Worldwide distribution of PSEN1 Met146Leu mutation: a large variability for a founder mutation.

OBJECTIVE: Large kindreds segregating familial Alzheimer disease (FAD) offer the opportunity of studying clinical variability as observed for presenilin 1 (PSEN1) mutations. Two early-onset FAD (EOFAD) Calabrian families with PSEN1 Met146Leu (ATG/CTG) mutation constitute a unique population descending from a remote common ancestor. Recently, several other EOFAD families with the same mutation have been described worldwide. METHODS: We searched for a common founder of the PSEN1 Met146Leu mutation in families with different geographic origins by genealogic and molecular analyses. We also investigated the phenotypic variability at onset in a group of 50 patients (mean age at onset 40.0 +/- 4.8 years) by clinical, neuropsychological, and molecular methodologies. RESULTS: EOFAD Met146Leu families from around the world resulted to be related and constitute a single kindred originating from Southern Italy before the 17th century. Phenotypic variability at onset is broad: 4 different clinical presentations may be recognized, 2 classic for AD (memory deficits and spatial and temporal disorientation), whereas the others are expressions of frontal impairment. The apathetic and dysexecutive subgroups could be related to orbital-medial prefrontal cortex and dorsolateral prefrontal cortex dysfunction. CONCLUSIONS: Genealogic and molecular findings provided evidence that the PSEN1 Met146Leu families from around the world analyzed in this study are related and represent a single kindred originating from Southern Italy. The marked phenotypic variability might reflect early involvement by the pathologic process of different cortical areas. Although the clinical phenotype is quite variable, the neuropathologic and biochemical characteristics of the lesions account for neurodegenerative processes unmistakably of Alzheimer nature.

Minimally invasive osteosynthesis in stable trochanteric fractures: a comparative study between Gotfried percutaneous compression plate and Gamma 3 intramedullary nail.

AIM: Our objective was to compare the results of PCCP (Percutaneous Compression Plate) device and Gamma 3 nail for the treatment of stable trochanteric hip fractures and to demonstrate that PCCP device is a minimally invasive system. METHOD: Prospective, randomized trial. Eighty patients aged 60 and over with stable trochanteric fracture were selected and then randomized using a table of randomized numbers. Length of time of operative procedure, hemoglobin levels at 6 and 48 h after surgery, packed cells units administered, and hospital stay were recorded. In addition, the postoperative complications in the first year after the surgery was collected. RESULTS: No differences were found in hospital stay, surgical time, blood loss, functional outcome at 1-year follow-up, neck-shaft angle, fracture collapse, and mortality. CONCLUSIONS: PCCP and Gamma 3 have not presented significant differences in any measured parameter for treatment of stable trochanteric fractures. Therefore, the PCCP system is shown to be as minimally invasive as the Gamma 3.

Placa de compresión percutánea (PCCP) en el tratamiento de las fracturas intertrocantéreas estables / The percutaneous compression plate (PCCP) in the treatment of stable intertrochanteric fractures

Objetivo. Estudiar los resultados de la placa de compresión percutánea (PCCP) en el tratamiento de las fracturas trocantéreas estables.Material y método. Estudio prospectivo de 42 pacientes con fractura trocantérea estable, según la clasificación de la AO/OTA, intervenidos entre 2003 y 2005 con placa decompresión percutánea (PCCP, percutaneous compressionplate). Fueron 12 varones y 30 mujeres, con una edad media de 82,3 años. Previo a la fractura, 19 pacientes presentaban una deambulación independiente, 16 deambulaban con bastones y 7 precisaban la ayuda de un andador o tercera persona.Resultados. El tiempo quirúrgico medio fue de 87 minutos,15 pacientes precisaron transfusión sanguínea con una media de 0,60 concentrados por paciente, y tuvieron un consumo medio de analgésicos de 3,5 días. La estancia media fue de 16,9 días. Posoperatoriamente el 73% tenían deambulación por sí mismos. Hubo 5 éxitus en el primer año posoperatorio. No hubo complicaciones quirúrgicas. Radiológicamente no hubo complicaciones mecánicas ni fracasos del material.Conclusiones. El sistema de placa de compresión percutánea PCCP nos parece válido y eficaz en el tratamiento de las fracturas trocantéreas estables (AU)

Purpose. To assess the results of the PCCP (percutaneouscompression plate) in the treatment of stable intertrochanteric fractures.Materials and methods. Prospective study of 42 patientswith a stable intertrochanteric fracture, classified according to the AO/OTA scale, implanted between 2003 and 2005 with a PCCP percutaneous compression plate. There were 12 males and 30 females, with a mean age of 82.3 years. Prior to the fracture, 19 patients were independent walkers, 16 required a walking-stick and 7 required a walking frame or someone’s assistance.Results. Mean OR time was 87 minutes. Fifteen patients required a blood transfusion with a mean of 0.60 concentrates per patient and a mean analgesic consumption period of 3.5 days. Mean hospital stay was 16.9 days. Postoperatively, 73% could ambulate independently. There were five deaths in the first year post-op. No surgical complications were recorded.Radiologically, there were no mechanical complicationsor material-related failures.Conclusions. The PCCP percutaneous compression platecomes across as a valid and effective system for the treatment of stable intertrochanteric fractures (AU)

Heterogeneity within a large kindred with frontotemporal dementia: a novel progranulin mutation.

BACKGROUND: Frontotemporal dementia (FTD) in several 17q21-linked families was recently explained by truncating mutations in the progranulin gene (GRN). OBJECTIVE: To determine the frequency of GRN mutations in a cohort of Caucasian patients with FTD without mutations in known FTD genes. METHODS: GRN was sequenced in a series of 78 independent FTD patients including 23 familial subjects. A different Calabrian dataset (109 normal control subjects and 96 FTD patients) was used to establish the frequency of the GRN mutation. RESULTS: A novel truncating GRN mutation (c.1145insA) was detected in a proband of an extended consanguineous Calabrian kindred. Segregation analysis of 70 family members revealed 19 heterozygous mutation carriers including 9 patients affected by FTD. The absence of homozygous carriers in a highly consanguineous kindred may indicate that the loss of both GRN alleles might lead to embryonic lethality. An extremely variable age at onset in the mutation carriers (more than five decades apart) is not explained by APOE genotypes or the H1/H2 MAPT haplotypes. Intriguingly, the mutation was excluded in four FTD patients belonging to branches with an autosomal dominant mode of inheritance of FTD, suggesting that another novel FTD gene accounts for the disease in the phenocopies. It is difficult to clinically distinguish phenocopies from GRN mutation carriers, except that language in mutation carriers was more severely compromised. CONCLUSION: The current results imply further genetic heterogeneity of frontotemporal dementia, as we detected only one GRN-linked family (about 1%). The value of discovering large kindred includes the possibility of a longitudinal study of GRN mutation carriers.

The effects of APOE and tau gene variability on risk of frontotemporal dementia.

Frontotemporal dementia (FTD) is a complex dementing syndrome whose genetic/non genetic risk factors are mostly unknown. Aim of the present work was to investigate whether APOE and/or tau gene variability does affect the risk of FTD. A sample of FTD cases (sporadic: n = 54; familial: n = 46, one subject per family) was collected in a genetically homogeneous population (Calabria, southern Italy) and analyzed in comparison with an age- and sex-matched control group (n = 180) extracted from the same population. Logistic regression analysis showed that APOE gene variability affects the probability of disease, with allele epsilon4 increasing (exp(beta1) = 2.68 with [1.51-4.76] 95% confidence interval; p = 0.001) and allele epsilon2 decreasing (exp(beta1) = 0.28 with [0.12-0.66] 95% confidence interval; p = 0.003) the risk of FTD. On the contrary, tau gene variability was ineffectual (exp(beta1) non significantly different from 1 for either H1 or H2 haplotypes), although a small effect was observed by the H1 haplotype in increasing the protective effect of the epsilon2 allele (p = 0.007).

Long-duration response to levodopa influences the pharmacodynamics of short-duration response in Parkinson's disease.

The long-duration response (LDR) to chronic levodopa treatment may mask the short-duration response (SDR) to a single dose of the drug in Parkinson's disease (PD). As a result, the measurement of SDR may be inaccurate for establishing levodopa dosing regimen in individual patients. To evaluate the possible contamination of SDR by LDR, we investigated in 16 patients with PD the characteristics of SDR to a single dose of levodopa administered after a prolonged washout from chronic therapy and after a 15-day treatment period with levodopa. Levodopa treatment produced a sustained LDR, and the SDR, measured on the 15th day of treatment, had lower magnitude and shorter duration than the response recorded after washout. Moreover, after treatment, SDR did not vary between patients with mild and severe PD, whereas, after washout, severely affected patients had larger but shorter SDR than mildly affected patients. The evaluation of SDR without the interference of LDR is critical in defining the characteristics of the therapeutic response to levodopa.

Short-term levodopa test assessed by movement time accurately predicts dopaminergic responsiveness in Parkinson's disease.

Short-term challenges with dopaminergic agents are used in patients with idiopathic Parkinson's disease (PD) to predict the therapeutic effect of sustained levodopa treatment, but false-negative results often occur. We prospectively evaluated 74 patients with clinically diagnosed IPD and compared the predictive value of a short-term levodopa test assessed by movement time (MT) with the predictive value obtained by the evaluation with the motor examination part of the Unified Parkinson's Disease Rating Scale (UPDRS-ME). The response to long-term levodopa was accurately predicted in 96% of patients by assessing the response to the short-term test with MT and in 80% of cases with UPDRS-ME. Similar predictive values were obtained by separately analyzing 21 de novo patients. The short-term test also accurately predicted the magnitude of improvement with long-term treatment. We conclude that the predictive value for long-term dopaminergic responsiveness may be further enhanced by evaluating the short-term pharmacologic challenges with MT analysis. This is particularly useful to select de novo patients for drug trials with dopaminergic agents.

The subacute levodopa test for evaluating long-duration response in Parkinson's disease.

The clinical relevance of a long-duration response (LDR) to levodopa therapy in Parkinson's disease (PD) has not been widely recognized. In 25 patients with moderate PD, we measured LDR on motor function after short periods of treatment with levodopa (subacute tests). Each subacute test lasted 15 days and consisted of the oral administration of levodopa at various interdose intervals (IDIs) of 48, 24, 12, 8, 6, and 5 hours. The goal for a subacute test was to achieve a satisfactory antiparkinsonian effect before the last levodopa dose (day 15), i.e., an LDR greater than 50% of the maximal response following an acute levodopa test (LDR-endpoint). Twenty-one patients (84%) reached the LDR-endpoint. The IDI at which levodopa was administered clearly differentiated patients who were otherwise clinically indistinguishable when evaluated at baseline off medication or after an acute levodopa test. The IDI schedule that produced a satisfactory LDR was specific for each patient, since longer DIs failed to produce the required LDR, and a shorter IDI schedule (resulting in larger cumulative dosage of levodopa) did not significantly enhance the response. Also, the LDR decay rate after discontinuation of treatment was individual for each patient and independent of the cumulative amount of levodopa administered. Both the IDI schedule and the LDR decay rate may reflect the ability of nigrostriatal neurons to store and to release dopamine formed from the exogenous precursor. The assessment of the LDR to levodopa by subacute tests is useful for establishing the appropriate dose of the drug, as well as for developing levodopa sparing strategies in PD patients.

Usefulness of movement time in the assessment of Parkinson's disease.

Reaction time (RT) and movement time (MT) are reported to be delayed in Parkinson's disease (PD), but their clinical utility and relationship with clinical findings is still uncertain. We investigated RT and MT in 22 PD patients at baseline conditions and following acute oral trials of levodopa and biperiden, an anticholinergic drug. At baseline conditions, RT and MT of PD patients were abnormally delayed compared with those of 16 normal control subjects. Both RT and MT were longer in more severely affected patients compared with the mild PD patients; in the mild PD patients with asymmetrical signs both responses were longer on the more affected side. Bradykinesia was the clinical symptom that best correlated with the objective measurements, with a stronger correlation for MT than for RT. The oral administration of levodopa significantly improved both the responses, whereas biperiden was ineffective. The magnitude of RT and MT improvement after levodopa differed; MT improvement was related to PD severity, whereas RT improvement was not. These results suggest that MT, rather than RT, is an objective, simple, and reliable tool to evaluate bradykinesia and its levodopa-induced modifications in PD.