Histopathological assessment of fatal ipsilateral intraparenchymal hemorrhages after the treatment of supraclinoid aneurysms with the Pipeline Embolization Device.

OBJECT: Delayed ipsilateral intraparenchymal hemorrhage has been observed following aneurysm treatment with the Pipeline Embolization Device (PED). The relationship of this phenomenon to the device and/or procedure remains unclear. The authors present the results of histopathological analyses of the brain sections from 3 patients in whom fatal ipsilateral intracerebral hemorrhages developed several days after uneventful PED treatment of supraclinoid aneurysms. METHODS: Microscopic analyses revealed foreign material occluding small vessels within the hemorrhagic area in all patients. Further analyses of the embolic materials using Fourier transform infrared (FTIR) spectroscopy was conducted on specimens from 2 of the 3 patients. Although microscopically identical, the quantity of material recovered from the third patient was insufficient for FTIR spectroscopy. RESULTS: FTIR spectroscopy showed that the foreign material was polyvinylpyrrolidone (PVP), a substance that is commonly used in the coatings of interventional devices. CONCLUSIONS: These findings are suggestive of a potential association between intraprocedural foreign body emboli and post-PED treatment-delayed ipsilateral intraparenchymal hemorrhage.

Translational gene mapping of cognitive decline.

The ability to maintain cognitive function during aging is a complex process subject to genetic and environmental influences. Alzheimer's disease (AD) is the most common disorder causing cognitive decline among the elderly. Among those with AD, there is broad variation in the relationship between AD neuropathology and clinical manifestations of dementia. Differences in expression of genes involved in neural processing pathways may contribute to individual differences in maintenance of cognitive function. We performed whole genome expression profiling of RNA obtained from frontal cortex of clinically non-demented and AD subjects to identify genes associated with brain aging and cognitive decline. Genetic mapping information and biological function annotation were incorporated to highlight genes of particular interest. The candidate genes identified in this study were compared with those from two other studies in different tissues to identify common underlying transcriptional profiles. In addition to confirming sweeping transcriptomal differences documented in previous studies of cognitive decline, we present new evidence for up-regulation of actin-related processes and down-regulation of translation, RNA processing and localization, and vesicle-mediated transport in individuals with cognitive decline.

Mutations of presenilin genes in dilated cardiomyopathy and heart failure.

Two common disorders of the elderly are heart failure and Alzheimer disease (AD). Heart failure usually results from dilated cardiomyopathy (DCM). DCM of unknown cause in families has recently been shown to result from genetic disease, highlighting newly discovered disease mechanisms. AD is the most frequent neurodegenerative disease of older Americans. Familial AD is caused most commonly by presenilin 1 (PSEN1) or presenilin 2 (PSEN2) mutations, a discovery that has greatly advanced the field. The presenilins are also expressed in the heart and are critical to cardiac development. We hypothesized that mutations in presenilins may also be associated with DCM and that their discovery could provide new insight into the pathogenesis of DCM and heart failure. A total of 315 index patients with DCM were evaluated for sequence variation in PSEN1 and PSEN2. Families positive for mutations underwent additional clinical, genetic, and functional studies. A novel PSEN1 missense mutation (Asp333Gly) was identified in one family, and a single PSEN2 missense mutation (Ser130Leu) was found in two other families. Both mutations segregated with DCM and heart failure. The PSEN1 mutation was associated with complete penetrance and progressive disease that resulted in the necessity of cardiac transplantation or in death. The PSEN2 mutation showed partial penetrance, milder disease, and a more favorable prognosis. Calcium signaling was altered in cultured skin fibroblasts from PSEN1 and PSEN2 mutation carriers. These data indicate that PSEN1 and PSEN2 mutations are associated with DCM and heart failure and implicate novel mechanisms of myocardial disease.

Minimal tethered cord syndrome associated with thickening of the terminal filum.

OBJECT: The authors investigated the occurrence of anatomical abnormalities of the terminal filum in children undergoing surgical filum lysis for minimal tethered cord syndrome (TCS). METHODS: Five consecutive children (age range 6-12 years) with medically refractory voiding dysfunction but no magnetic resonance (MR) imaging-documented lumbosacral abnormality on 1.5-tesla sequences underwent preoperative urodynamic studies consisting of calibrated uroflowmetry, cystometrography, and voiding cystourethrography. Urodynamic bladder function was abnormal in each case. A sixth child (5 years of age) who had progressive lower-extremity weakness, gait abnormality, and voiding dysfunction, but in whom there was no MR imaging-documented lumbosacral abnormality, was also included. These six children experienced improved bladder function after terminal filum lysis. Histologically, the terminal filum in these patients was fattier, thicker, and more densely fibrous than that in three reference patients undergoing incidental terminal filum lysis during selective dorsal rhizotomy or resection of a lumbar dermal sinus tract. All four patients with voiding dysfunction who underwent postoperative urodynamic testing experienced corresponding improvement in bladder function. CONCLUSIONS: Significant improvement of voiding dysfunction after surgical lysis of the terminal filum in children with MR imaging-documented normal lumbosacral spines was observed. In such children, in whom neurogenic dysfunction is identified by urodynamic testing, structural abnormalities of the terminal filum may exist. A prospective randomized controlled study of children undergoing surgical terminal filum lysis in cases of minimal TCS should be undertaken.

Comparison of clinical and neuropathologic diagnoses of Alzheimer's disease in 3 epidemiologic samples.

BACKGROUND: Studies of dementia in populations avoid many of the selection biases in clinical samples but require special evaluation and diagnostic methods to obtain high participation rates. To address this issue, we developed a unique in-home dementia assessment. We assessed validity of these assessments using neuropathologic confirmation of the clinical diagnosis in 3 epidemiologic samples. METHODS: Subjects were 175 participants in 3 ongoing studies of dementia. Two were population based and identified dementia by cognitive screening. The third study sought volunteers via advertisements. Dementia evaluations were then conducted at the participants' residences by specially trained nurses and psychometricians. Evaluation results were interpreted, and preliminary diagnoses were assigned by a geropsychiatrist or neurologist and a psychologist. Final diagnoses were assigned by a consensus panel of neurologists, geropsychiatrists, and psychologists. We compared the clinical diagnoses with the gold-standard neuropathologic diagnoses for those participants who subsequently underwent autopsy. RESULTS: Among the demented, the sensitivity of a clinical diagnosis of probable or possible Alzheimer's disease (AD) was 93% across the 3 studies. The rate of overall diagnostic agreement was 81%. Measures of agreement did not differ meaningfully across varying levels of dementia severity. CONCLUSIONS: Rates of neuropathologic confirmation for clinical AD diagnoses in these studies were similar to those reported from clinic-based samples. These results support the validity of clinical diagnoses of AD from a structured in-home assessment of community dwelling and institutionalized individuals using relatively economical methods of dementia screening and assessment.

Prion-associated increases in Src-family kinases.

The prion diseases result from the generation and propagation of an abnormal conformer of the prion protein. It is unclear how this molecular event disrupts neuronal function and viability. Current evidence argues it is not due to loss of normal prion protein activity or direct toxic effects of the abnormal conformer. Both the normal and abnormal prion proteins are glycosylphosphatidylinositol-linked membrane proteins. Conversion to the abnormal isoform results in the formation and accumulation of prion protein aggregates. Because aggregation of glycosylphosphatidylinositol-linked proteins activates Src-family kinases, the activation status and levels of the Src-family kinases in prion disease were investigated. Elevations of Src-family kinases were found in a cell culture model and two separate animal models of prion disease. The elevations in Src kinases preceded the onset of symptoms and occurred concurrently with the appearance of detergent-insoluble prion protein. In addition, the total level of kinases phosphorylated at tyrosine residues associated with activation was increased. Similar alterations were not present in brain homogenates from presymptomatic animals early in the disease course, prion protein-ablated animals, or end-stage Tg2576 mice overexpressing mutant amyloid precursor protein. Identification of similar elevations in cell culture and animal model systems suggests the elevations are a specific response to the presence of the disease-associated conformer. Abnormal regulation of these signal transduction cascades may be a key element in the cellular pathology of the prion diseases.

Intranuclear rod myopathy, a rare and morphologically striking variant of nemaline rod myopathy.

A 4-year-old boy with muscle weakness underwent skeletal muscle biopsies. Light microscopy showed distinct eosinophilic inclusions within the majority of muscle cell nuclei, but none in the cytoplasm. Electron microscopy revealed crystalline, round to rod-shaped inclusions in the muscle cell nuclei. The inclusions stained positively for alpha-actinin. Intranuclear inclusions identical to those seen here have been described in rare cases of nemaline rod myopathy, though almost always together with classic intracytoplasmic rods. This case illustrates the importance of electron microscopy in the diagnosis of rare myopathies and in the characterization of cellular inclusions of unknown origin.

Comparison of two superparamagnetic viral-sized iron oxide particles ferumoxides and ferumoxtran-10 with a gadolinium chelate in imaging intracranial tumors.

BACKGROUND AND PURPOSE: Ultrasmall superparamagnetic iron oxide particles result in shortening of T1 and T2 relaxation time constants and can be used as MR contrast agents. We tested four hypotheses by evaluating MR images of intracranial tumors after infusion of two iron oxide agents in comparison with a gadolinium chelate: 1) Ferumoxtran in contrast to ferumoxides can be used as an intravenous MR contrast agent in intracranial tumors; 2) ferumoxtran enhancement, albeit delayed, is similar to gadolinium enhancement; 3) ferumoxtran-enhanced MR images in contrast to gadolinium-enhanced MR images may be compared with histologic specimens showing the cellular location of iron oxide particles; 4) ferumoxtran can serve as a model for viral vector delivery. METHODS: In 20 patients, ferumoxides and ferumoxtran were intravenously administered at recommended clinical doses. MR imaging was performed 30 minutes and 4 hours after ferumoxides infusion (n = 3), whereas ferumoxtran-enhanced MR imaging (n = 17) was performed 6 and 24 hours after infusion in the first five patients and 24 hours after infusion in the remaining 12. MR sequences were spin-echo (SE) T1-weighted, fast SE T2- and proton density-weighted, gradient-recalled-echo T2*-weighted, and, in four cases, echo-planar T2-weighted sequences. Representative regions of interest were chosen on pre- and postcontrast images to compare each sequence and signal intensity. RESULTS: Despite some degree of gadolinium enhancement in all tumors, no significant T1 or T2 signal intensity changes were seen after ferumoxides administration at either examination time. Fifteen of 17 patients given ferumoxtrans had T1 and/or T2 shortening consistent with iron penetration into tumor. Histologic examination revealed minimal iron staining of the tumor with strong staining at the periphery of the tumors. CONCLUSION: 1) Ferumoxtran can be used as an intravenous MR contrast agent in intracranial tumors, mostly malignant tumors. 2) Enhancement with ferumoxtran is comparable to but more variable than that with the gadolinium chelate. 3) Histologic examination showed a distribution of ferumoxtran particles similar to that on MR images, but at histology the cellular uptake was primarily by parenchymal cells at the tumor margin. 4) Ferumoxtran may be used as a model for viral vector delivery in malignant brain tumors.