A systematic review on drugs for synaptic plasticity in the treatment of dementia.

The aim of the present systematic review (SR) was to provide an overview of all published and unpublished clinical trials investigating the safety and efficacy of disease-modifying drugs targeting synaptic plasticity in dementia. Searches on CT.gov and EuCT identified 27 trials (4 phase-1, 1 phase-1/2, 18 phase-2, 1 phase-2/3, 1 phase-3, 1 phase-4, and 1 not reported). Twenty of them completed, and seven are currently active or enrolling. The structured bibliographic searches yielded 3585 records. A total of 12 studies were selected on Levetiracetam, Masitinib, Saracatinib, BI 40930, Bryostatin 1, PF-04447943 and Edonerpic drugs. We used RoB tool for quality analysis of randomized studies. Efficacy was assessed as a primary outcome in all studies except one and the main scale used was ADAS-Cog (7 studies), MMSE and CDR (4 studies). Safety and tolerability were reported in eleven studies. The incidence of SAEs was similar between treatment and placebo. At the moment, only one molecule reached phase-3. This could suggest that research on these drugs is still preliminary. Of all, three studies reported promising results on Levetiracetam, Bryostatin 1 and Masitinib.

Altered oxidative stress profile in the cortex of mice fed an enriched branched-chain amino acids diet: possible link with amyotrophic lateral sclerosis?

Branched-chain amino acids (BCAAs), valine, isoleucine, and leucine, are widely used among athletes as dietary integrators. Although the occurrence of untoward effects of BCCA supplementation, with particular regard to neurological disturbances, cannot be excluded, no specific studies have been performed so far. The aim of this work was to evaluate the effects of a diet enriched in BCAAs on the expression of oxidative stress pathway genes in the brain of C57Bl/6J mice. Animals were fed a standard or a BCAA diet for 95 days starting from postnatal day 21 until sacrifice. BCAA treatment, at doses comparable to human usage, significantly down-regulated the expression of some antioxidant genes, while up-regulating the expression of some oxygen transporters. In conclusion, it appears that BCAAs administered by diet could alter some specific oxidative stress pathways in the brain. Caution should thus be exercised in the widespread use of BCAAs as dietary integrators in sports practice.

The London APP mutation (Val717Ile) associated with early shifting abilities and behavioral changes in two Italian families with early-onset Alzheimer's disease.

BACKGROUND/AIMS: Mutations in the amyloid precursor protein gene were the first to be recognized as a cause of Alzheimer's disease (AD). METHODS: We describe 2 Italian families showing the missense mutation in exon 17 of the amyloid precursor protein gene on chromosome 21 (Val717Ile), known as London mutation. RESULTS: In 1 family, this mutation was responsible for AD in 3 out of 7 siblings and it is also present in a fourth sibling who has only shown signs of executive dysfunction so far. Two subjects of the other family with AD diagnosis were carriers of the same mutation. CONCLUSION: All AD subjects showed a cognitive profile characterized by early impairment in long-term memory, shifting abilities and affective symptoms beginning in the fifth decade of life.

A novel PSEN2 mutation associated with a peculiar phenotype.

BACKGROUND: Mutations of presenilin 2 gene are a rare cause of familial Alzheimer disease (AD). We describe an Italian family with hereditary dementia associated with a novel mutation in the presenilin 2 gene. METHODS: Clinical investigations of the diseased subjects; interviews with relatives; studies of medical records; pedigree analysis; and neuroradiologic, neuropathologic, and molecular genetic studies were carried out in the pedigree. RESULTS: Genetic analysis showed a novel PSEN2 A85V mutation present in the proband and in all analyzed affected members, in a subject presenting with an amnesic mild cognitive impairment, and in a young, still asymptomatic subject. The proband showed a clinical phenotype indicative of Lewy body dementia and the neuropathologic examination demonstrated the presence of unusually abundant and widespread cortical Lewy bodies in addition to the hallmark lesions of AD. Other affected members exhibited a clinical phenotype typical of AD. CONCLUSIONS: Our findings add complexity to the spectrum of atypical phenotypes associated with presenilin mutations and should then be taken into account when considering the nosography of neurodegenerative diseases. They also support previous data that specific mutations of genes associated with familial Alzheimer disease may influence the presence and extent of Lewy bodies.

Changes in cholesterol metabolism are associated with PS1 and PS2 gene regulation in SK-N-BE.

Several lines of evidence suggest that the cholesterol content of neuronal membranes influences amyloid precursor protein (APP) processing; however, its role in transcriptional regulation of the cofactors for gamma-secretase, the key enzyme for the production of the Abeta peptide, is poorly understood. This study investigates whether the changes in cellular cholesterol metabolism modulate the expression of genes involved in the gamma-secretase complex function. The abundance of mRNA transcripts for presenilin 1 and 2 (PS1 and PS2), APP, and nicastrin were evaluated in neuroblastoma cells exposed either to serum-depleted medium or to low-density lipoproteins (LDL). Cholesterol esterification was markedly inhibited by mevinolin and U18666A, but was not significantly affected by any other of the tested treatments. gamma-Secretase genes and cofactors were not co-regulated and were not influenced by statin inhibition of cholesterol synthesis. Nicastrin and the APP isoforms showed constitutive expression. In the absence of exogenous lipids, cell PS1 and PS2 expression was induced by LDL and by lysosomal sequestration of cholesterol. However, a different pattern of induction of presenilin gene expression was observed in the latter condition, suggesting that lysosomal cholesterol levels are strong inducers of PS2 transcription. Taken together, these results indicate that lipid metabolism has a complex influence on gamma-secretase transcriptional pathways and, in particular, exogenous cholesterol and compartmentalization in neuroblastoma cells play a relevant role in regulating the transcription of presenilins, while modulation of the cholesterol biosynthesis pathway seems to exert a minor influence on the expression of gamma-secretase genes and cofactors.

PEN-2 gene mutation in a familial Alzheimer's disease case.

Genetic evidence indicates a central role of cerebral accumulation of beta-amyloid (Abeta) in the pathogenesis of Alzheimer's disease (AD). Beside presenilin 1 and 2, three other recently discovered proteins (Aph 1, PEN 2 and nicastrin) are associated with gamma-secretase activity, the enzymatic complex generating Abeta. Alterations in genes encoding these proteins were candidates for a role in AD. The PEN 2 gene was examined for unknown mutations and polymorphisms in sporadic and familial Alzheimer patients. Samples from age-matched controls (n=253), sporadic AD (SAD, n=256) and familial AD (FAD, n=140) were screened with DHPLC methodology followed by sequencing. Scanning the gene identified for the first time a missense mutation (D90N) in a patient with FAD. Three intronic polymorphisms were also identified, one of which had a higher presence of the mutated allele in AD subjects carrying the allele epsilon4 of apolipoprotein E than controls. The pathogenic role of the PEN-2 D90N mutation in AD is not clear, but the findings might lead to new studies on its functional and genetic role.

[Proteic marker of hypoxic-ischemic damage]. / Marker proteici del danno ipossico-ischemico.

Perinatal hypoxic injury is the major cause of normal neural developmental alterations. Recent studies concerning animal models show that an hypoxic/ischaemic event triggers a process taking to a synaptic architecture reorganization which induces a transient change in the synaptic (synapsin 1, SNAP 25, APP) and neuronal (MAP2, N-CAM, GAP-43 and presenilins) protein expression. Here we review the post-translational modifications of some proteins after hypoxic-ischaemic events. A deeper study on synaptic proteins plasticity could give an important key for the understanding of the recovery mechanisms of the nervous system.

[Incidence and onset of arterial hypertension and diabetic retinopathy in a population of subjects with diabetes mellitus]. / Considerazioni sulla incidenza e l'insorgenza dell'ipertensione arteriosa e retinopatia diabetica in una popolazione di soggetti affetti da diabete mellito.

The authors noticed a 50% increase in the incidence of arterial hypertension in diabetic subjects compared with non diabetic ones. Females are more affected in both types of diabetes mellitus and during the first ten years after onset of NIDDM. Diabetic retinopathy is more frequent in IDDM. In hypertensive diabetic females retinopathy is twice as frequent as in non-hypertensive female patients.

[Incidence and type of dyslipidemia in a diabetic population]. / Indagine sull'incidenza ed il tipo della dislipidemia in una popolazione diabetica.

The incidence of dyslipidemia in the diabetic patients tested was found to be twofold compared to the non diabetic population. The percentage was found to be higher in Fredrikson class IIb, unchanged in class IIa and diminished in class IVF.

[Autoimmune hypophysitis. Review of the literature and a case report]. / L'ipofisite autoimmune. Rassegna della letteratura e descrizione di un caso.

Lymphoid hypophysitis is a rare disease (fewer than 30 cases) which is associated with lymphocytic infiltration of the pituitary gland with complete or partial hypopituitarism, pituitary mass, and occurrence exclusively in women, often during pregnancy or in the postpartum period. The majority of the women had autoimmune endocrine and not endocrine disorders and in some cases antipituitary antibodies were present. For these reasons an autoimmune cause has been suggested. We report a patient in menopause with chronic thyroiditis and anti nuclear, anti smooth muscle and anti mitochondrial autoantibodies who developed a panhypopituitarism with an empty sella. This case is the third observation of a possible autoimmune atrophy of the pituitary.

[Influence of temperature and humidity on the reproductive efficiency of Ixodes ricinus (Linnaeus, 1758) and Hyalomma marginatum Koch, 1844 (Ixodoidea, Ixodidae)]. / Influenza della temperatura e dell'umidita' sull'efficienza riproduttiva di Ixodes ricinus (Linnaeus, 1758) e Hyalomma marginatum Koch, 1844 (Ixodoidea, Ixodidae).

Laboratory studies have been carried out on two species of ticks, I. ricinus and H. marginatum, showing different seasonal activity and different geographical distribution in nature. The purpose of the present study has been to investigate the effect of different combinations of temperature and humidity on the oviposition of I. ricinus and H. marginatum. An index of reproduction efficiency (no. eggs/wt female), established to relate the capacity of the females to produce eggs to their body weight, has been calculated; for I. ricinus 5 temperatures (18-20-25-27 and 30 degrees C) have been studied (Fig. 1), for H. marginatum 3 (25-30 and 32 degrees C) (Fig. 2) and for both species 2 R.H. (75-95%). An optimal range of temperature, within which the value of such an index doesn't change, has been demonstrated for both species by statistical testing (Table 1). A critical weight value as the minimum engorged female weight required for egg deposition has been identified with the weight of first female which has laid eggs. This weight, different in each species, is influenced by temperature and humidity.