A Case Report of a Novel Atypical Mycobacterial Infection: Mycobacterium Chimaera Hand Tenosynovitis.

CASE: A 76-year-old fisherman with a history of diabetes mellitus, coronary artery bypass grafting, and a previous ipsilateral elbow wound presented with a 1-year history of hand pain and swelling. Anti-inflammatories and antibiotics were administered without improvement. Magnetic resonance imaging and ultrasound demonstrated flexor tenosynovitis. Intraoperative cultures revealed Mycobacterium chimaera. The treatment course included 2 tenosynovectomies and a 1-year course of triple antimycobacterial therapy. CONCLUSION: Nontuberculous mycobacteria infections should be considered in cases of indolent tenosynovitis. M. chimaera should be considered in patients with a history of cardiopulmonary bypass given its association with cardiopulmonary heater-cooler units.

Radio-Pathomic Maps of Cell Density Identify Brain Tumor Invasion beyond Traditional MRI-Defined Margins.

BACKGROUND AND PURPOSE: Currently, contrast-enhancing margins on T1WI are used to guide treatment of gliomas, yet tumor invasion beyond the contrast-enhancing region is a known confounding factor. Therefore, this study used postmortem tissue samples aligned with clinically acquired MRIs to quantify the relationship between intensity values and cellularity as well as to develop a radio-pathomic model to predict cellularity using MR imaging data. MATERIALS AND METHODS: This single-institution study used 93 samples collected at postmortem examination from 44 patients with brain cancer. Tissue samples were processed, stained with H&E, and digitized for nuclei segmentation and cell density calculation. Pre- and postgadolinium contrast T1WI, T2 FLAIR, and ADC images were collected from each patient's final acquisition before death. In-house software was used to align tissue samples to the FLAIR image via manually defined control points. Mixed-effects models were used to assess the relationship between single-image intensity and cellularity for each image. An ensemble learner was trained to predict cellularity using 5 × 5 voxel tiles from each image, with a two-thirds to one-third train-test split for validation. RESULTS: Single-image analyses found subtle associations between image intensity and cellularity, with a less pronounced relationship in patients with glioblastoma. The radio-pathomic model accurately predicted cellularity in the test set (root mean squared error = 1015 cells/mm2) and identified regions of hypercellularity beyond the contrast-enhancing region. CONCLUSIONS: A radio-pathomic model for cellularity trained with tissue samples acquired at postmortem examination is able to identify regions of hypercellular tumor beyond traditional imaging signatures.

Papillary glioneuronal tumors: Distinctive cytological characteristics and cyto-histologic correlation.

Intraoperative cytological examination and cyto-histologic correlation of papillary glioneuronal tumors have rarely been described in detail in the literature. A 23-year-old female presented at our institution with seizure-like activity, and a 3.0 cm left temporal lobe hypoattenuating lesion. She was accurately diagnosed with papillary glioneuronal tumor on Intraoperative cytology. The patient subsequently proceeded to stealth-guided awake left temporal craniotomy, confirming the diagnosis. In this article, we present a detailed report of papillary glioneuronal tumor (extremely rare central nervous system neoplasm) describing the cytologic and histologic morphologic features, its differential diagnosis with review of the literature.

Visceral fat does not contribute to metabolic disease in lipodystrophy.

OBJECTIVES: Lipodystrophies are characterized by regional or generalized loss of adipose tissue and severe metabolic complications. The role of visceral adipose tissue (VAT) in the development of metabolic derangements in lipodystrophy is unknown. The study aim was to investigate VAT contribution to metabolic disease in lipodystrophy versus healthy controls. METHODS: Analysis of correlations between VAT volume and biomarkers of metabolic disease in 93 patients and 93 age/sex-matched healthy controls. RESULTS: Patients with generalized lipodystrophy (n = 43) had lower VAT compared with matched controls, while those with partial lipodystrophy (n = 50) had higher VAT versus controls. Both groups with lipodystrophy had lower leg fat mass versus controls (p < 0.05 for all; unpaired t-test). In both generalized and partial lipodystrophy, there was no correlation between VAT and glucose, triglycerides or high-density lipoprotein cholesterol (p > 0.05 for all; Spearman correlation). In controls matched to patients with generalized or partial lipodystrophy, VAT correlated with glucose (R = 0.42 and 0.36), triglycerides (R = 0.36 and 0.60) and high-density lipoprotein cholesterol (R = -0.34 and -0.64) (p < 0.05 for all; Spearman correlation). CONCLUSIONS: In contrast to healthy controls, metabolic derangements in lipodystrophy did not correlate with VAT volume. These data suggest that, in lipodystrophy, impaired peripheral subcutaneous fat deposition may exert a larger effect than VAT accumulation on the development of metabolic complications. Interventions aimed at increasing functional subcutaneous adipose tissue may provide metabolic benefit.

Progressing Bevacizumab-Induced Diffusion Restriction Is Associated with Coagulative Necrosis Surrounded by Viable Tumor and Decreased Overall Survival in Patients with Recurrent Glioblastoma.

BACKGROUND AND PURPOSE: Patients with recurrent glioblastoma often exhibit regions of diffusion restriction following the initiation of bevacizumab therapy. Studies suggest that these regions represent either diffusion-restricted necrosis or hypercellular tumor. This study explored postmortem brain specimens and a population analysis of overall survival to determine the identity and implications of such lesions. MATERIALS AND METHODS: Postmortem examinations were performed on 6 patients with recurrent glioblastoma on bevacizumab with progressively growing regions of diffusion restriction. ADC values were extracted from regions of both hypercellular tumor and necrosis. A receiver operating characteristic analysis was performed to define optimal ADC thresholds for differentiating tissue types. A retrospective population study was also performed comparing the overall survival of 64 patients with recurrent glioblastoma treated with bevacizumab. Patients were separated into 3 groups: no diffusion restriction, diffusion restriction that appeared and progressed within 5 months of bevacizumab initiation, and delayed or stable diffusion restriction. An additional analysis was performed assessing tumor O6-methylguanine-DNA-methyltransferase methylation. RESULTS: The optimal ADC threshold for differentiation of hypercellularity and necrosis was 0.736 × 10-3mm2/s. Progressively expanding diffusion restriction was pathologically confirmed to be coagulative necrosis surrounded by viable tumor. Progressive lesions were associated with the worst overall survival, while stable lesions showed the greatest overall survival (P < .05). Of the 40% of patients with O6-methylguanine-DNA-methyltransferase methylated tumors, none developed diffusion-restricted lesions. CONCLUSIONS: Progressive diffusion-restricted lesions were pathologically confirmed to be coagulative necrosis surrounded by viable tumor and associated with decreased overall survival. Stable lesions were, however, associated with increased overall survival. All lesions were associated with O6-methylguanine-DNA-methyltransferase unmethylated tumors.

Silicon detectors for combined MR-PET and MR-SPECT imaging.

Silicon based devices can extend PET-MR and SPECT-MR imaging to applications, where their advantages in performance outweigh benefits of high statistical counts.Silicon is in many ways an excellent detector material with numerous advantages, among others: excellent energy and spatial resolution, mature processing technology, large signal to noise ratio, relatively low price, availability, versatility and malleability. The signal in silicon is also immune to effects of magnetic field at the level normally used in MR devices. Tests in fields up to 7 T were performed in a study to determine effects of magnetic field on positron range in a silicon PET device. The curvature of positron tracks in direction perpendicular to the field's orientation shortens the distance between emission and annihilation point of the positron. The effect can be fully appreciated for a rotation of the sample for a fixed field direction, compressing range in all dimensions. A popular Ga-68 source was used showing a factor of 2 improvement in image noise compared to zero field operation. There was also a little increase in noise as the reconstructed resolution varied between 2.5 and 1.5 mm.A speculative applications can be recognized in both emission modalities, SPECT and PET.Compton camera is a subspecies of SPECT, where a silicon based scatter as a MR compatible part could inserted into the MR bore and the secondary detector could operate in less constrained environment away from the magnet. Introducing a Compton camera also relaxes requirements of the radiotracers used, extending the range of conceivable photon energies beyond 140.5 keV of the Tc-99m.In PET, one could exploit the compressed sub-millimeter range of positrons in the magnetic field. To exploit the advantage, detectors with spatial resolution commensurate to the effect must be used with silicon being an excellent candidate. Measurements performed outside of the MR achieving spatial resolution below 1 mm are reported.

Silicon as an Unconventional Detector in Positron Emission Tomography.

Positron emission tomography (PET) is a widely used technique in medical imaging and in studying small animal models of human disease. In the conventional approach, the 511 keV annihilation photons emitted from a patient or small animal are detected by a ring of scintillators such as LYSO read out by arrays of photodetectors. Although this has been a successful in achieving ~5mm FWHM spatial resolution in human studies and ~1mm resolution in dedicated small animal instruments, there is interest in significantly improving these figures. Silicon, although its stopping power is modest for 511 keV photons, offers a number of potential advantages over more conventional approaches. Foremost is its high spatial resolution in 3D: our past studies show that there is little diffculty in localizing 511 keV photon interactions to ~0.3mm. Since spatial resolution and reconstructed image noise trade off in a highly non-linear manner that depends on the PET instrument response, if high spatial resolution is the goal, silicon may outperform standard PET detectors even though it has lower sensitivity to 511 keV photons. To evaluate silicon in a variety of PET "magnifying glass" configurations, an instrument has been constructed that consists of an outer partial-ring of PET scintillation detectors into which various arrangements of silicon detectors can be inserted to emulate dual-ring or imaging probe geometries. Recent results have demonstrated 0.7 mm FWHM resolution using pad detectors having 16×32 arrays of 1.4mm square pads and setups have shown promising results in both small animal and PET imaging probe configurations. Although many challenges remain, silicon has potential to become the PET detector of choice when spatial resolution is the primary consideration.

Consequences of stopping and restarting leptin in an adolescent with lipodystrophy.

BACKGROUND/AIMS: Lipodystrophy encompasses a group of rare disorders characterized by deficiency of adipose tissue resulting in hypoleptinemia, and metabolic abnormalities including insulin resistance, diabetes, dyslipidemia, and nonalcoholic steatohepatitis. Leptin replacement effectively ameliorates these metabolic derangements. We report effects of leptin discontinuation and resumption in a child with acquired generalized lipodystrophy. METHODS: Intermittent treatment with leptin with follow-up over 5 years. RESULTS: Pretreatment metabolic abnormalities included insulin resistance, hypertriglyceridemia and steatohepatitis. Leptin was started at the age of 10 years. After 2 years, the family requested discontinuation of leptin due to lack of visible physical changes. Nine months later, worsened metabolic abnormalities and arrest of pubertal development were observed. Leptin was restarted, followed by improvements in metabolic parameters. Laboratory changes (before vs. 6 months after restarting leptin) were: fasting glucose from 232 to 85 mg/dl, insulin from 232 to 38.9 µU/ml, HbA(1c) from 7.5 to 4.8%, triglycerides from 622 to 96 mg/dl, ALT from 229 to 61 U/l, AST from 91 to 18 U/l, and urine protein:creatinine ratio from 5.4 to 0.3. Progression of puberty was observed 1 year after restarting leptin. CONCLUSION: Initial leptin therapy likely prevented progression of metabolic abnormalities. Treatment discontinuation led to rapid metabolic decomposition and pubertal arrest. Reintroduction of leptin reversed metabolic abnormalities and allowed normal pubertal progression.

Founder effect in the Horn of Africa for an insulin receptor mutation that may impair receptor recycling.

AIMS/HYPOTHESIS: Genetic insulin receptoropathies are a rare cause of severe insulin resistance. We identified the Ile119Met missense mutation in the insulin receptor INSR gene, previously reported in a Yemeni kindred, in four unrelated patients with Somali ancestry. We aimed to investigate a possible genetic founder effect, and to study the mechanism of loss of function of the mutant receptor. METHODS: Biochemical profiling and DNA haplotype analysis of affected patients were performed. Insulin receptor expression in lymphoblastoid cells from a homozygous p.Ile119Met INSR patient, and in cells heterologously expressing the mutant receptor, was examined. Insulin binding, insulin-stimulated receptor autophosphorylation, and cooperativity and pH dependency of insulin dissociation were also assessed. RESULTS: All patients had biochemical profiles pathognomonic of insulin receptoropathy, while haplotype analysis revealed the putative shared region around the INSR mutant to be no larger than 28 kb. An increased insulin proreceptor to ß subunit ratio was seen in patient-derived cells. Steady state insulin binding and insulin-stimulated autophosphorylation of the mutant receptor was normal; however it exhibited decreased insulin dissociation rates with preserved cooperativity, a difference accentuated at low pH. CONCLUSIONS/INTERPRETATION: The p.Ile119Met INSR appears to have arisen around the Horn of Africa, and should be sought first in severely insulin resistant patients with ancestry from this region. Despite collectively compelling genetic, clinical and biochemical evidence for its pathogenicity, loss of function in conventional in vitro assays is subtle, suggesting mildly impaired receptor recycling only.

Treatment of type B insulin resistance: a novel approach to reduce insulin receptor autoantibodies.

BACKGROUND: Type B insulin resistance belongs to a class of diseases caused by an autoantibody to a cell surface receptor. Blockade of insulin action results in hyperglycemia, hypercatabolism, severe acanthosis nigricans, and hyperandrogenism in women. This rare autoimmune disorder has been treated with various forms of immunosuppression with mixed success. METHODS: We describe 14 patients with type B insulin resistance referred to the National Institutes of Health, adding to an existing cohort of 24 patients. This report focuses on seven patients who were treated with an intensive combination protocol of rituximab, cyclophosphamide, and pulse corticosteroids aimed at control of pathogenic autoantibody production. Hematological, metabolic, and endocrine parameters, including fasting glucose, glycated hemoglobin, insulin dose, lipids, and testosterone, were monitored before and after treatment. RESULTS: All seven treated patients achieved remission, defined as amelioration of hyperglycemia, discontinuation of insulin therapy, and resolution of hyperandrogenism. Glycated hemoglobin has normalized in all seven treated patients. Remission was achieved on average in 8 months from initiation of treatment. The medication regimen was well tolerated, with no serious adverse events. CONCLUSIONS: In seven patients with type B insulin resistance, standardized treatment with rituximab, cyclophosphamide, and pulse steroids results in remission of the disease. Future studies will determine whether this treatment protocol can be applied to other autoantibody/cell surface receptor disease states.

Timing performance of the silicon PET insert probe.

Simulation indicates that PET image could be improved by upgrading a conventional ring with a probe placed close to the imaged object. In this paper, timing issues related to a PET probe using high-resistivity silicon as a detector material are addressed. The final probe will consist of several (four to eight) 1-mm thick layers of silicon detectors, segmented into 1 x 1 mm(2) pads, each pad equivalent to an independent p + nn+ diode. A proper matching of events in silicon with events of the external ring can be achieved with a good timing resolution. To estimate the timing performance, measurements were performed on a simplified model probe, consisting of a single 1-mm thick detector with 256 square pads (1.4 mm side), coupled with two VATAGP7s, application-specific integrated circuits. The detector material and electronics are the same that will be used for the final probe. The model was exposed to 511 keV annihilation photons from an (22)Na source, and a scintillator (LYSO)-PMT assembly was used as a timing reference. Results were compared with the simulation, consisting of four parts: (i) GEANT4 implemented realistic tracking of electrons excited by annihilation photon interactions in silicon, (ii) calculation of propagation of secondary ionisation (electron-hole pairs) in the sensor, (iii) estimation of the shape of the current pulse induced on surface electrodes and (iv) simulation of the first electronics stage. A very good agreement between the simulation and the measurements were found. Both indicate reliable performance of the final probe at timing windows down to 20 ns.

Efficacy of leptin therapy in the different forms of human lipodystrophy.

AIMS/HYPOTHESIS: Lipodystrophy is a rare disorder characterised by loss of adipose tissue, hypoleptinaemia, severe insulin resistance, diabetes and dyslipidaemia. The aims of this study were to determine whether leptin replacement in lipodystrophy patients ameliorates their metabolic abnormalities over an extended period of time and whether leptin therapy is effective in the different forms of lipodystrophy. METHODS: We conducted an open-label prospective study of patients with acquired forms of lipodystrophy and inherited forms of lipodystrophy secondary to mutations in the AGPAT2, SEIPIN (also known as BSCL2), LMNA and PPARgamma (also known as PPARG) genes. Between July 2000 and November 2008, 48 patients with lipodystrophy were treated with s.c. recombinant methionyl human leptin. RESULTS: Serum triacylglycerol and HbA(1c) levels declined dramatically with leptin therapy. Among 35 patients with data at baseline and 12 months, serum triacylglycerol fell by 59% (from 10.18 +/- 2.67 mmol/l to 4.16 +/- 0.99 mmol/l [means +/- SE]; p = 0.008) and HbA(1c) decreased by 1.5 percentage points (from 8.4 +/- 0.3% to 6.9 +/- 0.3%; p < 0.001). A significant reduction was seen in total cholesterol and a trend towards reduction was observed in LDL-cholesterol at 12 months. HDL-cholesterol was unchanged. Among generalised lipodystrophy patients, proteinuria diminished with leptin replacement. Patients with both acquired and inherited forms of lipodystrophy experienced decreases in serum triacylglycerol and HbA(1c) levels. CONCLUSIONS/INTERPRETATION: Leptin replacement in lipodystrophy patients leads to significant and sustained improvements in glycaemic control and dyslipidaemia. Leptin is effective in the various forms of lipodystrophy, whether they are acquired or inherited, generalised or partial. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT00025883 FUNDING: This work was supported by intramural research funding from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH).

Symmetry breaking of in-plane order in confined copolymer mesophases.

Packing of spherical-domain block copolymer mesophases confined to a thin film is investigated as a function of the number of layers n. We find an abrupt transition from hexagonal to orthorhombic in-plane ordering of domains when n is increased from 4 to 5. As n increases further (up to 23 in this study), the symmetry of the orthorhombic phase asymptotically approaches that of the body-centered cubic (110) plane. These results are interpreted in terms of the energetics of competing packings in the bulk and at the film interfaces. Detailed structural and thermodynamic properties are obtained with self-consistent field theory.

Elevated plasma adiponectin in humans with genetically defective insulin receptors.

CONTEXT: Adiponectin has been suggested to play a role in the etiopathogenesis of at least some forms of insulin resistance, in part based on a strong correlation between plasma levels of adiponectin and measures of insulin sensitivity. OBJECTIVE: The objective of the study was to establish whether this relationship is maintained at extreme levels of insulin resistance. DESIGN/SETTING: This was a cross-sectional study in a university teaching hospital of subjects recruited from the United Kingdom and the United States. PARTICIPANTS: Participants included 75 subjects with a range of syndromes of severe insulin resistance and 872 nondiabetic controls. OUTCOME MEASURES: Fasting plasma insulin, adiponectin, and leptin were measured. RESULTS: Unexpectedly, subjects with mutations in the insulin receptor, despite having the most severe degree of insulin resistance, had elevated plasma adiponectin [median 24.4 mg/liter; range 6.6-36.6 (normal adult range for body mass index 20 kg/m(2) = 3-19 mg/liter)], whereas all other subjects had low adiponectin levels (median 2.0 mg/liter; range 0.12-11.2). Plasma leptin in all but one subject with an insulin receptoropathy was low or undetectable [median 0.5 ng/ml; range 0-16: normal adult range for body mass index of < 25 kg/m(2) = 2.4-24.4 (female) and 0.4-8.3 ng/ml (male)]. CONCLUSIONS: We conclude that the relationship between plasma adiponectin and insulin sensitivity is complex and dependent on the precise etiology of defective insulin action and that the combination of high plasma adiponectin with low leptin may have clinical utility in patients with severe insulin resistance as a marker of the presence of a genetic defect in the insulin receptor.

Vascular and Alzheimer-type pathology in an autopsy study of African-Americans.

The authors studied 13 autopsy brains from a larger cohort of 270 African-Americans with a clinical diagnosis of Alzheimer disease (AD), vascular dementia (VaD), or stroke without dementia. Two subjects exhibited changes of pure VaD, 5 had pure AD, and 6 showed a mixture of AD pathology and strokes. Overall, there was good agreement between the pathologic diagnoses and the clinical diagnoses.

Tau epitope display in progressive supranuclear palsy and corticobasal degeneration.

Filamentous aggregates of the protein tau are a prominent feature of Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). However, the extent to which the molecular structure of the tau in these aggregates is similar or differs between these diseases is unclear. We approached this question by examining these disorders with a panel of antibodies that represent different structural, conformational, and cleavage-specific tau epitopes. Although each of these antibodies reveals AD pathology, they resolved into three classes with respect to PSP and CBD: AD2 and Tau-46.1 stained the most tau pathology in all cases; Tau-1, 2, 5, and 12 exhibited variable reactivity; and Tau-66 and MN423 did not reveal any tau pathology. In addition, hippocampal neurofibrillary tangles in these cases showed a predominantly PSP/CBD-like, rather than AD-like, staining pattern. These results indicate that the patterns of the tau epitopes represented by this panel that reside in the pathological aggregates of PSP and CBD are similar to each other but distinct from that of AD.

SEPT5_v2 is a parkin-binding protein.

Mutations in parkin are associated with various inherited forms of Parkinson's disease (PD). Parkin is a ubiquitin ligase enzyme that catalyzes the covalent attachment of ubiquitin moieties onto substrate proteins destined for proteasomal degradation. The substrates of parkin-mediated ubiquitination have yet to be completely identified. Using a yeast two-hybrid screen, we isolated the septin, human SEPT5_v2 (also known as cell division control-related protein 2), as a putative parkin-binding protein. SEPT5_v2 is highly homologous to another septin, SEPT5, which was recently identified as a target for parkin-mediated ubiquitination. SEPT5_v2 binds to parkin at the amino terminus and in the ring finger domains. Several lines of evidence have validated the putative link between parkin and SEPT5_v2. Parkin co-precipitates with SEPT5_v2 from human substantia nigra lysates. Parkin ubiquitinates SEPT5_v2 in vitro, and both SEPT5_v1 and SEPT5_v2 accumulate in brains of patients with ARJP, suggesting that parkin is essential for the normal metabolism of these proteins. These findings suggest that an important relationship exists between parkin and septins.

Relation of cerebral infarctions to dementia and cognitive function in older persons.

BACKGROUND: Cerebral infarctions are common in older persons but their relationship with dementia and cognitive function remains controversial. METHODS: Participants were 164 older Catholic nuns, priests, and brothers who underwent annual clinical evaluation and brain autopsy at death. The authors quantified number and volume of old cerebral infarctions on postmortem examination and determined the association with dementia and cognitive function proximate to death. Analyses controlled for age, sex, and education. RESULTS: A total of 58 (35.4%) subjects had cerebral infarctions: 29 had one infarction and 29 had multiple infarctions. In logistic regression analyses, infarctions increased the odds of dementia twofold (OR 2.12; 95% CI 1.06 to 4.25). The odds of dementia increased by 2.67-fold for multiple infarctions (95% CI 1.08 to 6.61), whereas the odds of dementia with single infarctions increased by 69% (95% CI 0.70 to 4.09). In linear regression analyses, there was a trend for multiple infarctions to be associated with lower global cognitive scores (-0.44 standard units, p = 0.057). Multiple infarctions were related to perceptual speed, visuospatial skills, and working memory, but not to episodic or semantic memory. The authors found similar results with infarction volume. In secondary analyses, only infarctions that were clinically evident during life were associated with dementia and cognitive function. CONCLUSION: Cerebral infarctions are associated with a twofold increase in odds of dementia. Odds are higher in persons with multiple, large, or clinically evident infarctions. In addition, cerebral infarctions do not affect all cognitive systems equally, showing the strongest association with perceptual speed and the weakest with episodic memory.

Apolipoprotein E epsilon4 allele, AD pathology, and the clinical expression of Alzheimer's disease.

OBJECTIVE: To test the hypothesis that the APOE epsilon4 allele is associated with the clinical manifestations of AD through an association with the pathologic hallmarks of disease. METHODS: Participants were older Catholic nuns, priests, and brothers who agreed to annual neurologic and neuropsychological evaluation for AD and other common neurologic conditions and brain autopsy at the time of death. There were 77 persons without dementia and 51 with probable AD; 38 participants had one or more epsilon4 alleles. RESULTS: In logistic regression analyses, controlling for age, sex, and education, the epsilon4 allele was strongly associated with the likelihood of clinical AD (odds = 3.46, 95% CI = 1.44 to 8.33). However, controlling for the effect of AD pathology, the association of the epsilon allele with clinical AD was reduced by >50% and was no longer significant (odds = 1.58, 95% CI = 0.56 to 4.43). Similarly, in linear regression analyses, controlling for age, sex, and education, the epsilon4 allele was strongly associated with level of cognitive function proximate to death (regression coefficient = -0.477, p = 0.005). However, after controlling for the effect of AD pathology, the association of the epsilon4 allele with level of cognition was reduced by >80% and was no longer significant (regression coefficient = -0.093). Similar results were found in analyses using separate measures of neuritic plaques, diffuse plaques, and neurofibrillary tangles, and in analyses of five different cognitive systems (episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability). CONCLUSIONS: The APOE epsilon4 allele appears to be associated with the clinical manifestations of AD through an association with the pathologic hallmarks of AD rather than another mechanism.

Pathological glial tau accumulations in neurodegenerative disease: review and case report.

Abnormal deposits of tau protein accumulate in glia in many neurodegenerative diseases. This suggests that in some instances the disease process may target glial tau, with neuronal degeneration a secondary consequence of this process. In this report, we summarize the pattern of glial tau pathology in various neurodegenerative disorders and add original findings from a case of sporadic frontotemporal dementia that exhibits astrocytic tau pathology. The neurodegenerative diseases span the spectrum of relative neuronal and glial tau involvement, from disorders affecting only neuronal tau to those in which abnormal tau deposits are found only in glia. From this, we conclude that glial tau can be a primary target of the disease process, and that this can lead to neuronal degeneration.