Chiara Zecca

Tau-Centric Targets and Drugs in Clinical Development for the Treatment of Alzheimer’s Disease

The failure of several Phase II/III clinical trials in Alzheimers disease (AD) with drugs targeting β-amyloid accumulation in the brain fuelled an increasing interest in alternative treatments against tau pathology, including approaches targeting tau phosphatases/kinases, active and passive immunization, and anti-tau aggregation. The most advanced tau aggregation inhibitor (TAI) is methylthioninium (MT), a drug existing in equilibrium between a reduced (leuco-methylthioninium) and oxidized form (MT+). MT chloride (methylene blue) was investigated in a 24-week Phase II clinical trial in 321 patients with mild to moderate AD that failed to show significant positive effects in mild AD patients, although long-term observations (50 weeks) and biomarker studies suggested possible benefit. The dose of 138 mg/day showed potential benefits on cognitive performance of moderately affected AD patients and cerebral blood flow in mildly affected patients. Further clinical evidence will come from the large ongoing Phase III trials for the treatment of AD and the behavioral variant of frontotemporal dementia on a new form of this TAI, more bioavailable and less toxic at higher doses, called TRx0237. More recently, inhibitors of tau acetylation are being actively pursued based on impressive results in animal studies obtained by salsalate, a clinically used derivative of salicylic acid.

A Novel Splice-Acceptor Site Mutation in GRN (c.709-2 A>T) Causes Frontotemporal Dementia Spectrum in a Large Family from Southern Italy

Heterozygous loss of function mutations in granulin represent a significant cause of frontotemporal lobar degeneration with ubiquitin and TDP-43 inclusions (FTLD-TDP). We report a novel GRN splice site mutation (c.709-2 A>T), segregating with frontotemporal dementia spectrum in a large family from southern Italy. The GRN c.709-2 A>T is predicted to result in the skipping of exon 8, leading to non-sense mediated mRNA decay. Moreover, the PGRN plasma levels in the GRN c.709-2 A>T carriers were significantly lower (24 ng/ml) compared to controls (142.7 ng/ml) or family members non-carriers (82.0 ng/ml) (p-value = 0.005, Kruskal Wallis), suggesting progranulin haploinsufficiency. We do not report any potential pathogenic GRN mutation in a follow-up cohort composed of 6 FTD families and 43 sporadic FTD cases, from the same geographic area. Our study suggests that GRN (c.709-2 A>T) is a novel and likely very rare cause of FTD in this Italian cohort. Finally, in line with previous studies, we show that GRN haploinsufficiency leads to a heterogeneous clinical picture, and plasma progranulin levels may be a reliable tool to identify GRN loss of function mutations. However, given that a) genetic and environmental factors, gender, and age may regulate PGRN plasma levels and b) plasma progranulin levels may not reflect PGRN levels in the central nervous system, we suggest that the measurement of progranulin in the plasma should always be coupled with genetic screening of GRN for mutations.

Amyotrophic lateral sclerosis and food intake

Abstract Objective: To verify if specific foods and nutrients could be risk factors or protective factors for amyotrophic lateral sclerosis (ALS). Methods: Patients with newly diagnosed ALS from three Italian administrative regions were included. For each patient, a healthy control, matched for age (±5 years), sex and administrative region of residence, was selected by a general practitioner. Cases and controls were interviewed by a trained investigator who filled a validated and reproducible food-frequency questionnaire. Daily intake of macronutrients, micronutrients, fatty acids, and total energy were estimated using an Italian food composition database. Results: Two hundred and twelve cases and 212 controls were included. A risk reduction was found for coffee and tea (odds ratios (OR) = 0.29, 95% CI 0.14–0.60), whole bread (OR = 0.55, 95% CI 0.31–0.99), raw vegetables (OR = 0.25, 95% CI 0.13–0.52) and citrus fruits (OR = 0.49, 95% CI 0.25–0.97). A risk increase was observed for red meat (OR = 2.96, 95% CI 1.46–5.99) and pork and processed meat (OR = 3.87, 95% CI 1.86–8.07). An increased risk was found for total protein (OR = 2.96, 95% CI 1.08–8.10), animal protein (OR = 2.91, 95% CI 1.33–6.38), sodium (OR = 3.96, 95% CI 1.45–10.84), zinc (OR = 2.78, 95% CI 1.01–7.83) and glutamic acid (OR = 3.63, 95% CI 1.08–12.2). Conclusions: Some foods/nutrients may be risk factors and others protective factors for ALS.

Late-night salivary cortisol (LNSC): data on biological variation

We analyzed blood samples from 20 apparently healthy laboratory workers (11 women, mean age 45 years, range 34‐63 years; 9 men, mean age 47 years, range 33‐66 years). The samples were obtained every three days for three times. Saliva samples were collected with a Salivette (Sarstedt, Numbrecht, Germany), with an insert containing a sterile polyester swab according to the instructions provided by the manufacturer.

Clinical and genetic analyses of familial and sporadic frontotemporal dementia patients in Southern Italy

We investigated the clinical differences between familial and sporadic frontotemporal dementia (FTD), screening for mutations in known FTD genes.

Influence of blood contamination on the salivary cortisol level

The salivary cortisol measurements are described to be an indication of plasma free cortisol concentrations in normal and pathological situations [1, 2]. Blood, can leak into oral fluids as a consequence of accidental injuries, of a poor oral health or periodontal disease but also during some infectious disease or as a result of factors that notoriously can damage the mucous membranes of the oral cavity (e.g., tobacco, alcohol overuse). When blood and its components leak in the saliva from the oral mucosa, may occur a misdetection of salivary hormones levels [3, 4]. This condition is a significant source of unsystematic error and affects our ability to detect the salivary cortisol concentration. Some authors have recommended to detect the presence of hemoglobin in the salivary sample using a filter-paper dipstick, a method originally designed for urine samples in order to eliminate or reduce blood interference. This method involves a chemical reaction to peroxidase, an enzyme normally present in the saliva and so could cause a high number of false positives [5]. Since transferrin is a protein found in very high concentrations in serum (mg/dL) under normal circumstances, but only in trace in oral fluid, other authors have suggested to assess it as a potential marker of salivary contamination with blood. In this case, it has been shown that occurs an increased transferrin levels measured by immunoassay, though the correlation between the salivary hormone levels and the blood contamination may be not linear [6]. It is also not clear what may be the economic disadvantages and which samples may

Pseudobulbar affect as a negative prognostic indicator in amyotrophic lateral sclerosis

To evaluate whether the presence of pseudobulbar affect (PBA) in an early stage of the disease influences survival in a population‐based incident cohort of amyotrophic lateral sclerosis (ALS).

Utilità della citofluorimetria a flusso su liquido da BAL nella diagnosi di Istiocitosi a cellule di Langerhans (ICL)

Le malattie polmonari interstiziali costituiscono un gruppo eterogeneo di malattie del parenchima polmonare a varia eziologia, presentazione clinica e radiografica, caratteristiche istopatologiche e decorso clinico. Sono state proposte diverse classificazioni con stratificazione in base alla presentazione clinica, ai reperti istopatologici e radiologici e alla risposta alla terapia con corticosteroidi [1]. L’istiocitosi polmonare a cellule di Langerhans (ICL) è un sottogruppo di patologia interstiziale polmonare caratterizzata dalla proliferazione di cellule di Langerhans nel polmone con distorsione e distruzione del parenchima polmonare (variazioni cistiche alla TC). Possono verificarsi manifestazioni extrapolmonari con il coinvolgimento di ossa, pelle, ghiandola pituitaria, fegato, linfonodi e tiroide [2]. L’ICL è una malattia rara, complessa e poco conosciuta. È dibattuto se classificare l’ICL come una malattia neoplastica, in base alle evidenze della clonalità delle cellule di Langerhans emerse da studi sull’espressione di “human androgen receptor” e della mutazione del BRAF, o come disordine immune in base all’alterata espressione di citochine [3]. La radiografia del torace è significativa nella maggior parte dei casi, mostrando un’infiltrazione micronodulare o reticolo nodulare e interstiziale del lobo medio e superiore. La presenza di reperti tipici alla TC ad alta risoluzione (High Resolution Computed Tomography, HRCT) è spesso sufficiente per stabilire la diagnosi di ICL; un quadro alla HRCT che evidenzia formazioni nodulari e cistiche con prevalenza nella metà superiore dei campi polmonari in un giovane fumatore rende la diagnosi quasi certa. Tuttavia, per stabilire una diagnosi certa, specialmente nei pazienti con presentazione radiologica atipi-