Are we social enough? Use of social media among members of the Italian Society of Neurology for the study of dementia.

BACKGROUND: Clinical researchers increasingly embrace social media in their professional lives. The digital revolution has provided new routes for sharing data, disseminating results, and promoting the impact of scientific findings. In this study, we explored the attitude of the members of the Italian Society of Neurology for the study of dementia (SINdem) to use social media with the aim to set up possible corrective actions to maximize digitalization benefits at the individual and community levels. METHOD: An ad hoc designed survey was implemented and distributed to the SINdem and SINdem4Juniors communities. It explored the different use of social media taking into account frequency, type of social media use (active vs passive; professional vs private). Descriptive statistical analyses were performed alongside statistical comparisons to highlight possible differences in the use. RESULTS: We collected 133 answers showing a prominent use of social media in private life (t(132) = 21.1, p < 0.001), with SINdem4Juniors members showing a higher private use compared to the older SINdem colleagues. Professional use was mainly limited to passive activities such as following others' social profiles (t(132) = 11.9, p < 0.001). DISCUSSION: Overall scenario suggests that professional use of social media is very limited in both SINdem and SINdem4juniors communities. This evidence points to an urgent need for training interventions and top-down strategies aimed at improving collaboration, dissemination, and sharing through social media among individuals belonging to the same scientific-professional community.

The Shortening of Leukocyte Telomere Length Contributes to Alzheimer's Disease: Further Evidence from Late-Onset Familial and Sporadic Cases.

Telomeres are structures at the ends of eukaryotic chromosomes that help maintain genomic stability. During aging, telomere length gradually shortens, producing short telomeres, which are markers of premature cellular senescence. This may contribute to age-related diseases, including Alzheimer's disease (AD), and based on this, several studies have hypothesized that telomere shortening may characterize AD. Current research, however, has been inconclusive regarding the direction of the association between leukocyte telomere length (LTL) and disease risk. We assessed the association between LTL and AD in a retrospective case-control study of a sample of 255 unrelated patients with late-onset AD (LOAD), including 120 sporadic cases and 135 with positive family history for LOAD, and a group of 279 cognitively healthy unrelated controls, who were all from Calabria, a southern Italian region. Following regression analysis, telomeres were found significantly shorter in LOAD cases than in controls (48% and 41% decrease for sporadic and familial cases, respectively; p < 0.001 for both). Interestingly, LTL was associated with disease risk independently of the presence of conventional risk factors (e.g., age, sex, MMSE scores, and the presence of the APOE-ε4 allele). Altogether, our findings lend support to the notion that LTL shortening may be an indicator of the pathogenesis of LOAD.

Rare Amyloid Precursor Protein Point Mutations Recapitulate Worldwide Migration and Admixture in Healthy Individuals: Implications for the Study of Neurodegeneration.

Genetic discoveries related to Alzheimer's disease and other dementias have been performed using either large cohorts of affected subjects or multiple individuals from the same pedigree, therefore disregarding mutations in the context of healthy groups. Moreover, a large portion of studies so far have been performed on individuals of European ancestry, with a remarkable lack of epidemiological and genomic data from underrepresented populations. In the present study, 70 single-point mutations on the APP gene in a publicly available genetic dataset that included 2504 healthy individuals from 26 populations were scanned, and their distribution was analyzed. Furthermore, after gametic phase reconstruction, a pairwise comparison of the segments surrounding the mutations was performed to reveal patterns of haplotype sharing that could point to specific cross-population and cross-ancestry admixture events. Eight mutations were detected in the worldwide dataset, with several of them being specific for a single individual, population, or macroarea. Patterns of segment sharing reflected recent historical events of migration and admixture possibly linked to colonization campaigns. These observations reveal the population dynamics of the considered APP mutations in worldwide human groups and support the development of ancestry-informed screening practices for the improvement of precision and personalized approaches to neurodegeneration and dementia.

COVID-19 vaccine uptake among family caregivers of people with dementia: The role of attitudes toward vaccination, perceived social support and personality traits.

People with dementia have an increased risk of contracting severe forms of COVID-19. Although in worldwide vaccination programs priority has been given to older people, having taken the vaccine does not totally eliminate the risk of contracting COVID-19 when one is in close contact with unvaccinated people. Thus, family caregivers' choices to remain unvaccinated against COVID-19 could have potentially lethal consequences for their relatives. To our knowledge, this study represents the first attempt within the international literature to analyze COVID-19 vaccine uptake among family caregivers of people with dementia and to identify some of the psychological factors, related to COVID-19 and vaccination behavior, that could facilitate or hinder vaccine uptake. Contact information for family caregivers was obtained from five different centers and associations throughout the Italian territory. Data were collected from 179 respondents during July-September 2021 using a cross-sectional web-based survey design. More than 75% of the respondents indicated that had been vaccinated against COVID-19 and reported receiving vaccine information mainly from print or electronic newspapers (86%), followed by TV (81%) and families (64.2%). In multivariable logistic regression analyses, worries about unforeseen future effects was significantly related to COVID-19 vaccine uptake, indicating that family caregivers concerned about potential side effects of vaccines were less likely to have been vaccinated against COVID-19 (OR = 0.60, CI = 0.40-0.89). Openness to experience was also related to COVID-19 vaccine uptake, with family caregivers higher on this trait being less likely to have been vaccinated against COVID-19 (OR = 0.83, CI = 0.71-0.98). Implications for targeting of vaccine-related messages are discussed.

Neuropsychiatric or Behavioral and Psychological Symptoms of Dementia (BPSD): Focus on Prevalence and Natural History in Alzheimer's Disease and Frontotemporal Dementia.

Neuropsychiatric or behavioral and psychological symptoms of dementia (BPSD) represent a heterogeneous group of non-cognitive symptoms that are virtually present in all patients during the course of their disease. The aim of this study is to examine the prevalence and natural history of BPSD in a large cohort of patients with behavioral variant of frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) in three stages: (i) pre-T0 (before the onset of the disease); (ii) T0 or manifested disease (from the onset to 5 years); (iii) T1 or advanced (from 5 years onwards). Six hundred seventy-four clinical records of patients with bvFTD and 1925 with AD, from 2006 to 2018, were studied. Symptoms have been extracted from Neuropsychiatric Inventory (NPI) and from a checklist of BPSD for all periods observed. In our population, BPSD affect up to 90% of all dementia subjects over the course of their illness. BPSD profiles of the two dementia groups were similar but not identical. The most represented symptoms were apathy, irritability/affective lability, and agitation/aggression. Considering the order of appearance of neuropsychiatric symptoms in AD and bvFTD, mood disorders (depression, anxiety) come first than the other BPSD, with the same prevalence. This means that they could be an important "red flag" in detection of dementia. With the increase of disease severity, aberrant motor behavior and wandering were significantly more present in both groups. Differences between BPSD in AD and bvFTD resulted only in prevalence: Systematically, in bvFTD, all the symptoms were more represented than in AD, except for hallucinations, depression, anxiety, and irritability. Given their high frequency and impact on management and overall health care resources, BPSD should not be underestimated and considered as an additional important diagnostic and therapeutic target both in patients with AD and bvFTD.

Antimicrobial Peptides (AMPs) in the Pathogenesis of Alzheimer's Disease: Implications for Diagnosis and Treatment.

Alzheimer's disease (AD) represents the most frequent type of dementia in elderly people. There are two major forms of the disease: sporadic (SAD)-whose causes are not completely understood-and familial (FAD)-with clear autosomal dominant inheritance. The two main hallmarks of AD are extracellular deposits of amyloid-beta (Aß) peptide and intracellular deposits of the hyperphosphorylated form of the tau protein (P-tau). An ever-growing body of research supports the infectious hypothesis of sporadic forms of AD. Indeed, it has been documented that some pathogens, such as herpesviruses and certain bacterial species, are commonly present in AD patients, prompting recent clinical research to focus on the characterization of antimicrobial peptides (AMPs) in this pathology. The literature also demonstrates that Aß can be considered itself as an AMP; thus, representing a type of innate immune defense peptide that protects the host against a variety of pathogens. Beyond Aß, other proteins with antimicrobial activity, such as lactoferrin, defensins, cystatins, thymosin ß4, LL37, histatin 1, and statherin have been shown to be involved in AD. Here, we summarized and discussed these findings and explored the diagnostic and therapeutic potential of AMPs in AD.

Accuracy of the clinical diagnosis of dementia with Lewy bodies (DLB) among the Italian Dementia Centers: a study by the Italian DLB study group (DLB-SINdem).

INTRODUCTION: Dementia with Lewy bodies (DLB) may represent a diagnostic challenge, since its clinical picture overlaps with other dementia. Two toolkits have been developed to aid the clinician to diagnose DLB: the Lewy Body Composite Risk Score (LBCRS) and the Assessment Toolkit for DLB (AT-DLB). We aim to evaluate the reliability of these two questionnaires, and their ability to enhance the interpretation of the international consensus diagnostic criteria. METHODS: LBCRS and AT-DLB were distributed to 135 Italian Neurological Centers for Cognitive Decline and Dementia (CDCDs), with the indication to administer them to all patients with dementia referred within the subsequent 3 months. We asked to subsequently apply consensus criteria for DLB diagnosis, to validate the diagnostic accuracy of the two toolkits. RESULTS: A total of 23 Centers joined the study; 1854 patients were enrolled. We found a prevalence of possible or probable DLB of 13% each (26% total), according to the consensus criteria. LBCRS toolkit showed good reliability, with a Cronbach alpha of 0.77, stable even after removing variables from the construct. AT-DLB toolkit Cronbach alpha was 0.52 and, after the subtraction of the "cognitive fluctuation" criterion, was only 0.31. Accuracy, sensitivity, and specificity were higher for LBCRS vs. AT-DLB. However, when simultaneously considered in the logistic models, AT-DLB showed a better performance (p < 0.001). Overall, the concordance between LBCRS positive and AT-DLB possible/probable was of 78.02% CONCLUSIONS: In a clinical setting, the LBCRS and AT-DLB questionnaires have good accuracy for DLB diagnosis.

A Comparison of Behavioral and Psychological Symptoms of Dementia (BPSD) and BPSD Sub-Syndromes in Early-Onset and Late-Onset Alzheimer's Disease.

BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) have a large impact on the quality of life of patients with Alzheimer's disease (AD). Few studies have compared BPSD between early-onset (EOAD) and late-onset (LOAD) patients, finding conflicting results. OBJECTIVE: The aims of this study were to: 1) characterize the presence, overall prevalence, and time of occurrence of BPSD in EOAD versus LOAD; 2) estimate the prevalence over time and severity of each BPSD in EOAD versus LOAD in three stages: pre-T0 (before the onset of the disease), T0 (from onset to 5 years), and T1 (from 5 years onwards); 3) track the manifestation of BPSD sub-syndromes (i.e., hyperactivity, psychosis, affective, and apathy) in EOAD versus LOAD at T0 and T1. METHODS: The sample includes 1,538 LOAD and 387 EOAD diagnosed from 1996 to 2018. Comprehensive assessment batteries, including the Neuropsychiatric Inventory (NPI), were administered at the first medical assessment and at different follow-up period. RESULTS: The overall prevalence for the most of BPSD was significantly higher in EOAD compared to LOAD whereas most BPSD appeared significantly later in EOAD patients. Between the two groups, from pre-T0 to T1 we recorded a different pattern of BPSD prevalence over time as well as for BPSD sub-syndromes at T0 and T1. Results on severity of BPSD did not show significant differences. CONCLUSION: EOAD and LOAD represent two different forms of a single entity not only from a neuropathological, cognitive, and functional level but also from a psychiatric point of view.

A Novel Mutation (D395A) in Valosin-Containing Protein Gene Is Associated With Early Onset Frontotemporal Dementia in an Italian Family.

Inclusion body myopathy (IBM) with Paget's disease of bone (PDB) and/or frontotemporal dementia (FTD) (IBMPFD) was recently identified as rare autosomal dominant disorder due to mutations in VCP gene. However, VCP mutations have also been documented in patients with amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth type 2 (CMT2) disease, and hereditary spastic paraplegia (HSP), underlining the heterogeneity of the phenotypes due to VCP mutations. In this study, we reported a novel missense heterozygous variant c.1184A > C (p.D395A) in exon 10 of VCP gene identified in three patients (two sisters and one brother) belonging to an Italian family. The patients underwent a detailed clinical evaluation including medical history, neurological examination, and neuropsychological assessment. Brain's morphologic and functional analysis was also performed. The whole picture was consistent with the criteria of behavioral variant frontotemporal dementia (bvFTD) without IBM and PBD. Our report confirms the high degree of heterogeneity of VCP disease. A VCP analysis should be considered for the genetic screening of familial bvFTD with an early onset also in absence of IBM or PDB signs.

Evolution of genetic testing supports precision medicine for caring Alzheimer's disease patients.

Genetic testing for Alzheimer's disease offers a molecular diagnosis to patients and their relatives and provides information on personal risk, reproductive choices, clinical trial eligibility, and treatment options. In the past, molecular testing was limited to detecting single variations in single genes. Currently, with the advent of next-generation sequencing, simultaneous analysis of more than 100 genes using the same DNA sample is possible. This approach allows the determination of gene mutations, genetic risk factors, genotypes at many pharmacogenomic loci, and the determination of a polygenic risk scores for stratification of risk. This article reviews the diagnostic genetic testing of Alzheimer's disease, from the first molecular approaches to recent advances in NGS, focusing on a precision medicine approach.

The largest caucasian kindred with dentatorubral-pallidoluysian atrophy: A founder mutation in italy.

BACKGROUND: Dentatorubral-pallidoluysian atrophy is a hereditary neurodegenerative disease prevalently reported in Japan but rare in Caucasians. The objective of this study was to reconstruct the pedigree of Italian dentatorubral-pallidoluysian atrophy familial cases describing their clinical features. METHODS: We investigated 6 apparently unrelated dentatorubral-pallidoluysian atrophy families comprising a total of 51 affected individuals: 13 patients were clinically examined, and for 38 patients clinical data were collected from clinical sources. The dentatorubral-pallidoluysian atrophy diagnosis was genetically confirmed in 18 patients. Genealogical data from historical archives were analyzed. RESULTS: All 6 families were unified in a large pedigree deriving from a founder couple originating from Monte San Giuliano (Italy) in the late 1500s, with 51 affected subjects over the last 4 generations. Wide phenotypical variability in age at onset and clinical features was confirmed. Epilepsy was more frequent in juvenile cases than in late adults, with cognitive/psychiatric and motor disorders observed regardless of age at onset. CONCLUSIONS: We have described the largest Caucasian dentatorubral-pallidoluysian atrophy pedigree from a single founder couple. The introduction of the dentatorubral-pallidoluysian atrophy gene in Italy could have arisen as a result of trade relationships between the Spanish or Portuguese and the Japanese in the 1500s. © 2019 International Parkinson and Movement Disorder Society.

Clinical guidance for the use of trazodone in major depressive disorder and concomitant conditions: pharmacology and clinical practice.

AIM: To provide a review of the clinically relevant evidence pertaining to the use of trazodone in major depressive disorder. METHODS: Medline and Cochrane Library searches were searched using the keywords 'trazodone' AND 'depression', to identify the most relevant literature pertinent to the pharmacological properties of trazodone and its use in clinical practice. Articles that were selected included basic pharmacology papers, clinical trials, clinical practice guidelines, and reviews. Related references were cross checked. European and United States prescribing information was reviewed as well. An effort was made to give weight to the information that was most relevant for daily clinical practice. RESULTS: Trazodone is an antidepressant with a mechanism of action that remains innovative and with a favorable profile for the treatment of depression. The appropriate antidepressant doses are usually 150-300 mg/day and are often higher than the doses that are used when trazodone is prescribed to augment the antidepressant effect of another medication, for instance when trazodone is prescribed to address insomnia in a patient treated with an SSRI. Trazodone is usually well tolerated and has a low risk of anticholinergic side effects, weight gain and sexual side effects. DISCUSSION: Trazodone is an established medication that is efficacious for the treatment of a broad array of depressive symptoms, including symptoms that are less likely to respond to other antidepressants (e.g. SSRI), such as insomnia. As an antidepressant, trazodone has proven as efficacious as the tricyclic and second-generation antidepressants and is tolerated relatively well. Trazodone may be helpful for patients with major depression and comorbid insomnia, anxiety or psychomotor agitation. CONCLUSIONS: Trazodone is efficacious antidepressants with a relatively low risks of side effects such as weight gain, sexual or anticholinergic effects (such as constipation, urinary retention, dry mouth). In addition to being able to control a wide range of depressive symptoms, trazodone may improve sleep and be particularly helpful for patients whose symptoms of depression include insomnia.

Prevalence of Delirium in a Population of Elderly Outpatients with Dementia: A Retrospective Study.

BACKGROUND: Delirium is a multifactorial geriatric syndrome and often occurs in patients with cognitive impairment. It also remains under-recognized, specifically in elderly outpatients, because signs of delirium might overlap with symptoms of dementia. OBJECTIVE: The aim of the present study is to retrospectively apply the chart-based delirium instrument on a cohort of elderly outpatients with dementia, to assess prevalence and features of delirium in this population. METHODS: We randomly selected 650 medical records of outpatients referred to the "Neurogenetic Regional Centre" (CRN) of Lamezia Terme. Each evaluation included demographics, medical history, drugs, type and severity of dementia, and cognitive and functional status. Delirium was identified by the application of the chart-based delirium instrument. RESULTS: The prevalence of delirium was 13.3%. The study population was divided, according to the presence of delirium, into two subgroups. Compared to the no delirium group, the delirium group was significantly older and had greater cognitive impairment with lower MMSE scores both at baseline and at the end of the follow up. They also had a significant lower score on the ADL and IADL. In this group, a higher intake of antihypertensive and antipsychotic drugs, together with a lower intake of cholinesterase inhibitors and memantine, was observed. CONCLUSIONS: In this study, the chart-based delirium instrument was applied to an outpatient population affected by dementia and followed for a long time. Our data confirm the importance that age and frailty play on the genesis of delirium and suggest attention should be paid to the pharmacological treatment of these patients.

The novel PSEN1 M84V mutation associated to frontal dysexecutive syndrome, spastic paraparesis, and cerebellar atrophy in a dominant Alzheimer's disease family.

We identified the novel PSEN1 pathogenic mutation M84V in 3 patients belonging to a large kindred affected by autosomal dominant Alzheimer's disease (AD). The clinical phenotype was characterized by early onset dementia in 14 affected subjects over 3 generations. Detailed clinical, imaging and genetic assessment was performed. We highlighted the presence of unusual symptoms such as frontal executive syndrome, psychosis and spastic paraparesis in these patients. Spastic paraparesis has been reported in other PSEN1 mutations in adjacent codons, suggesting that the position of the genetic defect may affect the clinical expression, although this phenotype can occur in mutations throughout the whole PSEN1 gene. Brain magnetic resonance imaging showed diffuse cortical atrophy, but also atrophy of cerebellar lobules, mainly involving Crus I, in 2 patients without cerebellar motor deficits. These neuroimaging results were consistent with recent findings about the association between sporadic AD and distinct and circumscribed cerebellar atrophy. The present work acknowledged the novel PSEN1 pathogenic mutation M84V and might contribute to the ongoing debate about the involvement of cerebellum in AD.

Role of Niemann-Pick Type C Disease Mutations in Dementia.

BACKGROUND: Several neurological and systemic diseases can cause dementia, beyond Alzheimer's disease. Rare genetic causes are often responsible for dementia with atypical features. Recently, mutations causative for Niemann-Pick type C disease (NPC) have also been implicated in neurodegenerative diseases. NPC is an autosomal recessive lipid storage disorder caused by mutations in NPC1 and NPC2 genes. In adults, clinical presentation mimicking other neurodegenerative diseases makes diagnosis difficult. Recent evidence suggests that heterozygous mutations in NPC genes may take on etiological significance. OBJECTIVE: To investigate the presence of NPC1 and NPC2 mutations in adults affected by neurodegenerative dementia plus. METHODS: We performed a genetic screening on 50 patients using a wide clinical and biochemical approach to characterize the phenotype of mutated patients. RESULTS: Sequencing analysis revealed four different and known heterozygous mutations in NPC1 and NPC2 genes. Patient 1 carried the p. F284LfsX26 in NPC1 and was affected by progressive supranuclear palsy-like syndrome. The remaining three patients showed a corticobasal syndrome and harbored the c.441+1G>A variant of NPC2 (patient 2), the missense p.N222 S mutation associated with the c.1947+8G>C variant in the splice region of intron 12 in NPC1 (patient 3), and the p.V30M mutation in NPC2 (patient 4), respectively. Filipin staining was abnormal in patients 1 and 2. mRNA analysis revealed an altered splicing of the NPC2 gene in patient 2. CONCLUSIONS: Heterozygous mutations of NPC1 and NPC2 genes could contribute to dementia plus, at least in a subset of patients. We highlight the occurrence of NPC1 and NPC2 heterozygous variants in dementia-plus as pathological event.

Angela R.: a familial Alzheimer's disease case in the days of Auguste D.

The rebuilding of the N family, a large Italian kindred affected by early-onset autosomal dominant Alzheimer's disease (AD), provided an important contribution to the discovery of Presenilin 1 (PSEN1), the main gene responsible for familial AD. This pedigree was identified with the help of medical records from the archives of the Psychiatric Hospital of Girifalco, Italy. The clinical record of Angela R., an ancestor of the N family, dating back to 1904, showed a clinical picture of Angela R., consistent with a diagnosis of non-amnestic probable AD, matching the "dysexecutive" phenotype described in her descendants. The a posteriori diagnosis of AD is supported by the evidence of the causative genetic mutation PSEN1-Met146Leu as well as neuropathological AD features in her genealogically proven descendants. The clinical case of Angela R. was recorded at the same time of Alzheimer's description of Auguste D. Its discovery crucially contributed to the genealogical reconstruction of the N family, linking came from different branches, which until then were unrelated, to the same kindred. The archives of the Girifalco Hospital represented a valuable source of medical and historical information and were essential to the research on Italian-American AD families that finally led to the identification of new genes.

The role of citicoline in cognitive impairment: pharmacological characteristics, possible advantages, and doubts for an old drug with new perspectives.

BACKGROUND: Citicoline is able to potentiate neuroplasticity and is a natural precursor of phospholipid synthesis, or rather serves as a choline source in the metabolic pathways for biosynthesis of acetylcholine. Several studies have shown that it can have beneficial effects both in degenerative and in vascular cognitive decline. The aim of the present study was to review the pharmacokinetics and pharmacodynamics of this drug and its role in cognitive impairment according to the present medical literature. METHODS: A MEDLINE(®) search was made using the following key words: citicoline, pharmacokinetics, pharmacodynamics, elderly, cognitive impairment, vascular dementia, and Alzheimer's disease. Recent studies on the possible role of citicoline in increasing sirtuin 1 (SIRT1) expression were assessed. Some personal studies were also considered, such as the VITA study and the IDEALE study. RESULTS: Administered by both oral and intravenous routes, citicoline is converted into two major circulating metabolites, cytidine and choline. It is metabolized in the gut wall and liver. Pharmacokinetic studies suggested that it is well absorbed and highly bioavailable with oral dosing. A number of studies have clearly shown the possible role of citicoline in cognitive impairment of diverse etiology. It can also modulate the activity/expression of some protein kinases involved in neuronal death and increases SIRT1 expression in the central nervous system. The VITA study and the IDEALE study suggested that both parenteral and oral citicoline are effective and safe. Other studies have clearly demonstrated citicoline's effects on several cognitive domains. Conversely, some studies did not point out any evidence of efficacy of this drug. CONCLUSION: Citicoline appears to be a promising agent to improve cognitive impairment, especially of vascular origin. In fact, so far it appears as a drug with the ability to promote "safe" neuroprotection, capable of enhancing endogenous protective. Large clinical trials are needed to confirm its benefits.

Haptoglobin interacts with apolipoprotein E and beta-amyloid and influences their crosstalk.

Beta-amyloid accumulation in brain is a driving force for Alzheimer's disease pathogenesis. Apolipoprotein E (ApoE) represents a critical player in beta-amyloid homeostasis, but its role in disease progression is controversial. We previously reported that the acute-phase protein haptoglobin binds ApoE and impairs its function in cholesterol homeostasis. The major aims of this study were to characterize the binding of haptoglobin to beta-amyloid, and to evaluate whether haptoglobin affects ApoE binding to beta-amyloid. Haptoglobin is here reported to form a complex with beta-amyloid as shown by immunoblotting experiments with purified proteins, or by its immunoprecipitation in brain tissues from patients with Alzheimer's disease. The interaction between ApoE and beta-amyloid was previously shown to be crucial for limiting beta-amyloid neurotoxicity and for promoting its clearance. We demonstrate that haptoglobin, rather than impairing ApoE binding to beta-amyloid, promotes to a different extent the formation of the complex between beta-amyloid and ApoE2 or ApoE3 or ApoE4. Our data suggest that haptoglobin and ApoE functions in brain should be evaluated taking into account their mutual interaction with beta-amyloid. Hence, the risk of developing Alzheimer's disease might not only be linked to the different ApoE isoforms, but also rely on the level of critical ligands, such as haptoglobin.

Association of the variant Cys139Arg at GRN gene to the clinical spectrum of frontotemporal lobar degeneration.

BACKGROUND: Progranulin protein (PGRN) is a cysteine-rich growth factor encoded by the progranulin gene (GRN). PGRN mutations were identified in patients with frontotemporal lobar degeneration (FTLD) and recently its role as risk factor has been described in patients with probable Alzheimer's disease (AD). To date, more than 100 genetic variants in GRN gene have been described and the pathogenic nature is still unclear for almost 36% of them. OBJECTIVE: Here, we describe three clinical cases carrying the PGRN variation Cys139Arg in order to increase the knowledge on the association of this variant to the clinical spectrum of FTLD. METHODS: The genetic analysis was performed using high resolution melting analysis. The Human Progranulin ELISA Kit was used in order to determine PGRN expression levels in the plasma samples. RESULTS: The three patients carrying the genetic variation showed three final different clinical diagnosis, respectively behavioral frontotemporal dementia, semantic dementia, and corticobasal syndrome, thus underlining the clinical heterogeneity typically associated with GRN mutations. All cases shared similar plasma PGRN levels that resulted intermediate between those measured in controls and in GRN null mutation carriers, showing a partial reduction of the protein in plasma. Moreover, according to the bioinformatics software, the Cys139Arg variation causes a decreased stability of the structure of the protein. CONCLUSION: We describe three new patients affected by neurological syndromes included in the clinical spectrum of FTLD carrying the Cys139Arg genetic variant, thus suggesting a possible implication in the pathogenesis of FTLD.

Estimating the inheritance of frontotemporal lobar degeneration in the Italian population.

Frontotemporal dementia (FTD) has a strong genetic basis, with familial forms occurring in 30-50% of cases. Causative genes have been identified, with an autosomal dominant pattern of inheritance. Notwithstanding, in a number of cases with positive family history no pathogenetic mutation has been reported, and the role of genetics in sporadic cases is still unclear. In the present study, we aim to estimate the genetic contribution to FTD using concordance among parent-offspring pairs. Heritability of early-onset (EO, <65 years) and late-onset (LO, ≥65 years) FTD was estimated by examining the concordance between parents and offspring. Probands with at least one parent whose dementia status was known were recruited from 15 Italian centers, and the presence or absence of dementia was considered in siblings. Different prevalence estimates, as available by literature data, were tested. A total of 260 probands and 1619 family members were considered in this study. We found that parent-offspring concordance in FTD was 6.25%, resulting in hereditability of 98.5% (95% confidence interval (CI): 85.0%-100.0%). Equal heritability for both sexes regardless of parental gender was reported. EO-FTD showed hereditability of 86.3% (95% CI: 77.0%-95.0%) and LO-FTD of 75.7% (95% CI: 65.0%-86.0%). Estimating the contribution of genetics in FTD may help in driving future genetic studies to identify new pathogenetic determinants. We suggest that in most of the cases FTD is a genetic-based disease, even in the elderly. Different inheritance modality might be considered in future work, beyond autosomal dominant disease.