ABSTRACT The esophageal-tracheal Combitube (Kendall-Sheridan Catheter Corp., Argyle, NY) is an ef... more ABSTRACT The esophageal-tracheal Combitube (Kendall-Sheridan Catheter Corp., Argyle, NY) is an effective device for providing adequate gas exchange. However, tracheal suctioning is impossible with the Combitube placed in the esophageal position. To eliminate this disadvantage, the Combitube was redesigned by creating an enlarged hole in the pharyngeal lumen that allows fiberoptic access, tracheal suctioning, and tube exchange over a guide wire. The two anterior, proximal perforations of regular Combitubes were replaced by a larger, ellipsoid-shaped hole. After the study was approved by the institutional review board, 20 patients with normal airways (Mallampati I or II) were studied. During general anesthesia, patients were esophageally intubated with the Combitube. A flexible bronchoscope was inserted and guided via the modified hole and glottic opening down the trachea. For the replacement procedure, a J tip guide wire was introduced through the bronchoscope. The bronchoscope and the Combitube were removed and a standard endotracheal tube was advanced over a guide catheter. Bronchoscopic evaluation of the trachea and guided replacement of the Combitube by an endotracheal tube was successful in all 20 study patients. The average time needed to perform airway exchange was 90 +/- 20 s (mean +/- SD). Arterial oxygen saturation and end-tidal carbon dioxide levels remained normal in all patients. No case of laryngeal trauma was observed during intubation or the airway exchange procedure. The redesigned Combitube enables fiberoptic bronchoscopy, fine-tuning of its position in the esophagus, and guided airway exchange in patients with normal airways. Further studies are warranted to demonstrate its value in patients with abnormal airways.
Microglial activation is an important pathogenic component of neurodegenerative disease processes... more Microglial activation is an important pathogenic component of neurodegenerative disease processes. This state of increased inflammation is associated not only with neurotoxic consequences but also neuroprotective effects, e.g., phagocytosis and clearance of amyloid in Alzheimer's disease. In addition, activation of microglia appears to be one of the major mechanisms of amyloid clearance following active or passive immunotherapy. Imaging techniques may provide a minimally invasive tool to elucidate the complexities and dynamics of microglial function and dysfunction in aging and neurodegenerative diseases. Imaging microglia in vivo in live subjects by confocal or two/multiphoton microscopy offers the advantage of studying these cells over time in their native environment. Imaging microglia in human subjects by positron emission tomography scanning with translocator protein-18 kDa ligands can offer a measure of the inflammatory process and a means of detecting progression of disease and efficacy of therapeutics over time.
Psychosis occurs in 40-60% of Alzheimer's disease (AD) subjects, is heritable, and indicates ... more Psychosis occurs in 40-60% of Alzheimer's disease (AD) subjects, is heritable, and indicates a more rapidly progressive disease phenotype. Neuroimaging and postmortem evidence support an exaggerated prefrontal cortical synaptic deficit in AD with psychosis. Microtubule-associated protein tau is a key mediator of amyloid-β-induced synaptotoxicity in AD, and differential mechanisms of progressive intraneuronal phospho-tau accumulation and interneuronal spread of tau aggregates have recently been described. We hypothesized that psychosis in AD would be associated with greater intraneuronal concentration of phospho-tau and greater spread of tau aggregates in prefrontal cortex. We therefore evaluated prefrontal cortex phospho-tau in a cohort of 45 AD cases with and without psychosis. Intraneuronal phospho-tau concentration was higher in subjects with psychosis, while a measure of phospho-tau spread, volume fraction, was not. Across groups both measures were associated with lower scor...
The phenotype of IBMPFD [inclusion body myopathy with Paget's disease of ... more The phenotype of IBMPFD [inclusion body myopathy with Paget's disease of the bone and frontotemporal dementia (FTD)] associated with valosin-containing protein (VCP) mutation is described in three families. Probands were identified based on a pathological diagnosis of frontotemporal lobar degeneration with TDP-43-positive inclusions type IV. VCP sequencing was carried out. Clinical data on affected family members were reviewed. Ohio family: four subjects presented muscle weakness and wasting. (One subject had both neuropathic and myopathic findings and another subject showed only evidence of myopathy. The etiology of weakness could not be ascertained in the remaining two subjects.) Two individuals also showed Parkinsonism (with associated FTD in one of the two). The proband's brain displayed FTLD-TDP type IV and Braak stage five Parkinson's disease (PD). A VCP R191Q mutation was found. Pennsylvania family: 11 subjects developed IBMPFD. Parkinsonism was noted in two mutation carriers, whilst another subject presented with primary progressive aphasia (PPA). A novel VCP T262A mutation was found. Indiana family: three subjects developed IBMPFD. FTD was diagnosed in two individuals and suspected in the third one who also displayed muscle weakness. A VCP R159C mutation was found. We identified three families with IBMPFD associated with VCP mutations. Clinical and pathological PD was documented for the first time in members of two families. A novel T262A mutation was found. One individual had PPA: an uncommon presentation of IBMPFD.
Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently be... more Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.
ABSTRACT The esophageal-tracheal Combitube (Kendall-Sheridan Catheter Corp., Argyle, NY) is an ef... more ABSTRACT The esophageal-tracheal Combitube (Kendall-Sheridan Catheter Corp., Argyle, NY) is an effective device for providing adequate gas exchange. However, tracheal suctioning is impossible with the Combitube placed in the esophageal position. To eliminate this disadvantage, the Combitube was redesigned by creating an enlarged hole in the pharyngeal lumen that allows fiberoptic access, tracheal suctioning, and tube exchange over a guide wire. The two anterior, proximal perforations of regular Combitubes were replaced by a larger, ellipsoid-shaped hole. After the study was approved by the institutional review board, 20 patients with normal airways (Mallampati I or II) were studied. During general anesthesia, patients were esophageally intubated with the Combitube. A flexible bronchoscope was inserted and guided via the modified hole and glottic opening down the trachea. For the replacement procedure, a J tip guide wire was introduced through the bronchoscope. The bronchoscope and the Combitube were removed and a standard endotracheal tube was advanced over a guide catheter. Bronchoscopic evaluation of the trachea and guided replacement of the Combitube by an endotracheal tube was successful in all 20 study patients. The average time needed to perform airway exchange was 90 +/- 20 s (mean +/- SD). Arterial oxygen saturation and end-tidal carbon dioxide levels remained normal in all patients. No case of laryngeal trauma was observed during intubation or the airway exchange procedure. The redesigned Combitube enables fiberoptic bronchoscopy, fine-tuning of its position in the esophagus, and guided airway exchange in patients with normal airways. Further studies are warranted to demonstrate its value in patients with abnormal airways.
Microglial activation is an important pathogenic component of neurodegenerative disease processes... more Microglial activation is an important pathogenic component of neurodegenerative disease processes. This state of increased inflammation is associated not only with neurotoxic consequences but also neuroprotective effects, e.g., phagocytosis and clearance of amyloid in Alzheimer's disease. In addition, activation of microglia appears to be one of the major mechanisms of amyloid clearance following active or passive immunotherapy. Imaging techniques may provide a minimally invasive tool to elucidate the complexities and dynamics of microglial function and dysfunction in aging and neurodegenerative diseases. Imaging microglia in vivo in live subjects by confocal or two/multiphoton microscopy offers the advantage of studying these cells over time in their native environment. Imaging microglia in human subjects by positron emission tomography scanning with translocator protein-18 kDa ligands can offer a measure of the inflammatory process and a means of detecting progression of disease and efficacy of therapeutics over time.
Psychosis occurs in 40-60% of Alzheimer's disease (AD) subjects, is heritable, and indicates ... more Psychosis occurs in 40-60% of Alzheimer's disease (AD) subjects, is heritable, and indicates a more rapidly progressive disease phenotype. Neuroimaging and postmortem evidence support an exaggerated prefrontal cortical synaptic deficit in AD with psychosis. Microtubule-associated protein tau is a key mediator of amyloid-β-induced synaptotoxicity in AD, and differential mechanisms of progressive intraneuronal phospho-tau accumulation and interneuronal spread of tau aggregates have recently been described. We hypothesized that psychosis in AD would be associated with greater intraneuronal concentration of phospho-tau and greater spread of tau aggregates in prefrontal cortex. We therefore evaluated prefrontal cortex phospho-tau in a cohort of 45 AD cases with and without psychosis. Intraneuronal phospho-tau concentration was higher in subjects with psychosis, while a measure of phospho-tau spread, volume fraction, was not. Across groups both measures were associated with lower scor...
The phenotype of IBMPFD [inclusion body myopathy with Paget's disease of ... more The phenotype of IBMPFD [inclusion body myopathy with Paget's disease of the bone and frontotemporal dementia (FTD)] associated with valosin-containing protein (VCP) mutation is described in three families. Probands were identified based on a pathological diagnosis of frontotemporal lobar degeneration with TDP-43-positive inclusions type IV. VCP sequencing was carried out. Clinical data on affected family members were reviewed. Ohio family: four subjects presented muscle weakness and wasting. (One subject had both neuropathic and myopathic findings and another subject showed only evidence of myopathy. The etiology of weakness could not be ascertained in the remaining two subjects.) Two individuals also showed Parkinsonism (with associated FTD in one of the two). The proband's brain displayed FTLD-TDP type IV and Braak stage five Parkinson's disease (PD). A VCP R191Q mutation was found. Pennsylvania family: 11 subjects developed IBMPFD. Parkinsonism was noted in two mutation carriers, whilst another subject presented with primary progressive aphasia (PPA). A novel VCP T262A mutation was found. Indiana family: three subjects developed IBMPFD. FTD was diagnosed in two individuals and suspected in the third one who also displayed muscle weakness. A VCP R159C mutation was found. We identified three families with IBMPFD associated with VCP mutations. Clinical and pathological PD was documented for the first time in members of two families. A novel T262A mutation was found. One individual had PPA: an uncommon presentation of IBMPFD.
Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently be... more Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.
Uploads