Barcelona scale for buccophonatory apraxia: Quantitative assessment tool.

INTRODUCTION: Currently there is no tool to quantify buccophonatory apraxia to stratify, compare and monitor patients longitudinally in an objective manner. Our aim in this study is to create a quantitative scale for buccophonatory apraxia and evaluate it in patients with the non-fluent/grammatical variant of primary progressive aphasia (nfvPPA) and other neurodegenerative diseases that occur with speech and/or language problems. METHODS: The scale was designed based on useful elements in the assessment of buccophonatory apraxia and the total was quantified in seconds. The scale was administered to 64 participants with diagnoses of: nfvPPA, semantic variant of primary progressive aphasia (svPPA), logopenic variant of primary progressive aphasia (lvPPA), Huntington's disease, Parkinson's disease, as well as a group of healthy controls. RESULTS: Patients showed a significantly higher score compared to controls. The nfvPPA group had the highest mean score on the scale (429 seconds ± 278). The scale was useful to differentiate vnfPPA from svPPA and Parkinson's disease (area under curve [AUC] of 0.956 and 0.989, respectively), but less to differentiate it from Huntington's disease (AUC = 0.67) and lvPPA. There was a statistically significant relationship between total score and disease severity in nfvPPA (P < .029). CONCLUSIONS: The Barcelona scale for buccophonatory apraxia could be useful to quantitatively evaluate buccophonatory apraxia in different neurodegenerative diseases, and compare patients, especially in nfvPPA.

Spanish-dementia knowledge assessment scale (DKAS-S): psychometric properties and validation.

BACKGROUND: Alzheimer's disease (AD) is the most frequent cause of cognitive impairment. Community knowledge of the disease has proven to be a very important aspect of the development of interventions and the evaluation of their effectiveness. However, it is necessary to have standardized and recognized tools in different languages. The aim of the current study was to develop a cross-cultural adaptation of the Spanish Dementia Knowledge Assessment Scale (DKAS-S) and to assess their psychometric properties with cohorts of health students and professional and non-professional caregivers of AD patients from several regions of Spain. METHODS: We developed and translated the DKAS into Spanish following the forward-back-forward translation procedure. Then, we performed a cross-sectional study to assess the validity, reliability and feasibility of the DKAS-S. We also performed an analysis to obtain test-retest reliability measures. The study was performed in four medical centres across three regions in Spain. From May to September 2019, we administered the scale to students, professional and non-professional caregivers; including a subgroup of non-professional caregivers of patients with early-onset AD (< 65 years). RESULTS: Eight hundred forty-six volunteer participants completed the DKAS-S: 233 students (mean age 26.3 ± 9.2 years), 270 professional caregivers (mean age 42.5 ± 11.7 years) and 343 non-professional caregivers of AD patients. (mean age was 56.4 ± 13.16). The DKAS-S showed good internal consistency (Cronbach's α = 0.819) and good test-retest reliability (time 1: 28.1 ± 8.09 vs time 2: 28.8 ± 7.96; t = - 1.379; p = 0.173). Sensitivity to change was also significant in a subgroup of 31 students who received education related to AD and dementias between each administration (time 1: 25.6 ± 6.03) to (time 2: 32.5 ± 7.12; t = - 5.252, p = 0.000). The validity of the construct was verified by confirmatory factor analysis, although there were challenges in the inclusion of some items in the original 4 factors. CONCLUSIONS: The 25-item DKAS-S showed good psychometric properties for validity and reliability and the factorial analysis when it was administered to a population of students and professional and non-professional caregivers. It was a useful instrument for measuring levels of knowledge about dementia in Spanish population.

Globular glial tauopathy caused by MAPT P301T mutation: clinical and neuropathological findings.

OBJECTIVE: To describe the clinical, biochemical, and neuropathological findings of an autosomal dominant globular glial tauopathy caused by the P301T mutation at the MAPT gene. METHODS: Five patients from two unrelated pedigrees underwent clinical evaluation. Genetic analysis, brain pathological examination, and biochemical analysis of tau were performed. RESULTS: The patients studied were 3 men and 2 women with a mean age at onset of 52.2 years and mean disease duration of 5.2 years. Three patients presented a corticobasal syndrome, one patient an asymmetric pyramidal syndrome compatible with primary lateral sclerosis, and one patient a frontotemporal dementia. In both pedigrees (4 patients) Sanger sequencing showed the p.P301T mutation in exon 10 of the MAPT gene. Neuropathological findings consisted of atrophy of frontal and temporal lobes with marked spongiosis and astrogliosis, and abundant phosphorylated tau protein deposits in the frontal and temporal cortex, limbic area, basal ganglia, and brain stem. The most striking finding was the presence of oligodendroglial 4R phospho-tau globular positive inclusions in the white matter and cortex. Globose-type neurofibrillary neuronal tangles, and in particular astrocytic globular inclusions and coarse tufts, were present in the grey matter. Biochemical analysis of sarkosyl-insoluble fractions revealed two tau bands of 64 and 68 kDa and case-dependent bands of lower molecular weight. CONCLUSION: This is the first pathological and biochemical study of the MAPT p.P301T mutation showing variable clinical manifestation and neuropathological phenotype of globular glial tauopathy not only among different families but also within families.

Clinical applicability of diagnostic biomarkers in early-onset cognitive impairment.

BACKGROUND AND PURPOSE: Several diagnostic biomarkers are currently available for clinical use in early-onset cognitive impairment. The decision on which biomarker is used in each patient depends on several factors such as its predictive value or tolerability. METHODS: There were a total of 40 subjects with early-onset cognitive complaints (<65 years of age): 26 with Alzheimer's disease (AD), five with frontotemporal dementia and nine with diagnostic suspicion of non-neurodegenerative disorder. Clinical and neuropsychological evaluation, lumbar puncture for cerebrospinal fluid (CSF) AD core biochemical marker determination, medial temporal atrophy evaluation on magnetic resonance imaging, amyloid-positron emission tomography (PET) and 18 F-fluorodeoxyglucose-PET were performed. Neurologists provided pre- and post-biomarker diagnosis, together with diagnostic confidence and clinical/therapeutic management. Patients scored the tolerability of each procedure. RESULTS: Cerebrospinal fluid biomarkers and amyloid-PET increased diagnostic confidence in AD (77.4%-86.2% after CSF, 92.4% after amyloid-PET, P < 0.01) and non-neurodegenerative conditions (53.6%-75% after CSF, 95% after amyloid-PET, P < 0.05). Biomarker results led to diagnostic (32.5%) and treatment (32.5%) changes. All tests were well tolerated. CONCLUSIONS: Biomarker procedures are well tolerated and have an important diagnostic/therapeutic impact on early-onset cognitive impairment.

Capillaroscopy 2016: new perspectives in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disorder of unknown aetiology characterized by early impairment of the microvascular system. Nailfold microangiopathy and decreased peripheral blood perfusion are typical clinical aspects of SSc. The best method to evaluate vascular injury is nailfold videocapillaroscopy, which detects peripheral capillary morphology, and classifies and scores the abnormalities into different patterns of microangiopathy. Microangiopathy appears to be the best evaluable predictor of the disease development and has been observed to precede the other symptoms by many years. Peripheral blood perfusion is also impaired in SSc, and there are different methods to assess it: laser Doppler and laser speckle techniques, thermography and other emerging techniques.

[Can epidemiological factors affect the 2-year outcomes after surgery for degenerative lumbar disease in terms of quality of life, disability and post-surgical pain?]. / Pueden influir las variables epidemiológicas el resultado a los 2 años de una cirugía por enfermedad lumbar degenerativa en términos de calidad de vida, discapacidad y dolor postoperatorio?

PURPOSE: To evaluate the influence of epidemiological factors on the outcomes of surgery for degenerative lumbar disease in terms of quality of life, disability and chronic pain. MATERIAL AND METHOD: A total of 263 patients who received surgery for degenerative lumbar disease (2005-2008) were included in the study. The epidemiological data collected were age, gender, employment status, and co-morbidity. The SF-36, Oswestry Disability Index (ODI), Core Outcomes Measures Index (COMI), and VAS score for lumbar and sciatic pain were measure before and 2 years after surgery. The correlation between epidemiological data and questionnaire results, as well as any independent prognostic factors, were assessed in the data analysis. RESULTS: The mean age of the patients was 54.0 years (22-86), and 131 were female (49.8%). There were 42 (16%) lost to follow-up. Statistically significant correlations (P<.05) were observed between age, gender, co-morbidity, permanent sick leave, and pre-operative pain with changes in the ODI, COMI, physical and SF-36 mental scales, and lumbar and sciatic VAS. Linear regression analysis showed permanent sick leave and age as predictive factors of disability (ß=14.146; 95% CI: 9.09 - 29.58; P<.01 and ß=0.334; 95% CI: 0.40 - 0.98, P<.05, respectively), and change in quality of life (ß=-8.568; 95% CI: -14.88 - -2.26; p<.01 and ß=-0.228, IC 95% CI: -0.40 - -0.06, P<.05, respectively). CONCLUSION: Based on our findings, age and permanent sick leave have to be considered as negative epidemiologic predictive factors of the outcome of degenerative lumbar disease surgery.

Fabrication of hierarchical micro-nanotopographies for cell attachment studies.

We report on the development of micro/nanofabrication processes to create hierarchical surface topographies that expand from 50 nm to microns in size on different materials. Three different approaches (named FIB1, FIB2, and EBL) that combine a variety of techniques such as photolithography, reactive ion etching, focused ion beam lithography, electron beam lithography, and soft lithography were developed, each one providing different advantages and disadvantages. The EBL approach was employed to fabricate substrates comprising channels with features between 200 nm and 10 µm in size on polymethylmethacrylate (PMMA), which were then used to investigate the independent or competitive effects of micro- and nanotopographies on cell adhesion and morphology. Rat mesenchymal stem cells (rMSCs) were cultured on four different substrates including 10 µm wide and 500 nm deep channels separated by 10 µm distances (MICRO), 200 nm wide and 100 nm deep nanochannels separated by 200 nm distances (NANO), their combination in parallel (PARAL), and in a perpendicular direction (PERP). Rat MSCs behaved differently on all tested substrates with a high degree of alignment (as measured by both number of aligned cells and average angle) on both NANO and MICRO. Furthermore, cells exhibited the highest level of alignment on PARAL, suggesting a synergetic effect of the two scales of topographies. On the other hand, cells on PERP exhibited the lowest alignment and a consistent change in morphology over time that seemed to be the result of interactions with both micro- and nanochannels positioned in the perpendicular direction, also suggesting a competitive effect of the topographies.

Decreased striatal dopamine transporter uptake in the non-fluent/agrammatic variant of primary progressive aphasia.

BACKGROUND AND PURPOSE: Patients with the non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA) may develop atypical parkinsonian syndromes. However, there is no current biomarker to assess which patients are at high risk of developing parkinsonism. 123I-2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane (123I-FP-CIT)-SPECT detects striatal dopamine dysfunction in vivo. The objective of the present study was to study whether non-fluent/agrammatic patients without parkinsonism at baseline present decreased striatal 123I-FP-CIT uptake. METHODS: Visual and semi-quantitative assessments of the striatal 123I-FP-CIT uptake ratio were carried out in 15 patients with nfvPPA, eight patients with the logopenic variant of PPA (lvPPA) and 18 controls. To rule out progranulin mutations or underlying Alzheimer's disease (AD), serum progranulin levels and cerebrospinal fluid (CSF) biomarkers of AD (Aß42 , total-tau, phosphorylated-tau181 ) were determined. A second 123I-FP-CIT-SPECT analysis in the biomarker-enriched groups was also carried out. RESULTS: Patients with nfvPPA presented reduced striatal 123I-FP-CIT binding, especially in the left hemisphere (P = 0.002), compared with controls. All lvPPA patients had normal striatal 123I-FP-CIT uptake. 123I-FP-CIT striatal binding in nfvPPA patients with normal progranulin and CSF biomarker levels (nfvPPA/bio-) was also significantly reduced (P < 0.05) compared with lvPPA patients with positive AD biomarkers. Sixty-four per cent (9/14) of nfvPPA patients and 80% of nfvPPA/bio- patients (8/10) showed a diminished individual left striatal 123I-FP-CIT uptake ratio. On follow-up, seven nfvPPA/bio- patients developed parkinsonism (median 1.9 years; range 1.2-2.9), six of them with baseline reduced 123I-FP-CIT uptake. CONCLUSIONS: Reduced striatal tracer uptake in nfvPPA patients prior to clinical parkinsonism can be detected by 123I-FP-CIT-SPECT, especially in those with nfvPPA/bio-, suggesting subclinical nigrostriatal degeneration. Decreased striatal 123I-FP-CIT binding might identify PPA patients at increased risk of developing atypical parkinsonian syndromes, probably related to tau-pathology.

Neuroimaging and biochemical markers in the three variants of primary progressive aphasia.

BACKGROUND/AIM: To investigate in variants of primary progressive aphasia (PPA) the association between current clinical and neuroimaging criteria and biochemical/genetic markers at the individual level. METHODS: Thirty-two PPA patients were classified as non-fluent/agrammatic (nfvPPA), semantic (svPPA), or logopenic variant (lvPPA) or as unclassifiable (uPPA). In all patients, we evaluated the neuroimaging criteria (magnetic resonance imaging and/or single photon emission computed tomography/positron emission tomography) of each variant and studied serum progranulin levels, APOE genotype and Alzheimer's disease (AD)-cerebrospinal fluid (CSF) biomarkers. Cases with a first-degree family history of early-onset dementia were genetically tested. RESULTS: Ten of 15 (66%) nfvPPA, 5/5 (100%) svPPA and 7/7 (100%) lvPPA patients showed at least one positive neuroimaging-supported diagnostic criterion. All lvPPA and 3/5 (60%) uPPA patients presented AD-CSF biomarkers, which were absent in nfvPPA and svPPA cases. Four (27%) nfvPPA patients had dementia-causing mutations: 2 carried a GRN mutation and 2 the C9ORF72 hexanucleotide expansion. CONCLUSIONS: There was an excellent association between clinical criteria and neuroimaging-supported biomarkers in svPPA and lvPPA, as well as with AD-CSF biochemical markers in the lvPPA. Neuroimaging, biochemical and genetic findings in nfvPPA were heterogeneous. Incorporating biochemical/genetic markers into the PPA clinical diagnosis would allow clinicians to improve their predictions of PPA neuropathology, especially in nfvPPA and uPPA cases.

Clinical features and APOE genotype of pathologically proven early-onset Alzheimer disease.

OBJECTIVES: Early-onset Alzheimer disease (EOAD) diagnosis often represents a challenge because of the high frequency of atypical presentations. Our aim was to describe the clinical features, APOE genotype, and its pathologic correlations of neuropathologic confirmed EOAD. METHODS: Retrospective review of clinical data (age at onset, family history, clinical presentation, diagnostic delay, diagnosis) and APOE genotype of patients with neuropathologically confirmed EOAD (<60 years). RESULTS: Forty cases were selected. Mean age at onset was 54.5 years (range 46-60). The mean disease duration was 11 years with a mean diagnostic delay of 3.1 years. A total of 37.5% had a nonmemory presentation. Behavioral/executive dysfunction was the most prevalent atypical presentation. Incorrect initial clinical diagnoses were common (53%) in patients with atypical presentations, but rare when anterograde amnesia was the presenting symptom (4%). The incorrect initial clinical diagnoses were 2 behavioral variant frontotemporal lobar degeneration, 2 normal pressure hydrocephalus, 1 semantic dementia, 1 primary progressive aphasia, 1 corticobasal degeneration, 1 pseudodementia with depression, and 1 unclassifiable dementia. APOE genotype was ε3/ε3 in 59%, with no significant differences between typical and atypical presentations. APOE ε4 was 3.3 times more frequent in subjects with family history of AD. A total of 97.5% of the cases presented advanced neurofibrillary pathology. A total of 45% of the patients had concomitant Lewy body pathology although localized in most cases and without a significant clinical correlate. CONCLUSION: One third of patients with pathologic confirmed EOAD presented with atypical symptoms. Patients with EOAD with nonamnestic presentations often receive incorrect clinical diagnoses.

PICOGEN: five years experience with a genetic counselling program for dementia.

INTRODUCTION: We describe the 5 year experience of a genetic counselling program for familial dementias (the PICOGEN program). METHODS: The neurologist selected the candidates for genetic testing in the screening visit based on family history and phenotype (Alzheimer disease-AD, frontotemporal lobar degeneration-FTLD, or prion disease). Asymptomatic subjects who decided to know their genetic status were evaluated within a structured protocol by the psychiatrist and psychologist prior to entering the program and followed up afterwards. RESULTS: A total of 87 patients from 72 families were candidates for the genetic study, 20 of the 72 families had a family history of autosomal dominant early-onset dementia (ADEOD). A pathogenic mutation was found in 22 patients (8 PSEN1, 1 PSEN2, 1 APP, 4 MAPT, 8 PRNP), 5 of which had not been previously described. All positive cases, except for 1 PSEN1 (12.5%) and 4 PRNP (50%) showed ADEOD. In 3 ADEOD cases (15%) no pathogenic mutation was found. After individual genetic counselling, 24/54 asymptomatic subjects at risk decided to have the pre-symptomatic study, of whom 10 (42%) were carriers of the pathogenic mutation. In the follow up, no major psychiatric complication was observed. CONCLUSIONS: In our series, family history of ADEOD was a sensitive criterion for the detection of pathogenic mutations in AD and FTLD but not in prion diseases. No genetic anomalies were detected in 15% of the ADEOD cases using conventional diagnostic procedures, and 43% of pre-symptomatic subjects at risk who received individual genetic counselling decided to have the study. The pre-symptomatic diagnosis proved to be safe under these conditions.

[New mutation in the PSEN1 (E120G) gene associated with early onset Alzheimer's disease]. / Nueva mutación en el gen PSEN1 (E120G) asociada a enfermedad de Alzheimer de inicio precoz.

OBJECTIVE: To describe a novel mutation in exon 5 of the presenilin 1 gene (E120G)associated with early-onset autosomal dominant Alzheimer's disease (AD). PATIENT AND METHODS: The proband was a man who began with memory loss and progressive cognitive decline at the age of 34. His father and his sister suffered from early-onset cognitive decline. The genetic study performed on the blood sample using the single strand conformation polymorphism (SSCP) technique did not detect any abnormality suggestive of the presence of a mutation in PSEN1, PSEN2, and APP. In the last stage of the disease the patient had seizures and gait alteration. He died at the age of 44. Coding exons 3-12 of PSEN1 were studied by direct sequencing using isolated DNA from frozen brain tissue of the proband. RESULTS: The neuropathological examination showed the presence of frequent amyloid plaques and neurofibrillary tangles and severe amyloid angiopathy. The direct sequencing of the PSEN1 gene disclosed the presence of the E120G mutation. CONCLUSIONS: E120G is a novel mutation in PSEN1 that probably causes early-onset autosomal dominant AD. Absence of genetic alterations in screening techniques (SSCP) does not rule out the presence of mutations. We recommend direct sequencing for the genetic study of patients with early-onset autosomal dominant AD.

A novel PSEN1 mutation (K239N) associated with Alzheimer's disease with wide range age of onset and slow progression.

OBJECTIVE: To describe a novel mutation (K239N) in the PSEN1 associated with familial Alzheimer's disease (AD). METHODS AND RESULTS: The proband was a man who developed cognitive decline with marked behavioural abnormalities at age 57. At age 70, he was admitted into a psychiatric facility because of aggressiveness and a suicide attempt. Family history was consistent with autosomal dominant AD. One of the two other family members studied presented also with prominent behavioural symptoms at age 42 and has also been forced into a psychiatric facility because of aggressiveness at age 56. The remainder patient has presented a prototypical AD, but starting at age 71. Direct sequencing of PSEN1 in the three living affected members disclosed a heterozygous G to C transition in exon 7 of PSEN1 leading to the K239N mutation. CONCLUSION: The K239N mutation is associated with autosomal dominant AD with a wide range of age of onset and incomplete penetrance at the age of 65, prominent behavioural features and slow progression.

A novel presenilin 1 mutation (V261L) associated with presenile Alzheimer's disease and spastic paraparesis.

BACKGROUND AND PURPOSE: We report a novel mutation in exon 8 of the presenilin 1 (PSEN1) gene (V261L) associated with early-onset autosomal dominant Alzheimer's disease and spastic paraparesis. METHODS AND RESULTS: The proband was a woman who developed insidious cognitive decline with predominant memory loss and gait disorder secondary to spasticity at the age of 40. Her brother and her mother had a similar disease in the fifth decade of life. The feature of amnestic presentation with spastic paraparesis is consistent with the majority of mutations in the exon 8 of the PSEN1 1 gene. CONCLUSIONS: Screening for PSEN1 mutations is especially likely to be productive when directed toward persons with positive family history and with age at onset of under 60.

[Psychological impact of the diagnosis of Alzheimer's disease]. / Impacto psicológico del diagnóstico de la enfermedad de Alzheimer.

INTRODUCTION: The communication of the diagnosis of Alzheimer's disease (AD) may represent important emotional distress for the patient and his/her caregiver. This present work aimed to investigate if the disclosure of the diagnosis generates any emotional or psychological impact on the patient or his/her caregiver. PATIENTS AND METHODS: Thirty-three consecutive AD patients (NINCDS/ADRDA criteria) and their main caregivers were evaluated before and after the diagnosis disclosure. Patients were evaluated with the Neuropsychiatric Inventory Questionnaire (NPI-Q) and the Geriatric Depression Scale (GDS) and caregivers were evaluated with Beck's Depression Inventory (BDI), State-Trait Anxiety Inventory (STAI), the stress subscale from the NPI-Q and Zarit's burden interview. RESULTS: A total of 26 patients wanted to receive the diagnosis. AD diagnosis disclosure did not produce any significant clinical or emotional changes in the patient. On the contrary, the caregivers were significantly affected by AD diagnosis disclosure. This was reflected on the BDI scores, that increased from 6.9+/-6.5 to 9.7+/-7.5 (p=0.003). CONCLUSIONS: AD diagnosis may be safely disclosed to the patient. However, the caregivers should be carefully followed-up since depressive symptoms are common after diagnosis disclosure.

A novel mutation in the PSEN1 gene (L286P) associated with familial early-onset dementia of Alzheimer type and lobar haematomas.

The aim of this study was to describe a novel mutation in exon 8 of the presenilin gene (L286P) associated with early-onset autosomal dominant Alzheimer's disease (AD) and lobar haematomas. The proband was a woman who developed cognitive decline with predominant memory loss at the age of 35 years. The patient died at the age of 54 years and the neuropathological examination confirmed the diagnosis of AD. Three of her four siblings, one parent and one sibling of her parent had suffered from cognitive decline at ages between 35 and 42 years. Three of them also presented lobar haematomas. The neuropathological examination, available in one of them, disclosed the presence of severe amyloid angiopathy as the cause of the haematoma. The study of PSEN1 gene with single strand conformation polymorphism technique failed to show abnormalities suggestive of mutations. Direct sequencing disclosed the presence of a missense mutation in codon 286 (L286P) in the proband and her already affected descendent, which was absent in the healthy sibling. L286P is a novel mutation in PSEN1 that causes familial early-onset AD and brain haematomas related to amyloid angiopathy.

Phase I clinical study of the novel epothilone B analogue BMS-310705 given on a weekly schedule.

BACKGROUND: BMS-310705, a water-soluble semi-synthetic analogue of epothilone B, was selected for clinical development because of its in vivo anti-tumour activity and toxicity profile similar to that of ixabepilone, currently the most extensively evaluated and promising epothilone B analogue. The improved solubility of BMS-310705 allowed a cremophore-free formulation that avoided the need for pre-medication. PATIENTS AND METHODS: Two schedules were tested, one with drug administrations on days (D) 1, 8 and 15 followed by 1-week's rest, the other with administrations on D1 and 8 (D1&8 schedule) followed by 1-week's rest. Treatment was given as a 15-min infusion without pre-medication against hypersensitivity. The plasma pharmacokinetics of BMS-310705 was studied in 30 patients. An accelerated titration design 2B was applied for dose escalations. Twenty-seven patients were accrued in the D1, 8, 15 and 32 in the D1&8 schedule. RESULTS: The dose was escalated from 5-30 mg/m(2)/week with diarrhoea as dose-limiting toxicity; 15 and 20 mg/m(2) were the recommended doses in the D1, 8, 15 and D1&8 schedule, respectively. Other frequent non-haematological toxicities were neurotoxicity, mainly paraesthesia, asthenia and myalgia. Preliminary results showed linear pharmacokinetics along the range of doses tested with a short half-life. Five objective responses were reported. CONCLUSIONS: Further clinical development of BMS-310705 might be worthwhile in solid tumours where ixabepilone or other epothilones are not indicated.

MAPT gene duplications are not a cause of frontotemporal lobar degeneration.

Recurrent deletions of the 17q21.31 region encompassing the microtubule-associated protein tau (MAPT) gene have recently been described in patients with mental retardation. This region is flanked by segmental duplications that make it prone to inversions, deletions and duplications. Since gain-of-function mutations of the MAPT gene cause frontotemporal lobar degeneration (FTLD) characterized by deposition of tau protein, we hypothesize that MAPT duplication affecting gene dosage could also lead to disease. Gene dosage alterations have already been found to be involved in the etiology of neurodegenerative disorders caused by protein or peptide accumulation, such as Alzheimer's and Parkinson's diseases. To determine whether MAPT gene copy number variation is involved in FTLD, 70 patients with clinical diagnosis of FTLD and no MAPT mutation (including 12 patients with pathologically proven tau-positive FTLD) were screened by using multiplex ligation probe amplification (MLPA) with specific oligonucleotide probes. No copy number variation in the MAPT gene was observed in cases. Although our study was limited by the relatively small number of patients, it does not support the theory that chromosomal rearrangements in this region are a cause of FTLD.

Brain tau expression and correlation with the H1/H1 tau genotype in frontotemporal lobar degeneration patients.

Alterations in tau mRNA splicing and association with H1/H1 tau genotype have been described in some sporadic tauopathies. We evaluated the 4R/3R tau mRNA ratio in 18 patients with frontotemporal lobar degeneration (FTLD), and the effect of the H1/H1 genotype on this ratio. The 4R/3R mRNA ratio in frontal cortex was similar in FTLD patients and controls. The H1/H1 genotype carriers showed a significant increase in 4R/3R mRNA ratio, suggesting that this genotype could modulate the tau mRNA splicing.