Use of Statins and Hip Fracture Risk: a Case-Control Study.

PURPOSE OF THE STUDY To evaluate a possible association between hip fracture and statin use. MATERIAL AND METHODS In this case-control study we compared the use of statins between two groups of 210 patients: the first group (case group) included patients hospitalized for hip fractures while the second group (control group) included patients who did not suffer femur bone injuries. The two groups were matched for age, sex, year of hospitalization and possible confounding factors. Inside the group of cases, we also evaluated the differences in terms of fracture type, presence of previous fragility fracture and mortality between statin users and non-users. RESULTS The use of statins was most common among patients without previous fractures (OR=0.54; 95% CI=0.33-0.89; p=0.0138), especially in older patients (OR=0.40; 95% CI=0.22-0.76). We did not find any significant difference in statin intake between men and women in the control group. In the case group, those who did not use statins were more likely to undergo a medial hip fracture (28.5% vs 16.1%). Patients from case group also presented a greater mortality (27.9% vs 19.35%) and an higher percentage of previous hip fractures (20.11% vs 9.7%). However, they didn't presented a significant higher rate of fragility fractures in other sites. DISCUSSION AND CONCLUSIONS Our study suggests a reduced hip fracture risk, especially in cases aged 80 or more, a different fracture pattern (lower percentage of medial fractures) and a reduced mortality at 9 months in patients treated with HMG-CoA reductase inhibitors, confirming the previous evidences reported in literature. Key words: statin, hip fractures, fracture risk, osteoporosis.

Giant cell tumor of extremities, surgical treatment and local adjuvants: which is the most effective?

Giant cell tumour (GCT) represents 5% of all primitive bone tumours. Standard surgical treatment of GCT includes intralesional excision or segmental resection. Curettage has a higher recurrence rate (10-25% in stage 2 or 3 but does preserve adjacent joint function. The use of local adjuvants such as phenol, alcohol, H2O2, Argon or cement may decrease recurrence rate, yet which local adjuvant works best is still, to this day, controversial. A series of 109 patients with GCT of the extremity, surgical treated in a single Institution from 2016 to 2018, were analysed in a retrospective study. The purpose of our study was to report the incidence of recurrence rate in patients with GCT of limbs treated in a single institution with different local adjuvants. The results of the present study suggests that curettage in association to cryoablation seems to reduce the recurrence rate compared to "classic" local adjuvants.

Total hip replacement: a retrospective multicentric analysis on re-intervention rate after single component revision.

Total hip arthroplasty (THA) revision is a procedure consisting in the replacement of a single or multiple implant components and could take place once or more times (re-revision). The aim of this multicentre study is to evaluate the benefits of single component revision in respect of the principles that define implant stability. Two hundred and forty-two patients underwent THA revision at Orthopaedic Clinic of Pisa and Versilia (ITA) from January 2007 to December 2016. We have systematically excluded revisions due to septic or traumatic prosthesis loosening, revisions of both implant components (cotyle and stem) and replacement alone. To evaluate implant stability, we used preoperative X ray and intra-operative mechanical stress tests, applying accredited criteria. Two hundred and twenty-six patients (93%) underwent a single procedure of THA revision: 193 had cotyle replacement and 33 had femoral stem replacement. The remaining 16 (7 %) underwent at least two procedures: 10 of them had consecutive failure of the same component, while the other 6 had revision of the other component after the first procedure. Considering our cases series, we can assert that single component revision is the best choice when no signs of loosening are present on the remaining component. Nevertheless, an accurate evaluation with unanimous radiological criteria and intraoperative testing is essential for the surgeon to choose the most suitable treatment.

Mesangiogenic Progenitor Cells and musculoskeletal tissue regeneration: differences between adipose-derived and bone marrow-derived cells?

Mesangiogenic Progenitor cells (MPCs) have been isolated from human bone marrow mononuclear cells (hBM-MNCs) and attracted particular attention for their ability to efficiently differentiate into exponentially growing mesenchymal stromal cells (MSCs) and toward endothelial lineage, suggesting the term "mesangiogenic". Coupling mesengenesis and angiogenis, MPCs has been hypothesized retaining a great tissue regenerative potential in musculoskeletal tissues regeneration. Bone marrow and adipose tissue (AT) represent most promising adult multipotent cell sources attempting to repair bone and cartilage, with controversial results regarding advantages applying BM- or AT-derived cells. As different culture determinants as well as tissue of origins, could strongly affect regenerative potential of cell preparations, we hypothesize that MPCs counterpart could have a role in defining efficacy of applying a cell-based medicinal product in musculoskeletal tissue repair. Here we present convincing data demonstrating that the ex vivo progenitors of MPCs are tissue specific and can be detected exclusively in hBM-MNCs.

Regional pattern of microgliosis in sporadic Creutzfeldt-Jakob disease in relation to phenotypic variants and disease progression.

AIMS: The aim of this study was to describe the regional profiles of microglial activation in sporadic Creutzfeldt-Jakob disease (sCJD) subtypes and analyse the influence of prion strain, disease duration and codon 129 genotype. METHODS: We studied the amount/severity and distribution of activated microglia, protease-resistant prion protein (PrPSc ) spongiform change, and astrogliosis in eight regions of 57 brains, representative of the entire spectrum of sCJD subtypes. RESULTS: In each individual subtype, the regional extent and distribution of microgliosis significantly correlated with PrPSc deposition and spongiform change, leading to subtype-specific 'lesion profiles'. However, large differences in the ratio between PrPSc load or the score of spongiform change and microglial activation were seen among disease subtypes. Most significantly, atypical sCJD subtypes such as VV1 and MM2T showed a degree of microglial activation comparable to other disease variants despite the relatively low PrPSc deposition and the less severe spongiform change. Moreover, the mean microglial total load was significantly higher in subtype MM1 than in MM2C, whereas the opposite was true for the PrPSc and spongiform change total loads. Finally, some sCJD subtypes showed distinctive regional cerebellar profiles of microgliosis characterized by a high granular/molecular layer ratio (MV2K) and/or a predominant involvement of white matter (MVK and MM2T). CONCLUSIONS: Microglial activation is an early event in sCJD pathogenesis and is strongly influenced by prion strain, PRNP codon 129 genotype and disease duration. Microglial lesion profiling, by highlighting strain-specific properties of prions, contributes to prion strain characterization and classification of human prion diseases, and represents a valid support to molecular and histopathologic typing.

A local anesthesia without tourniquet for distal fibula hardware removal after open reduction and internal fixation: the safe use of epinephrine in the foot. A randomized clinical study.

Hardware removal after surgical treatment fracture is one of the most common procedures in orthopaedic daily activity. A percentage from 14.5 to 21 of total removal involves the ankle joint. Trying to reduce the important socio-economic impact of this surgical procedure, we thought to perform it using the Wide Awake Local Anaesthesia Without Tourniquet (WALANT), a particular technique presented by D. Lalonde that associated a local anaesthetic drug with epinephrine in order to obtain an effective haemostatic effect despite the lack of a tourniquet. Nowadays, the WALANT efficiency and safety in hand surgery is widely demonstrated in literature but there are no data about its use in lower limb extremity surgeries. Authors performed a randomized study with 60 patients whom underwent distal fibula hardware removal between 2014 and 2016; they were divided into two groups: Group A under loco-regional anaesthesia with tourniquet and Group B under WALANT. We did not find significant differences in term of maximum pain level felt during the anaesthesiologic and surgical procedure. However, the use of WALANT significantly reduced post-operative pain levels. The WALANT procedures also reduced the number of hospitalization days. No differences in term of post-operative complication rates were found. In conclusion, the WALANT can be considered as a suitable option for distal fibula hardware removal in selected patients; it shows important clinical and economic advantages compared to the traditional loco-regional anaesthesia with tourniquet. This study also lays the foundation for the use of the WALANT beyond the field of hand surgery only.

Polymethylmethacrylate-augmented fenestreted pedicle-screw fixation in low bone quality patients: a case series and literature review.

The use of pedicle screws in low bone quality patients implicates risks of secondary implant loosening for grip lack. In fact, the result is a reduced mechanical stability at bone-screw interface and consequently an increased chance of pullout and hardware failure. Augmentation techniques have been described for many years and fenestrated screws that allow cement injection is one of them. This is a retrospective observational study of patients treated at our department with polymethylmethacrylate- (PMMA) augmented fenestrated screws. Indications for posterior instrumentation were traumatic fracture in osteoporotic spine, oncological disease, post-traumatic deformity, degenerative disease, revision surgery and sickle cell disease fractures. Implant stability was evaluated with X-Rays and CT scan performed 3 days after surgery and every 3 months during the follow-up. Accuracy of screw placement was evaluated with Heary classification. Fifty-three surgical treatments in 52 patients were performed and 247 PMMA augmented fenestrated screws were placed. According to the Heary classification, 96.21% resulted Grade I, 1.8% Grade II, 2% Grade IV. A total of 17 complications occurred. Fenestrated screw augmentation should be performed in selected patients in whom the bone quality is insufficient to guarantee implant stability. These screws may result useful in complex cases as revision surgeries, osteoporosis and tumour affections where bone quality is highly compromised.

Cryotherapy efficacy and safety as local therapy in surgical treatment of musculoskeletal tumours. A retrospective case series of 143 patients.

Cryotherapy, also called Cryoablation (CA), is a technique that provides a local treatment to various pathological conditions. In Musculoskeletal tumours management, Cryoablation is well accepted and validated as a treatment in palliative cures for metastatic patients. Recently, CA has been proposed also as an alternative to radiofrequency ablation in osteoid osteoma and other benign tumour treatment with promising results. Cryotherapy with argon ice-balls as local adjuvant in open surgery is a tool that can provide enlargement of surgical margins if used properly. There is still not enough evidence supporting use of cryotherapy as local adjuvant in Musculoskeletal open surgery as the series cited above are very small and there is no comparative RCT between local adjuvant therapies including CA. One-hundred-and-eighty-three patients were treated with Cryoablation from 2000 and 2018 in the Musculoskeletal Tumours Surgery Unit of Careggi (Florence) and the University 2nd Clinic of Pisa. In our study group, 38 patients (26.6%) were affected by bone metastasis, 16 patients (11.1%) by aneurismal bone cysts or angiomas, 22 patients (15.4%) by low-grade malignant musculoskeletal tumours, 2 patients (1,4%) by fibromatosis, 63 patients (44.1%) by benign musculoskeletal tumours (principally Giant Cell Tumours-GCT) and 2 patients (1.4%) by Osteosarcomas. In 125 cases (87.4%), CA has been used as an adjuvant therapy, in 12 cases (8.4%) as a percutaneous ablation therapy and in 6 cases (4.2%) as adjuvant to remove tumoral lesions 'en bloc' or as a 'poor technique' for its sterilizing effect on previously resected bones. Mean follow-up was 10 years. Twenty-three patients (16%) were classified as Alive with Disease (AWD) due to local recurrence or tumour progression (14 metastases, 5 low-grade malignant bone tumours, 4 Giant Cell Tumours). Eight patients died due to the disease (6 metastases, 2 osteosarcomas), while 1 died from leukaemia. One-hundred-and-eleven patients (78%) were classified as Continues Disease Free (CDF). All patients reported decrease in pain-related symptoms after surgery and all surgeons reported better control of blood loss. Three cases (2%) of local skin necrosis or wound dehiscence were reported. No local recurrences were reported after fibromatosis ablation. Our results confirm that CA could be considered as a safe and effective technique to treat various conditions as adjuvant and palliative therapy. In particular, in open surgery, cryotherapy as an adjuvant treatment could lead to very low rates of recurrence in locally aggressive tumours like Giant Cell Tumours. These results could be generalized but a better understanding about indications and outcomes can be reached studying CA in specific populations with comparation to other adjuvant techniques.

Clinical and radiographic short mid-term outcomes of primary total stabilizer knee arthroplasty.

A successful Total Knee Arthroplasty (TKA) requires stability, but rarely in primary TKA, a prosthesis with more constraint than a posterior-stabilizer (PS) is necessary. In patients with severe varus/valgus deformities with incompetent collateral ligaments or in knees that cannot be adequately balanced after ligaments release, a total-stabilizer (TS) prosthesis may be required. The purpose of our retrospective study is to evaluate clinical and radiographic outcomes at short mid-term follow-up in patients treated with a TS TKA. Between January 2013 and August 2016, 36 patients (38 knees) were treated with Stryker Triathlon TS cemented implants. Clinical and radiographic evaluation were performed preoperatively and postoperatively at 1 month, 3 months, 6 months, 1 year and at 1-year intervals thereafter. At final follow-up, 33 patients (35 knees) remained and were included in this study and followed with a mean follow-up of 26.6 months. Clinical evaluation was performed using the Western Ontario and McMaster Universities Arthritis Index (WOMAC score) and the Knee Society rating system that is subdivided into a knee score (KS) that rates only the knee joint itself and a functional score (FS). Knee Score (KS) and Functional Score (FS) increased significantly from a mean pre-operative value of 48 and 45, respectively, to a post-operative value at last follow-up of 86 and 82, respectively. Also WOMAC score improved significantly: the mean pre-operative WOMAC score was 45, while the mean post-operative WOMAC score, at last follow-up, was 19. The difference between pre- and post- operative results was significant at statistical analysis. In our opinion, when the adequately prosthesis balancing isn't possible, because of primary or secondary severe varus/valgus deformity or severe soft tissues retraction, an available option is to perform a total knee arthroplasty with a total stabilizer polyethylene insert. TS prosthesis gives more stability during the most of ROM and, in addition, Triathlon system provides surgeons the possibility to choose a more constrained implant, than a standard PS one, during surgical procedure saving the bone stock. Our experience with this kind of prosthesis has provided good clinical and radiographic outcomes at a short mid-term follow-up with a low-rate of complications.

Bone cement implantation syndrome: a thromboelastographic study of the effect of bone cement on coagulation.

Bone cement implantation syndrome (BCIS) is a rare form of intraoperative pulmonary embolism (EP) that occurs during cementation. It can be explained by two main theories: the monomer mediated model and the mechanic model. Our goal is to evaluate thromboelastographic changes in patients undergoing surgery for femoral neck fractures. We recruited 32 patients with a femoral neck fracture. The average age was 81.91 years (range 62-95). The patients were divided in two different groups: cemented hip arthroplasty (CC, 13 patients) and other surgical non-cemented techniques (SC, non-cemented hip arthroplasty, osteosynthesis). The coagulation was evaluated by TEG in the early pre-operatory (time A) and post-operatory (time B), both on native blood and on blood added with Heparinase. We used the t-test to compare the differences between the two groups. The coagulation index CI was modified on hypercoagulability by surgery in both groups, but without statistical significance between the two groups (p>0.05). R parameter decreases between time A and time B in the same way in both groups (p>0.05). Parameter MA had no major variations between time A and B, without statistical significance (p>0.05). From our study it is evident that although the surgery would result in a change in the layout of the TEG toward hypercoagulability, this is similar both in cemented and non-cemented surgical interventions for femoral neck fractures in elderly patients. An altered coagulation does not appear to be the cause or a factor in determining the BCIS.

Use of autologous bone marrow cells concentrate enriched with platelet-fibrin on extensor mechanism allograft reconstruction for extensor mechanism failure following total knee arthroplasty.

Allografts techniques remain the best reconstructive strategy for chronic extensor mechanism lesions after total knee arthroplasty (3) but outcomes depend strictly on the host tissue-allograft junctions healing. The purpose of this study is to evaluate if modern techniques of adding autologous bone marrow cells concentrate enriched with platelet-rich fibrin, provide better healing of the allograft. We present the case of an 86 years old patient affected by patellar tendon rupture after TKA. A whole extensor mechanism allograft was performed adding a bone marrow cells concentrate enriched with platelet-rich fibrin on the host tissue-allograft junctions. Preoperatively and at each follow-up the value of Knee Society Score and radiographic consolidation signs were recorded. Radiographic controls showed clear signs of consolidation already at 1 months follow-up and a solid fusion at 3 months. This case report describes a valid method to improve healing using a tissue-construct engineered with stem cells and growth factors.

Complications and survival of megaprostheses after resection of bone metastases.

Treatment of bone metastases is often palliative, aiming at pain control and stabilization or prevention of pathological fractures. However, a complete resection with healing purposes can be performed in selected cases. The aim of our work was to evaluate the survival of megaprostheses used for reconstruction after bone metastases. Between January 2001 and March 2015, we implanted 169 Megasystem-C® (Waldemar LINK® GmbH & Co. KG, Hamburg, Germany) after bone metastasis resection. Patients, 95 females and 74 males, were operated at an average age of 61 (12-87) years for proximal femoral resection in 135 (79.9%) cases, distal femur in 24 (14.2%), proximal tibia in 6 (3.6%), total femur in 3 (1.8%) and intercalary femur in 1 (0.6%). Mostly, breast cancer metastases (30.8%), kidney (17.8%) and lung (14.2%) were treated. At an average follow-up of 21 (1-150) months, we found a 99.4% overall limb salvage and a 96.1% overall survival rate at 1 year, 92.8% at 2 years, and 86.8% at 5 and 10 years. We found 9 (5.3%) mobilization cases of the proximal femoral implant, 3 needed surgical reduction; 2 (1.2%) cases of aseptic loosening of the prosthetic stem; 2 (1.2%) periprotetic infection cases, one requiring a 2-stage revision. Few literature studies have evaluated the survival of megaprosthetic implant in the treatment of bone metastases. Our data show how in this specific context the rate of complications is significantly lower than expected in general orthopedic orthopedic surgery. The use of modular prostheses is a valid reconstructive strategy after bone metastasis resection in selected patients. The rate of short-term complications is exceptionally low; further studies will have to confirm this in the longer term.

Correlation between gamma glutamyltransferase fractions and bone quality.

Gamma-glutamyltransferase (GGT) has been recently identified as a bone-resorbing factor. The aim of this study was to investigate the association between plasma GGT fractions levels and bone quality. Plasma GGT fractions were analysed by gel-filtration chromatography. Bone quality was established quantitatively by two micro-CT derived microarchitectural parameters: the BV/TV (mineralised bone volume/total volume), and the SMI (structure model index) that describes the rod-like (low resistant) or plate-like (high-resistant) shape of bone trabeculae. We enrolled 93 patients hospitalised for elective total hip replacement (group Arthrosis, n=46) or for proximal femoral fracture (group Fracture, n=47). Patients within the first quartile of BV/TV (Q1, osteoporotic patients, n=6) showed higher levels of b-GGT fraction [median (min-max): 3.37 (1.42­6.81)] compared to patients with normal bone density (fourth quartile Q4, n=10; 1.40 (0.83­4.36); p=0.0393]. Also, according to SMI, b-GGT value was higher in the subgroup with bone fragility [Q1, n=8: 1.36 (0.43­4.36); Q4, n=8: 5.10 (1.4 ­7.60); p=0.0117]. In conclusion, patients characterised by fragile bone structure showed specifically higher levels of plasma b-GGT activity thus suggesting fractional GGT analysis as a possible biomarker in the diagnosis of osteoporosis.

The correlation between preoperative levels of albumin and tlc and mortality in patients with femoral neck fracture.

A femoral neck fracture in an elderly patient often represents a major challenge for the orthopaedic surgeon who has to face not only the fracture, but also all the multiple issues related to age. Among others, malnutrition has been recognised as an important factor associated with severe aggravation in these patients. One-hundred-and-forty-seven patients were enrolled to investigate the use of two markers of patient nutritional status, i.e. serum albumin level and total leukocyte count (TLC), as predictors of mortality in the elderly patient suffering from proximal femur fracture. We found that low preoperative values of serum albumin and TLC proved to be directly related to worse outcomes. Therefore, these exams can be useful to identify patients with a femoral neck fracture that have higher risk of malnutrition and consequent higher mortality and that can benefit from some measures, such as albumin or protein nutritional supplement.

Divergent clinical and neuropathological phenotype in a Gerstmann-Sträussler-Scheinker P102L family.

OBJECTIVES: Gerstmann-Sträussler-Scheinker syndrome belongs to the genetic prion diseases being associated with mutations in the prion protein gene (PRNP). The most common is the point mutation at codon 102, leading to the substitution of proline to leucine (P102L). Previous reports have indicated a phenotypic heterogeneity among individuals with this mutation. Here, we describe the clinical and pathological phenotype in members of the first Finnish kindred with the P102L mutation in the PNRP gene. MATERIALS AND METHODS: Genetic and clinical information was available in five members of a family, while a systematic histologic and immunohistochemical assessment of the post-mortem brain was carried out in three. RESULTS: Clinical presentation, disease duration and the clinical phenotype (ataxia vs dementia) varied between patients. There was a significant correlation between clinical symptoms and the neuroanatomical distribution of prion protein-immunoreactive aggregates, i.e. subtentorial predominance in ataxia vs cortical predominance in dementia. A significant concomitant Alzheimer is disease-related pathology was observed in the brain of one patient with dementia as onset symptom. CONCLUSIONS: This is the first Scandinavian family carrying the P102L mutation in the PRNP gene. Gerstmann-Sträussler-Scheinker syndrome should be considered in the differential diagnosis when handling with patients with ataxia and/or dementia of unclear aetiology.

Augmented Reality as a Tool to Guide Patient-Specific Templates Placement in Pelvic Resections.

Patient-specific templates (PST) have become a useful tool for guiding osteotomy in complex surgical scenarios such as pelvic resections. The design of the surgical template results in sharper, less jagged resection margins than freehand cuts. However, their correct placement can become difficult in some anatomical regions and cannot be verified during surgery. Conventionally, pelvic resections are performed using Computer Assisted Surgery (CAS), and in recent years Augmented Reality (AR) has been proposed in the literature as an additional tool to support PST placement. This work presents an AR task to simplify and improve the accuracy of the positioning of the template by displaying virtual content. The focus of the work is the creation of the virtual guides displayed during the AR task. The system was validated on a patient-specific phantom designed to provide a realistic setup. Encouraging results have been achieved. The use of the AR simplifies the surgical task and optimizes the correct positioning of the cutting template: an average error of 2.19 mm has been obtained, lower than obtained with state-of-the-art solutions. In addition, supporting PST placement through AR guidance is less time-consuming than the standard procedure that solely relies on anatomical landmarks as reference.

Identification of recurrent genetic patterns from targeted sequencing panels with advanced data science: a case-study on sporadic and genetic neurodegenerative diseases.

BACKGROUND: Targeted Next Generation Sequencing is a common and powerful approach used in both clinical and research settings. However, at present, a large fraction of the acquired genetic information is not used since pathogenicity cannot be assessed for most variants. Further complicating this scenario is the increasingly frequent description of a poli/oligogenic pattern of inheritance showing the contribution of multiple variants in increasing disease risk. We present an approach in which the entire genetic information provided by target sequencing is transformed into binary data on which we performed statistical, machine learning, and network analyses to extract all valuable information from the entire genetic profile. To test this approach and unbiasedly explore the presence of recurrent genetic patterns, we studied a cohort of 112 patients affected either by genetic Creutzfeldt-Jakob (CJD) disease caused by two mutations in the PRNP gene (p.E200K and p.V210I) with different penetrance or by sporadic Alzheimer disease (sAD). RESULTS: Unsupervised methods can identify functionally relevant sources of variation in the data, like haplogroups and polymorphisms that do not follow Hardy-Weinberg equilibrium, such as the NOTCH3 rs11670823 (c.3837 + 21 T > A). Supervised classifiers can recognize clinical phenotypes with high accuracy based on the mutational profile of patients. In addition, we found a similar alteration of allele frequencies compared the European population in sporadic patients and in V210I-CJD, a poorly penetrant PRNP mutation, and sAD, suggesting shared oligogenic patterns in different types of dementia. Pathway enrichment and protein-protein interaction network revealed different altered pathways between the two PRNP mutations. CONCLUSIONS: We propose this workflow as a possible approach to gain deeper insights into the genetic information derived from target sequencing, to identify recurrent genetic patterns and improve the understanding of complex diseases. This work could also represent a possible starting point of a predictive tool for personalized medicine and advanced diagnostic applications.

Allelic origin of the abnormal prion protein isoform in familial prion diseases.

The hallmark of prion diseases is the presence of an aberrant isoform of the prion protein (PrP(res)) that is insoluble in nondenaturing detergents and resistant to proteases. We investigated the allelic origin of PrP(res) in brains of subjects heterozygous for the D178N mutation linked to fatal familial insomnia (FFI) and a subtype of Creutzfeldt-Jakob disease (CJD178), as well as for insertional mutations associated with another CJD subtype. We found that in FFI and CJD178 subjects, only mutant PrP was detergent-insoluble and protease-resistant. Therefore, PrP(res) derives exclusively from the mutant allele carrying the D178N mutation. In contrast, in the CJD subtype harboring insertional mutations, wild-type PrP was also detergent-insoluble and likely to be protease-resistant. Our findings indicate that the participation of the wild-type PrP in the formation of PrP(res) depends on the type of mutations, providing an insight into the molecular mechanisms underlying the phenotypic heterogeneity in familial prion diseases.

Tau gene mutation in familial progressive subcortical gliosis.

Familial forms of frontotemporal dementias are associated with mutations in the tau gene. A kindred affected by progressive subcortical gliosis (PSG), a rare form of presenile dementia, has genetic linkage to chromosome 17q21-22. This kindred (PSG-1) is included in the 'frontotemporal dementias and Parkinsonism linked to chromosome 17' group along with kindreds affected by apparently different forms of atypical dementias. Some of these kindreds have mutations in the tau gene. We report here that PSG-1 has a tau mutation at position +16 of the intron after exon 10. The mutation destabilizes a predicted stem-loop structure and leads to an over-representation of the soluble four-repeat tau isoforms, which assemble into wide, twisted, ribbon-like filaments and ultimately result in abundant neuronal and glial tau pathology. The mutations associated with PSG and other atypical dementias can be subdivided into three groups according to their tau gene locations and effects on tau. The existence of tau mutations with distinct pathogenetic mechanisms may explain the phenotypic heterogeneity of atypical dementias that previously led to their classification into separate disease entities.