Evaluating Semantic Knowledge Through a Semantic Association Task in Individuals With Dementia.

Conceptual knowledge is supported by multiple semantic systems that are specialized for the analysis of different properties associated with object concepts. Various types of semantic association between concrete concepts-categorical (CA), encyclopedic (EA), functional (FA), and visual-encyclopedic (VEA) associations-were tested through a new picture-to-picture matching task (semantic association task, SAT). Forty individuals with Alzheimer's disease (AD), 13 with behavioral variant of frontotemporal dementia (bv-FTD), 6 with primary progressive aphasia (PPA), and 37 healthy participants were tested with the SAT. Within-group comparisons highlighted a global impairment of all types of semantic association in bv-FTD individuals but a disproportionate impairment of EA and FA, with relative sparing of CA and VEA, in AD individuals. Single-case analyses detected dissociations in all dementia groups. Conceptual knowledge can be selectively impaired in various types of neurodegenerative disease on the basis of the specific cognitive process that is disrupted.

Anxiety and Depression Are Not Related to Increasing Levels of Burden and Stress in Caregivers of Patients With Alzheimer's Disease.

Sixty-nine dyads of patients with Alzheimer's disease and primary caregivers have been followed up for 1 year to evaluate cognitive (Mini-Mental State Examination), functional (Instrumental Activities of Daily Living), and behavioral (Neuropsychiatric Inventory) decline of patient in relation to burden (Caregiver Burden Inventory), stress (Relative Stress Scale), anxiety (State-Trait Anxiety Inventory Y), and depression (Beck Depression Inventory) reported by the caregivers. After 1 year of observation, cognitive and functional scores worsened while behavioral problems remained unchanged and relatively mild in patients. After 1 year, caregivers' scores of scales of anxiety and depression decreased significantly, while stress scores remained unchanged and burden slightly increased. In our opinion, the unexpected improvement in psychological situation of caregivers may be mainly due to educational interventions focused on knowledge of the disease with a particular attention directed toward emotional support and individual needs.

Complexity in neuropsychological assessments of cognitive impairment: A network analysis approach.

In a neuropsychological assessment, each test aims at measuring a single cognitive function. However, test performance depends on an interconnected system of cognitive functions and individual characteristics. For a better understanding of cognitive deficits, it is fundamental to recognize this complexity and study the relationships between test performances. This study aims to evaluate complexity in neuropsychological assessment through network analysis (NA) in 165 healthy older adults, 191 patients with Alzheimer's disease (AD), and 129 patients with vascular encephalopathy (VaE). NA is a flexible method to explore different domains where many variables are correlated with each other, and the relationships are key for understanding the domains. We included general aspects of individual differences (i.e., age, sex, years of education) and the raw scores of a clinically used neuropsychological battery in the network. Healthy subjects showed a segregated pattern, suggesting a good specificity of each test in measuring a specific cognitive function. Moreover, the scores were related to age and education. In the patient groups, the identified patterns changed in a consistent manner, showing less specificity and new relationships between the various tests, thereby reducing the impact of age and education on the performance. In particular, AD patients showed worse performance on the tests but also a different balance between different tasks, suggesting a reorganization of the cognitive system and not a mere decline. These results provide a new perspective in looking at the complexity of cognitive function assessment.

The Mediating Role of Romantic Attachment in the Relationship Between Attachment to Parents and Aggression.

BACKGROUND: A secure attachment style could promote more intimacy in romantic relationships, while an insecure attachment style could be correlated with less positive romantic relationships in adulthood. Numerous studies have noted that a secure attachment to parents was correlated with lower levels of aggression, whereas insecure attachments were associated with higher levels of aggression. We aimed to investigate the role of the attachment system as a mediator of the expression of aggressiveness during adolescence. Specifically, we considered that the attachment to parents and peers could influence one's attachment to a romantic partner. METHODS: We empirically tested whether there were relationships of parent and peer attachment on aggressiveness mediated by romantic attachment style. Participants of the study included 411 students. RESULTS: Results indicated that for males an insecure father-child attachment style seems to be associated with higher levels of anxiety and avoidance in romantic attachments and then with aggressiveness. For females, an insecure mother-child attachment style seems to be associated with higher levels of aggressiveness. CONCLUSION: The attachment to parents and to peers plays a key role in defining romantic attachment according to gender, and these dimensions in turn tend to affect the levels of aggressiveness.

Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial.

BACKGROUND: This study reports the findings of the first large-scale Phase III investigator-driven clinical trial to slow the rate of cognitive decline in Alzheimer disease with a dihydropyridine (DHP) calcium channel blocker, nilvadipine. Nilvadipine, licensed to treat hypertension, reduces amyloid production, increases regional cerebral blood flow, and has demonstrated anti-inflammatory and anti-tau activity in preclinical studies, properties that could have disease-modifying effects for Alzheimer disease. We aimed to determine if nilvadipine was effective in slowing cognitive decline in subjects with mild to moderate Alzheimer disease. METHODS AND FINDINGS: NILVAD was an 18-month, randomised, placebo-controlled, double-blind trial that randomised participants between 15 May 2013 and 13 April 2015. The study was conducted at 23 academic centres in nine European countries. Of 577 participants screened, 511 were eligible and were randomised (258 to placebo, 253 to nilvadipine). Participants took a trial treatment capsule once a day after breakfast for 78 weeks. Participants were aged >50 years, meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's disease Criteria (NINCDS-ADRDA) for diagnosis of probable Alzheimer disease, with a Standardised Mini-Mental State Examination (SMMSE) score of ≥12 and <27. Participants were randomly assigned to 8 mg sustained-release nilvadipine or matched placebo. The a priori defined primary outcome was progression on the Alzheimer's Disease Assessment Scale Cognitive Subscale-12 (ADAS-Cog 12) in the modified intention-to-treat (mITT) population (n = 498), with the Clinical Dementia Rating Scale sum of boxes (CDR-sb) as a gated co-primary outcome, eligible to be promoted to primary end point conditional on a significant effect on the ADAS-Cog 12. The analysis set had a mean age of 73 years and was 62% female. Baseline demographic and Alzheimer disease-specific characteristics were similar between treatment groups, with reported mean of 1.7 years since diagnosis and mean SMMSE of 20.4. The prespecified primary analyses failed to show any treatment benefit for nilvadipine on the co-primary outcome (p = 0.465). Decline from baseline in ADAS-Cog 12 on placebo was 0.79 (95% CI, -0.07-1.64) at 13 weeks, 6.41 (5.33-7.49) at 52 weeks, and 9.63 (8.33-10.93) at 78 weeks and on nilvadipine was 0.88 (0.02-1.74) at 13 weeks, 5.75 (4.66-6.85) at 52 weeks, and 9.41 (8.09-10.73) at 78 weeks. Exploratory analyses of the planned secondary outcomes showed no substantial effects, including on the CDR-sb or the Disability Assessment for Dementia. Nilvadipine appeared to be safe and well tolerated. Mortality was similar between groups (3 on nilvadipine, 4 on placebo); higher counts of adverse events (AEs) on nilvadipine (1,129 versus 1,030), and serious adverse events (SAEs; 146 versus 101), were observed. There were 14 withdrawals because of AEs. Major limitations of this study were that subjects had established dementia and the likelihood that non-Alzheimer subjects were included because of the lack of biomarker confirmation of the presence of brain amyloid. CONCLUSIONS: The results do not suggest benefit of nilvadipine as a treatment in a population spanning mild to moderate Alzheimer disease. TRIAL REGISTRATION: Clinicaltrials.gov NCT02017340, EudraCT number 2012-002764-27.

CHRNA7 Gene and Response to Cholinesterase Inhibitors in an Italian Cohort of Alzheimer's Disease Patients.

Previous studies suggest that genetic variants in CHRNA7, which encodes for the major subunit of the acetylcholine receptor (α7-nAChR), are associated with the clinical response to cholinesterase inhibitors (ChEI) in Alzheimer's disease (AD) patients. We sought to replicate the association of two SNPs in the CHRNA7 gene, rs6494223 and rs8024987, with response to ChEI treatment in an Italian cohort of 169 AD patients, further extending the study to gene-level analysis. None of the tested variants was associated with clinical response. However, rs6494223 showed a consistent effect direction (OR = 1.4; p = 0.17), which after meta-analysis with previous study yielded a significant result (OR = 1.57, p = 0.02, I2 = 0%).

Prevalence of peripheral nervous system complications after major heart surgery.

We evaluated 374 consecutive patients from May 2013 to April 2014 who underwent major cardiac surgery. Each patient had an interview and a neurological clinical examination during the rehabilitation period. Patients with possible peripheral nervous system (PNS) complications underwent further electrodiagnostic tests. Among 374 patients undergoing major heart surgery (coronary artery bypass grafting, valvular heart surgery, ascending aortic aneurysm repair) 23 (6.1 %) developed 34 new PNS complications. We found four brachial plexopathies; four carpal tunnel syndromes; five critical illness neuropathies; three worsening of pre-existing neuropathies; two involvement of X, one of IX and one of XII cranial nerves; three peroneal (at knee), one saphenous, two median (at Struthers ligament), six ulnar (at elbow) mononeuropathies; two meralgia parestheticas. Diabetes is a strong risk factor for PNS complications (p = 0.002); we could not find any other relationship of PNS complications with clinical conditions, demographic data (gender, age) or type of surgical intervention. The mononeuropathies of right arms can be related to ipsilateral vein cannulation; position of body and stretching from chest wall retraction may be the cause of mononeuropathies of left arms (more frequent); the use of saphenous vein and position of the limbs may be the cause of mononeuropathies of the legs; surgical and anesthetical procedures can injure cranial nerves; respiratory failure and infection during the first days after surgery can cause critical illness neuropathies. Careful preoperative assessment and intraoperative management may reduce the risk of long-term PNS complications after cardiac surgery.

A genome-wide screening and SNPs-to-genes approach to identify novel genetic risk factors associated with frontotemporal dementia.

Frontotemporal dementia (FTD) is the second most prevalent form of early onset dementia after Alzheimer's disease (AD). We performed a case-control association study in an Italian FTD cohort (n = 530) followed by the novel single nucleotide polymorphisms (SNPs)-to-genes approach and functional annotation analysis. We identified 2 novel potential loci for FTD. Suggestive SNPs reached p-values ∼10(-7) and odds ratio > 2.5 (2p16.3) and 1.5 (17q25.3). Suggestive alleles at 17q25.3 identified a disease-associated haplotype causing decreased expression of -cis genes such as RFNG and AATK involved in neuronal genesis and differentiation and axon outgrowth, respectively. We replicated this locus through the SNPs-to-genes approach. Our functional annotation analysis indicated significant enrichment for functions of the brain (neuronal genesis, differentiation, and maturation), the synapse (neurotransmission and synapse plasticity), and elements of the immune system, the latter supporting our recent international FTD-genome-wide association study. This is the largest genome-wide study in Italian FTD to date. Although our results are not conclusive, we set the basis for future replication studies and identification of susceptible molecular mechanisms involved in FTD pathogenesis.

Transmembrane protein 106B gene (TMEM106B) variability and influence on progranulin plasma levels in patients with Alzheimer's disease.

We carried out an association study of transmembrane protein 106B gene (TMEM106B) rs1020004 A/G, rs6966915C/T, and rs1990622 A/G in a population of 656 patients with Alzheimer's disease (AD) and 619 controls, and tested whether the rs1990622 influences plasma progranulin levels. No differences in allele and genotype distribution were observed between cases and controls, even stratifying according to APOE status (p > 0.05). No differences in progranulin plasma levels were found between carriers of the rs1990622 and non-carriers. TMEM106b variability does not influence AD risk or plasma levels. Replication, preferably in a population with pathological confirmation, is required to confirm these results.

CHF5074 reduces biomarkers of neuroinflammation in patients with mild cognitive impairment: a 12-week, double-blind, placebo-controlled study.

As neuroinflammation is an early event in the pathogenesis of Alzheimer' s disease, new selective antiinflammatory drugs could lead to promising preventive strategies. We evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of CHF5074, a new microglial modulator, in a 12-week, double-blind, placebo-controlled, parallel groups, ascending dose study involving 96 MCI patients. Subjects were allocated into three successive study cohorts to receive ascending, titrated doses of CHF5074 (200, 400 or 600 mg/day) or placebo. Vital signs, cardiac safety, neuropsychological performance and safety clinical laboratory parameters were assessed on all subjects. Plasma samples were collected throughout the study for measuring drug concentrations, soluble CD40 ligand (sCD40L) and TNF-α. At the end of treatment, cerebrospinal fluid (CSF) samples were optionally collected after the last dose to measure drug levels, ß- amyloid1-42 (Aß42), tau, phospho-tau181, sCD40L and TNF-α. Ten patients did not complete the study: one in the placebo group (consent withdrawn), two in the 200-mg/day treatment group (consent withdrawn and unable to comply) and seven in the 400-mg/day treatment group (five AEs, one consent withdrawn and one unable to comply). The most frequent treatment-emergent adverse events were diarrhea, dizziness and back pain. There were no clinically significant treatmentrelated clinical laboratory, vital sign or ECG abnormalities. CHF5074 total body clearance depended by gender, age and glomerular filtration rate. CHF5074 CSF concentrations increased in a dose-dependent manner. At the end of treatment, mean sCD40L and TNF-α levels in CSF were found to be inversely related to the CHF5074 dose (p=0.037 and p=0.001, respectively). Plasma levels of sCD40L in the 600-mg/day group were significantly lower than those measured in the placebo group (p=0.010). No significant differences between treatment groups were found in neuropsychological tests but a positive dose-response trend was found on executive function in APOE4 carriers. This study shows that CHF5074 is well tolerated in MCI patients after a 12-week titrated treatment up to 600 mg/day and dose-dependently affects central nervous system biomarkers of neuroinflammation.

Disruption of structural connectivity along the dorsal and ventral language pathways in patients with nonfluent and semantic variant primary progressive aphasia: a DT MRI study and a literature review.

Nonfluent (NFV) and semantic (SV) variants of primary progressive aphasia (PPA) are associated with distinct patterns of focal cortical atrophy and underlying pathology. Previous diffusion tensor (DT) MRI studies showed a more ventral white matter (WM) involvement in SV patients and a more widespread frontal involvement in NFV. Aim of this manuscript is twofold. First, we wished to provide a brief state-of-the-art review on WM damage in PPA. Second, we used DT MRI to assess the topography of WM microstructural damage along dorsal and ventral language pathways and corpus callosum in patients with NFV and SV. Our findings show that the two PPA variants share an overlapping pattern of dorsal and ventral pathway abnormalities. In addition to these common abnormalities, variant-specific WM changes were also found, with NFV patients having a more severe damage to the dorsal (fronto-parietal) WM connections within the left superior longitudinal fasciculus/arcuate and SV patients showing a greater left ventral tract involvement (inferior longitudinal and uncinate fasciculi). These findings offer evidence that both dorsal and ventral language networks may contribute to the relatively selective deficits in NFV and SV patients.

Autosomal dominant frontotemporal lobar degeneration due to the C9ORF72 hexanucleotide repeat expansion: late-onset psychotic clinical presentation.

BACKGROUND: A hexanucleotide repeat expansion in the first intron of C9ORF72 has been shown to be responsible for a high number of familial cases of amyotrophic lateral sclerosis or frontotemporal lobar degeneration (FTLD). Atypical presentations have been described, particularly psychosis. METHODS: We determined the frequency of the hexanucleotide repeat expansions in a population of 651 FTLD patients and compared the clinical characteristics of carriers and noncarriers. In addition, we genotyped 21 patients with corticobasal syndrome, 31 patients with progressive supranuclear palsy, and 222 control subjects. RESULTS: The pathogenic repeat expansion was detected in 39 (6%) patients with FTLD (17 male and 22 female subjects); however, it was not detected in any corticobasal syndrome and progressive supranuclear palsy patients or controls. Twenty-four of 39 carriers had positive family history for dementia and/or amyotrophic lateral sclerosis (61.5%), whereas only 145 of 612 noncarriers had positive family history (23.7%; p<.000001). Clinical phenotypes of carriers included 29 patients with the behavioral variant frontotemporal dementia (bvFTD; 5.2% of all bvFTD cases), 8 with bvFTD/motor neuron disease (32% bvFTD/motor neuron disease cases), 2 with semantic dementia (5.9% of patients with semantic dementia), and none with progressive nonfluent aphasia. The presentation with late-onset psychosis (median age = 63 years) was more frequent in carriers than noncarriers (10/33 vs. 3/37, p = .029), as well as the presence of cognitive impairment at onset (15/33 vs. 5/37; p = .0039). CONCLUSIONS: The repeat expansion in C9ORF72 is a common cause of FTLD and often presents with late-onset psychosis or memory impairment.

Multiplex assessment of a panel of 16 serum molecules for the differential diagnosis of Alzheimer's disease.

One of the current challenge in Alzheimer's disease (AD) is the identification of reliable biomarkers that might improve diagnostic accuracy, possibly correlating with the disease progression and patient's response to therapy. As the clinically validated AD biomarkers evaluate cerebrospinal fluid (CSF) parameters, the need for less invasive diagnostic markers is well evident. To this respect, blood circulating cytokines or growth factors have provided some encouraging results, even though no clinically validated to date. In 2007 Ray et al suggested a panel of 18 circulating molecules that might increase AD diagnostic accuracy. In an attempt of replicating their data, we designed a multiplex fluorimetric assay comprising 16 independent analytes and covering 15 out of the 18 described proteins. We collected serum samples from three diagnostic groups: probable AD (n=33), matched healthy controls (CNT, n=23) and non AD demented (NAD, n=14). After correction for age, we found an increased level of EGF-1 in AD in comparison to CNT and NAD, while an increase of TRAIL-R4 was found in NAD. However, evaluation of specificity/sensitivity by ROC curve analysis gave weak evidence of diagnostic accuracy (area under the curve = 0.63 and 0.66 for EGF and TRAIL-R4, respectively). Finally, we tried to find a diagnostic classifier by a multivariate algorithm. We found indication of diagnostic evidence for AD only, while NAD samples did not show a diagnostic pattern.

Pharmacogenomics in Alzheimer's disease: a genome-wide association study of response to cholinesterase inhibitors.

We conducted a genome-wide association study in a cohort of 176 Italian Alzheimer's disease (AD) patients with extreme phenotype of response to cholinesterase inhibitors. Patients were classified into responders in case of positive, stable, or ≤1 worsening of mini-mental state examination score and into nonresponders if >3 points worsening during a median follow-up of 0.85 years of treatment. Forty-eight single-nucleotide polymorphisms were selected for replication in 198 additional AD-treated patients. By using the dichotomous response trait and a quantitative trait approach (change of mini-mental state examination), a nominal replication and evidence of association when combining data were achieved for 2 single-nucleotide polymorphisms associated with response to treatment: rs6720975A (pcombined = 2.9 × 10(-5), beta regression coefficient: 1.61) and rs17798800A (pcombined = 6.8 × 10(-6), odds ratio = 0.38, 95% confidence interval = 0.25-0.58). Rs6720975 maps in the intronic region of PRKCE, a protein kinase involved in several cellular functions, whereas rs17798800 is intergenic and, according to expression quantitative trait locus (eQTL) analysis, it acts as a cis-regulator of NBEA, an A kinase-anchoring protein playing a substantial role in the maturation of the nervous system. Despite its limitations, this project paves the way for the application of personalized medicine in AD patients and for collaborative efforts in this field.

Expression of the transcription factor Sp1 and its regulatory hsa-miR-29b in peripheral blood mononuclear cells from patients with Alzheimer's disease.

Altered gene expression occurs in central nervous system disorders, including Alzheimer's disease (AD). Transcription factor Sp1 (specificity protein 1) can regulate the expression of several AD-related proteins, including amyloid-ß protein precursor and tau. Sp1 is regulated by oxidative stress, and Sp1 mRNA was found to be upregulated in AD cortex and hippocampus. The distribution of three single nucleotide polymorphisms (SNPs), including rs7300593, rs17695156, and rs12821290, covering 100% Sp1 genetic variability, has been determined in a population of 393 AD patients as compared with 412 controls. In addition, expression analysis of Sp1 and its regulatory microRNAs (hsa-miR-29b and hsa-miR-375) has been performed in peripheral blood mononuclear cells (PBMCs), together with Sp1 protein analysis. No differences in all three SNP distributions were observed in AD patients as compared with controls. Stratifying according to gender, a significantly decreased frequency of Sp1 rs17695156 T allele was observed in male patients versus male controls. Significantly increased Sp1 relative expression levels were observed in PBMCs from AD patients as compared with controls. Western blot analysis paralleled mRNA increase in AD patients versus controls and correlated positively with Sp1 mRNA levels. Significantly decreased relative expression levels of hsa-miR-29b, but not of hsa-miR-375, were observed in AD patients versus controls and correlated negatively with Sp1 mRNA levels. According to these results, Sp1 and its regulatory hsa-miR-29b are deregulated in AD patients, possibly leading to aberrant production of downstream target genes involved in the pathogenesis. Moreover, Sp1 rs176951056 T allele is likely a protective factor in the male population.

Monocyte chemoattractant protein-1 promoter polymorphism and plasma levels in alzheimer's disease.

BACKGROUND: Neurodegenerative disorders such Alzheimer's disease (AD) are often characterized by senile plaques and neurofibrillary tangle. In addition, reactive astrogliosis, microglia activation and a chronic inflammation are found in AD brain. Activated microglia has been reported to express a large number of beta chemokines including monocyte chemoattractant protein-1 (MCP-1). The potential role of MCP-1 in AD pathogenesis is supported by the over expression of MCP-1 associated with an increase of amyloid deposition in transgenic mice. MCP-1 protein may be regulated by a single nucleotide polymorphism (SNP) occurring at position -2518 of the MCP-1 gene promoter. In this paper we correlated the A-2518G MCP-1 SNP distribution in three different populations: AD, control and MCI (mild cognitive impairment) population to evaluate whether this SNP might be a risk factor for AD or for MCI-AD conversion. MCP-1 plasma levels were also measured and correlated to the cognitive impairment (CIND) and AD risk. RESULTS: No differences in genotype distribution and allele frequencies of A-2518G MCP-1 SNP among AD patients, MCI subjects and controls were observed even after APOEe4 variation adjustment with logistic regression. However in MCI subjects, followed up for two years, this SNP appears to influence the progression of the disease; being the G allele slightly more frequent in MCI patients that developed AD. MCP-1 plasma levels were different among CIND (cognitive impairment but no dementia), AD and controls. The MCP-1 A-2518G promoter polymorphism did not affect MCP-1 plasma levels within the three populations. CONCLUSIONS: MCP-1 G allele did not affect the risk of AD, but slightly influenced MCI conversion to AD and MCP-1 plasma levels were increased in subjects with preclinical AD.

Genetics and expression analysis of the specificity protein 4 gene (SP4) in patients with Alzheimer's disease and frontotemporal lobar degeneration.

Transcription factor Sp4 (Specificity protein 4) levels are increased in the brain of patients with Alzheimer's disease (AD), and Sp4 colocalizes with neurofibrillary tangles. Moreover, SP4 is a susceptibility gene for bipolar disorder and schizophrenia, which share many clinical features with frontotemporal lobar degeneration (FTLD). The distribution of three tagging single nucleotide polymorphisms(SNPs)-rs9639379, rs10272006, and rs6461569-has been determined in a population of 352 patients diagnosed clinically with AD, 290 patients with FTLD, and 341 age-matched controls. Expression analysis of SP4 was performed in peripheral blood mononuclear cells (PBMC). No significant differences in either allelic or genotypic frequency of the three SNPs were found (p > 0.05), even stratifying according to gender and to the apolipoprotein E status. Significantly increased SP4 relative expression levels were observed in PBMC from patients with AD as compared with controls (7.132 ± 1.301 versus 3.396 ± 0.829, p < 0.050) and a similar trend was shown in patients with FTLD compared with controls (6.525 ± 1.500 versus 3.396 ± 0.829, p = 0.073). According to these results, SP4 gene does not act as a susceptibility factor either for AD or FTLD. However, Sp4 mRNA levels are upregulated in patients, possibly resulting in an aberrant expression of downstream target genes involved in the pathogenesis of both diseases.

GOOD or BAD responder? Behavioural and neuroanatomical markers of clinical response to donepezil in dementia.

We explored the neuropsychological and neuromorphometrical differences between probable Alzheimer's disease patients showing a good or a bad response to nine months treatment with donepezil. Before treatment, the neuropsychological profile of the two patient groups was perfectly matched. By the ninth month after treatment, the BAD-responders showed a decline of the MMSE score together with a progressive impairment of executive functions. A voxel-based morphometry investigation (VBM), at the time of the second neuropsychological assessment, showed that the BAD-responders had larger grey and white matter atrophies involving the substantia innominata of Meynert bilaterally, the ventral part of caudate nuclei and the left uncinate fasciculus, brain areas belonging to the cholinergic pathways. A more widespread degeneration of the central cholinergic pathways may explain the lack of donepezil efficacy in those patients not responding to a treatment that operates on the grounds that some degree of endogeneous release of acetylcholine is still available.

Replication study to confirm the role of CYP2D6 polymorphism rs1080985 on donepezil efficacy in Alzheimer's disease patients.

Alzheimer's disease (AD) is a neurodegenerative disorder often treated with donepezil, an acetylcholinesterase inhibitor. Response to donepezil is variable, probably based on patients' genetic background in donepezil metabolizing enzymes, including cytochrome 2D6 (CYP2D6). We evaluated the association between clinical response to donepezil and a common variant (rs1080985) of CYP2D6, previously reported to be associated with poor response to the drug. In a sample of 415 AD cases, we found evidence of association between rs1080985 and response to donepezil after 6 months of therapy (OR [95% CI]: 1.74 [1.01-3.00], p = 0.04). Rs1080985 might be useful as predictor of poor response to short-term donepezil treatment.

CSF metabolites in the differential diagnosis of Alzheimer's disease from frontal variant of frontotemporal dementia.

The early differentiation between Alzheimer's disease (AD) and frontal variant of frontotemporal dementia (fvFTD) is frequently difficult, albeit critical for the adequate management of patients and their caregivers. In order to assess the accuracy of CSF levels of beta-amyloid 1-42 (Aß), tau (τ) and Thr 181-phosphorilated tau (Pτ) in the early differentiation of AD from fvFTD, we designed a prospective study in which patients have been followed up for at least 2 years. Seventy-two patients with AD and 42 patients with fvFTD showed significantly different CSF levels of Pτ (increased in AD, p = 0.0001), Aß (reduced in AD, p = 0.03), and ratios of Pτ to Aß (p = 0.003). ROC analyses showed that the ratio Pτ/Αß is able to predict diagnosis with an AUC of 0.73 (optimal level being 0.16) corresponding to a sensitivity of 80% and a specificity of 68%. Our findings suggest that CSF metabolites may be the important tools in the early differential diagnosis between AD and fvFTD, albeit to be correlated with clinical, neuropsychological and bio imaging features.