction between APOE promoter and AD: an Italian case-control study.

Eur J Hum Genet 2009 Jul 28;17(7):938-45. Epub 2009 Jan 28.

Institute of Neurology, Department of Neuroscience, Catholic University School of Medicine, Rome, Italy.

The single nucleotide polymorphisms (SNPs) rs449647, rs769446 and rs405509 in the promoter region of the APOE gene have been variously suggested to be epsilon 4-independent risk factors for Alzheimer's disease (AD). A previous Italian study found that the rs449647 was significantly associated with late-onset AD. The aim of this study was to verify whether these APOE promoter SNPs are genetic risk factors for AD and to investigate their interaction with the common APOE polymorphism. A total of 169 clinically diagnosed AD patients and 99 cognitively intact age-matched controls were included in the study. Significant associations with AD independent from sex, age and APOE/epsilon 4 status were found for rs449647 A/A and rs405509 G/G genotypes (positive), and rs449647 A/T and rs405509 T/T genotypes (negative). Haplotype frequency estimation at the APOE locus showed significant associations for the ATG4, ATT4 and ACG3 (positive) and ATT2, ATT3 and TCG3 (negative) haplotypes. Therefore this study confirms the role of the rs449647 A/A genotype as risk factor for AD in Italy and suggests that promoter genotypes and APOE haplotypes might have a complex function in AD-associated genetic risk factors.
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http://dx.doi.org/10.1038/ejhg.2008.263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2986491PMC
July 2009

Psychotic symptoms in Alzheimer's disease and 5-HTTLPR polymorphism of the serotonin transporter gene: evidence for an association.

J Alzheimers Dis 2009 ;16(1):173-80

Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy.

The occurrence of psychotic symptoms is common in Alzheimer's disease (AD), configuring a possibly distinguished clinical entity defined "Psychosis in Alzheimer's Disease" (AD-P). In order to investigate demographic clinical and biological variables potentially associated to the occurrence of AD-P, 148 AD patients were selected. Mini-Mental State Examination (MMSE), Activities of Daily Living (ADL), and Instrumental Activities of Daily Living (IADL) scores, socio-economic status and 5-HTTLPR and APOE gene polymorphisms were determined for each subject. AD-P patients were significantly more frequent carriers of the long (L) allele of 5-HTTLPR. The percentage of AD-P increased with the number of copies of the L-allele: 13% among S homozygote; 36% among heterozygotes; 51% among L-homozygotes. No difference resulted between AD-P and non-psychotic AD (AD-NP) in the distribution of the epsilon4 allele of APOE. The risk of AD-P was increased in L/L homozygous (OR = 7.25, p = 0.003) and, to a lesser extent, in heterozygous (OR = 3.91; p = 0.018). Backward logistic regression analysis showed that the risk for AD-P was increased in older subjects (OR = 1.07; p = 0.018) while an increase of MMSE score was protective (OR = 0.90; p = 0.004). The occurrence of AD-P resulted significantly related to age at examination, cognitive status, and to the presence of the 5-HTTLPR L-allele.
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http://dx.doi.org/10.3233/JAD-2009-0950DOI Listing
March 2009

The RELN locus in Alzheimer's disease.

J Alzheimers Dis 2008 Jul;14(3):335-44

Geriatric Unit & Gerontology-Geriatric Research Laboratory, Department of Medical Sciences, I.R.C.C.S. Casa Sollievo dalla Sofferenza, San Giovanni Rotondo (FG), I-71013, Italy.

Reelin, a serine protease encoded by the RELN gene, is part of the apolipoprotein E (apoE) biochemical pathway that is involved in the pathogenesis of Alzheimer's disease (AD). Sex-related differences in the epidemiology, pathology and clinical characteristics of AD have been reported. To explore the potential contribution of RELN gene variants in the pathogenesis of AD, we investigated three polymorphisms spanning the RELN locus, i.e., a triplet tandem repeat in the 5'UTR and two single-nucleotide polymorphisms (SNPs) rs607755 and rs2229874, located in the splice-junction of exon 6 and in the coding region of exon 50. The analysis was made in 223 sporadic AD patients and 181 age-matched controls of Caucasian ethnicity. Significant differences between AD patients and controls were found in distribution of 5'UTR and rs607755 genotypes, whereas no differences were found in the distribution of rs2229874 genotypes. When patients and controls were divided according to sex, significant differences in genotype distribution were found in females and not in males, also after adjustment for APOE genotypes. These findings suggest that RELN gene variants may play a role in the pathogenesis of AD, particularly in females.
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http://dx.doi.org/10.3233/jad-2008-14308DOI Listing
July 2008

Survival in Alzheimer's disease is shorter in women carrying heterozygosity at codon 129 of the PRNP gene and no APOE epsilon 4 allele.

Dement Geriatr Cogn Disord 2008 7;25(4):354-8. Epub 2008 Mar 7.

Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.

We assessed the role of the APOE genotype and prion protein polymorphism at codon 129 in predicting the clinical duration of 92 neuropathologically confirmed sporadic Alzheimer's disease patients. Analyses of survival showed that the absence of the APOE epsilon 4 allele in heterozygous codon 129 PRNP carriers is a negative predictor of survival. When this subgroup of patients was stratified by sex, the effect of APOE was observed in women, but not in men.
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http://dx.doi.org/10.1159/000119730DOI Listing
June 2008

Association analysis of GRIN2B, encoding N-methyl-D-aspartate receptor 2B subunit, and Alzheimer's disease.

Dement Geriatr Cogn Disord 2008 26;25(3):287-92. Epub 2008 Feb 26.

Geriatric Unit & Gerontology-Geriatrics Research Laboratory, Department of Medical Sciences, San Giovanni Rotondo, Italy.

Background: The glutamatergic neurotransmitter systems play a crucial role in memory formation and information processing. Alterations in this system contribute to the manifestation of symptoms in Alzheimer's disease (AD). Glutamate transmits signals via the N-methyl-D-aspartate receptors (NMDARs).

Aims: The potential involvement of polymorphisms in the GRIN2B gene, encoding subunit 2B of the NMDA receptor, in the risk for AD was evaluated.

Methods: We investigated the 3 single-nucleotide polymorphisms (SNPs) rs1019385, rs1806201 and rs890, i.e. the G(-200)-->T transversion in the 5'UTR, the A(2664)-->G transition in exon 13 and the G(5072)-->T transition in the 3'UTR of the GRIN2B gene, in 222 Caucasian AD patients and 170 healthy Caucasian age-matched controls.

Results: No differences were found in the overall distribution of the single-nucleotide polymorphism genotypes between AD patients and healthy controls, even when the analysis was adjusted for sex, age and APOE. As expected from genotype frequencies, no differences were found in the distribution of the estimated allele and haplotype frequencies between AD patients and healthy controls.

Conclusion: In this study no significant association between polymorphisms in the GRIN2B gene and AD was observed. Further investigations of polymorphisms in the gene encoding the NMDA receptor 2B subunit in AD patients with different genetic setting are needed to clarify their role in the pathogenesis of AD.
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http://dx.doi.org/10.1159/000118634DOI Listing
May 2008

Apolipoprotein E epsilon4 allele differently affects the patterns of neuropsychological presentation in early- and late-onset Alzheimer's disease patients.

Dement Geriatr Cogn Disord 2004 18;18(2):125-31. Epub 2004 Jun 18.

Department of Neurology, Catholic University of Rome, Rome, Italy.

The presence of the apolipoprotein E (APOE) epsilon4 allele is a definite risk factor for the onset of Alzheimer's disease (AD). Its presence seems to affect especially the memory in the early stage of the disease, but the effect on the progression of the disease and survival is still controversial. Some longitudinal studies could be influenced by variables other than APOE, such as the response to medical treatment, rehabilitation therapy and inclusion of patients at different stages of progression at baseline. Moreover, the inclusion in the same study sample of patients of different ages at onset of the disease (below 65 or above 80 years) appears arbitrary. In our study, we evaluated a population of newly diagnosed untreated AD patients at their first neuropsychological examination and with the onset of their first symptoms not longer than 3 years ago. In order to analyse the different effects of the APOE epsilon4 allele on the different ages at the onset of the disease, we split the study sample into two groups: (1) subjects under 65 years [early-onset AD (EOAD); n = 30] and subjects over 70 years [late-onset AD (LOAD); n = 41], excluding subjects with an age of onset between 66 and 69 years. Our results show that the APOE epsilon4 allele carriers are characterised by a different neuropsychological pattern at the disease onset; however, only in the EOAD group is this effect significant: in EOAD, the epsilon4 allele carriers obtained worse performances in learning, long-term verbal memory and general intelligence tasks. On the contrary, in LOAD patients, the pattern of cognitive impairment at the onset is not dependent on the possession of an epsilon4 allele in the genotype. Such data could suggest a careful control of the study sample concerning age at the onset of the disease since APOE could play a different role in EOAD and LOAD mainly due to the different pathogenic mechanism at the onset and evolution of AD.
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http://dx.doi.org/10.1159/000079191DOI Listing
February 2005

Methylenetetrahydrofolate reductase and angiotensin converting enzyme gene polymorphisms in two genetically and diagnostically distinct cohort of Alzheimer patients.

Neurobiol Aging 2003 Nov;24(7):933-9

Laboratory of Molecular Pathology and Gene Therapy, IRCCS H Casa Sollievo della Sofferenza, Opera di Padre Pio da Pietrelcina, San Giovanni Rotondo (FG), Italy.

The role of methylenetetrahydrofolate reductase (MTHFR) and angiotensin converting enzyme (ACE) gene polymorphisms as risk factors for the occurrence of Alzheimer's disease (AD) is still controversial. In this study, we investigated the common MTHFR C677-->T and ACE insertion/deletion (I/D) gene polymorphisms as risk factors for AD in two genetically and diagnostically distinct cohort of Alzheimer's patients. We analyzed a neuropathologically confirmed American cohort of 124 AD patients and 97 elderly controls, and a clinically diagnosed Italian cohort of 126 probable AD cases, 106 elderly controls, and a community-based sample of 1232 subjects aged under 65 years. No difference was found in polymorphism distribution between cases and controls in both study cohorts. We also tested a possible association between the polymorphisms investigated. No interaction was found between the MTHFR and ACE alleles. Moreover, no association was found for the ACE and MTHFR polymorphisms with age at onset, disease duration and MMSE score at observation. Thus, in our study, MTHFR C677-->T and ACE I/D polymorphisms do not appear to confer an added risk for AD.
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http://dx.doi.org/10.1016/s0197-4580(03)00040-xDOI Listing
November 2003