Elio Scarpini

The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers.

The cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)‐42, total‐tau (T‐tau), and phosphorylated‐tau (P‐tau) demonstrate good diagnostic accuracy for Alzheimers disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimers Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch‐to‐batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program.

APOE and Alzheimer disease: a major gene with semi-dominant inheritance

Apolipoprotein E (APOE) dependent lifetime risks (LTRs) for Alzheimer Disease (AD) are currently not accurately known and odds ratios alone are insufficient to assess these risks. We calculated AD LTR in 7351 cases and 10 132 controls from Caucasian ancestry using Rochester (USA) incidence data. At the age of 85 the LTR of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers, consistent with semi-dominant inheritance of a moderately penetrant gene. Using PAQUID (France) incidence data, estimates were globally similar except that at age 85 the LTRs reached 68 and 35% for APOE 44 and APOE 34 female carriers, respectively. These risks are more similar to those of major genes in Mendelian diseases, such as BRCA1 in breast cancer, than those of low-risk common alleles identified by recent GWAS in complex diseases. In addition, stratification of our data by age groups clearly demonstrates that APOE4 is a risk factor not only for late-onset but for early-onset AD as well. Together, these results urge a reappraisal of the impact of APOE in Alzheimer disease.

Transcranial direct current stimulation improves recognition memory in Alzheimer disease

Objective: To evaluate the cognitive effect of transcranial direct current stimulation (tDCS) over the temporoparietal areas in patients with Alzheimer disease (AD). Methods: In 10 patients with probable AD, we delivered anodal tDCS (AtDCS), cathodal tDCS (CtDCS), and sham tDCS (StDCS) over the temporoparietal areas in three sessions. In each session recognition memory and visual attention were tested at baseline (prestimulation) and 30 minutes after tDCS ended (poststimulation). Results: After AtDCS, accuracy of the word recognition memory task increased (prestimulation: 15.5 ± 0.9, poststimulation: 17.9 ± 0.8, p = 0.0068) whereas after CtDCS it decreased (15.8 ± 0.6 vs 13.2 ± 0.9, p = 0.011) and after StDCS it remained unchanged (16.3 ± 0.7 vs 16.0 ± 1.0, p = 0.75). tDCS left the visual attention-reaction times unchanged. Conclusion: Transcranial direct current stimulation (tDCS) delivered over the temporoparietal areas can specifically affect a recognition memory performance in patients with Alzheimer disease (AD). Because tDCS is simple, safe and inexpensive, our finding prompts studies using repeated tDCS, in conjunction with other therapeutic interventions for treating patients with AD.

Effect of rivastigmine on delay to diagnosis of Alzheimer's disease from mild cognitive impairment: the InDDEx study

OBJECTIVE To assess the effect of rivastigmine in patients with mild cognitive impairment (MCI) on the time to clinical diagnosis of Alzheimers disease (AD) and the rate of cognitive decline. METHODS The study was a double-blind, randomised, placebo-controlled trial of up to 48 months. All patients had MCI operationally defined by having cognitive symptoms, a global clinical dementia rating stage of 0.5, a score of less than 9 on the New York University delayed paragraph recall test, and by not meeting the diagnostic criteria for AD. Primary efficacy variables were time to clinical diagnosis of AD, and change in performance on a cognitive test battery. This study is registered with the US National Institutes of Health clinical trials database (ClinicalTrials.gov), number NCT00000174. FINDINGS Of 1018 study patients enrolled, 508 were randomly assigned to rivastigmine and 510 to placebo; 17.3% of patients on rivastigmine and 21.4% on placebo progressed to AD (hazard ratio 0.85 [95% CI 0.64-1.12]; p=0.225). There was no significant difference between the rivastigmine and placebo groups on the standardised Z score for the cognitive test battery measured as mean change from baseline to endpoint (-0.10 [95% CI -0.63 to 0.44], p=0.726). Serious adverse events were reported by 141 (27.9%) rivastigmine-treated patients and 155 (30.5%) patients on placebo; adverse events of all types were reported by 483 (95.6%) rivastigmine-treated patients and 472 (92.7%) placebo-treated patients. The predominant adverse events were cholinergic: the frequencies of nausea, vomiting, diarrhoea, and dizziness were two to four times higher in the rivastigmine group than in the placebo group. INTERPRETATION There was no significant benefit of rivastigmine on the progression rate to AD or on cognitive function over 4 years. The overall rate of progression from MCI to AD in this randomised clinical trial was much lower than predicted. Rivastigmine treatment was not associated with any significant safety concerns.

Molecular mechanisms involved in lymphocyte recruitment in inflamed brain microvessels: critical roles for P-selectin glycoprotein ligand-1 and heterotrimeric G(i)-linked receptors.

Lymphocyte recruitment into the brain is a critical event in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis. We developed a novel intravital microscopy model to directly analyze through the skull the interactions between lymphocytes and the endothelium in cerebral venules of mice. No adhesive interactions were observed between lymphocytes and the nonactivated endothelium in the cerebral microcirculation. When brain venules were activated by pretreating mice with TNF-α or LPS, proteolipid protein 139–151 autoreactive T lymphocytes rolled and arrested; notably, only a few peripheral lymph node cells rolled and firmly adhered. Abs anti-P-selectin glycoprotein ligand-1 and anti-E- and P-selectin blocked tethering and rolling of autoreactive lymphocytes, suggesting that P-selectin glycoprotein ligand-1/endothelial selectins are critical in the recruitment of lymphocytes in inflamed brain venules. E- and P-selectin were expressed on cerebral vessels upon in vivo activation and had a patchy distribution during the preclinical phase of active and passive experimental autoimmune encephalomyelitis. LFA-1/ICAM-1 and α4 integrins/VCAM-1 supported rolling, but were not relevant to rolling velocity. Firm arrest was mainly mediated by LFA-1 and ICAM-1. Pretreatment of autoreactive lymphocytes with pertussis toxin blocked integrin-dependent arrest, implicating a requirement for Gi protein-dependent signaling in vessels from nonlymphoid districts. In conclusion, our data unveils the molecular mechanisms controlling the recruitment of autoreactive lymphocytes in inflamed cerebral vessels and suggest new insights into the pathogenesis of autoimmune inflammatory diseases of the CNS.

A Polymorphism in CALHM1 Influences Ca2+ Homeostasis, Aβ Levels, and Alzheimer's Disease Risk

Alzheimers disease (AD) is a genetically heterogeneous disorder characterized by early hippocampal atrophy and cerebral amyloid-beta (Abeta) peptide deposition. Using TissueInfo to screen for genes preferentially expressed in the hippocampus and located in AD linkage regions, we identified a gene on 10q24.33 that we call CALHM1. We show that CALHM1 encodes a multipass transmembrane glycoprotein that controls cytosolic Ca(2+) concentrations and Abeta levels. CALHM1 homomultimerizes, shares strong sequence similarities with the selectivity filter of the NMDA receptor, and generates a large Ca(2+) conductance across the plasma membrane. Importantly, we determined that the CALHM1 P86L polymorphism (rs2986017) is significantly associated with AD in independent case-control studies of 3404 participants (allele-specific OR = 1.44, p = 2 x 10(-10)). We further found that the P86L polymorphism increases Abeta levels by interfering with CALHM1-mediated Ca(2+) permeability. We propose that CALHM1 encodes an essential component of a previously uncharacterized cerebral Ca(2+) channel that controls Abeta levels and susceptibility to late-onset AD.

RhoA and ζ PKC Control Distinct Modalities of LFA-1 Activation by Chemokines: Critical Role of LFA-1 Affinity Triggering in Lymphocyte In Vivo Homing

Chemokines regulate rapid leukocyte adhesion by triggering a complex modality of integrin activation. We show that the small GTPase RhoA and the atypical zeta PKC differently control lymphocyte LFA-1 high-affinity state and rapid lateral mobility induced by chemokines. Activation of LFA-1 high-affinity state and lateral mobility is controlled by RhoA through the activity of distinct effector regions, demonstrating that RhoA is a central point of diversification of signaling pathways leading to both modalities of LFA-1 triggering. In contrast, zeta PKC controls LFA-1 lateral mobility but not affinity triggering. Blockade of the 23-40 RhoA effector region prevents induction of LFA-1 high-affinity state as well as lymphocyte arrest in Peyers patch high endothelial venules. Thus, RhoA controls the induction of LFA-1 high-affinity state by chemokines independently of zeta PKC, and this is critical to support chemokine-regulated homing of circulating lymphocytes.

SQSTM1 mutations in frontotemporal lobar degeneration and amyotrophic lateral sclerosis

Objective: There is increasing evidence that common genetic risk factors underlie frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Recently, mutations in the sequestosome 1 (SQSTM1) gene, which encodes p62 protein, have been reported in patients with ALS. P62 is a multifunctional adapter protein mainly involved in selective autophagy, oxidative stress response, and cell signaling pathways. The purpose of our study was to evaluate the frequency of SQSTM1 mutations in a dataset of unrelated patients with FTLD or ALS, in comparison with healthy controls and patients with Paget disease of bone (PDB). Methods: Promoter region and all exons of SQSTM1 were sequenced in a large group of subjects, including patients with FTLD or ALS, healthy controls, and patients with PDB. The clinical characteristics of patients with FTLD or ALS with gene mutations were examined. Results: We identified 6 missense mutations in the coding region of SQSTM1 in patients with either FTLD or ALS, none of which were found in healthy controls or patients with PDB. In silico analysis suggested a pathogenetic role for these mutations. Furthermore, 7 novel noncoding SQSTM1 variants were found in patients with FTLD and patients with ALS, including 4 variations in the promoter region. Conclusions: SQSTM1 mutations are present in patients with FTLD and patients with ALS. Additional studies are warranted in order to better investigate the role of p62 in the pathogenesis of both FTLD and ALS.

Efficacy of souvenaid in mild alzheimer's disease: Results from a randomized, controlled trial

Souvenaid aims to improve synapse formation and function. An earlier study in patients with Alzheimers disease (AD) showed that Souvenaid increased memory performance after 12 weeks in drug-naïve patients with mild AD. The Souvenir II study was a 24-week, randomized, controlled, double-blind, parallel-group, multi-country trial to confirm and extend previous findings in drug-naïve patients with mild AD. Patients were randomized 1:1 to receive Souvenaid or an iso-caloric control product once daily for 24 weeks. The primary outcome was the memory function domain Z-score of the Neuropsychological Test Battery (NTB) over 24 weeks. Electroencephalography (EEG) measures served as secondary outcomes as marker for synaptic connectivity. Assessments were done at baseline, 12, and 24 weeks. The NTB memory domain Z-score was significantly increased in the active versus the control group over the 24-week intervention period (p = 0.023; Cohens d = 0.21; 95% confidence interval [-0.06]-[0.49]). A trend for an effect was observed on the NTB total composite z-score (p = 0.053). EEG measures of functional connectivity in the delta band were significantly different between study groups during 24 weeks in favor of the active group. Compliance was very high (96.6% [control] and 97.1% [active]). No difference between study groups in the occurrence of (serious) adverse events. This study demonstrates that Souvenaid is well tolerated and improves memory performance in drug-naïve patients with mild AD. EEG outcomes suggest that Souvenaid has an effect on brain functional connectivity, supporting the underlying hypothesis of changed synaptic activity.

Behavioral symptoms in mild cognitive impairment

The authors investigated neuropsychiatric symptoms in mild cognitive impairment (MCI) from baseline data of the Investigation in the Delay to Diagnosis of AD with Exelon (InDDEx) study (n = 1,010). Neuropsychiatric symptoms were reported in 59% of subjects (Neuropsychiatric Inventory [NPI]). NPI+ subjects had significantly greater impairment on global, cognitive, and functional scores than NPI− subjects. The presence of neuropsychiatric symptoms appears to be a marker of MCI severity.