Validation of a suite of ERP and QEEG biomarkers in a pre-competitive, industry-led study in subjects with schizophrenia and healthy volunteers.

OBJECTIVE: Complexity and lack of standardization have mostly limited the use of event-related potentials (ERPs) and quantitative EEG (QEEG) biomarkers in drug development to small early phase trials. We present results from a clinical study on healthy volunteers (HV) and patients with schizophrenia (SZ) that assessed test-retest, group differences, variance, and correlation with functional assessments for ERP and QEEG measures collected at clinical and commercial trial sites with standardized instrumentation and methods, and analyzed through an automated data analysis pipeline. METHODS: 81 HV and 80 SZ were tested at one of four study sites. Subjects were administered two ERP/EEG testing sessions on separate visits. Sessions included a mismatch negativity paradigm, a 40 Hz auditory steady-state response paradigm, an eyes-closed resting state EEG, and an active auditory oddball paradigm. SZ subjects were also tested on the Brief Assessment of Cognition (BAC), Positive and Negative Syndrome Scale (PANSS), and Virtual Reality Functional Capacity Assessment Tool (VRFCAT). RESULTS: Standardized ERP/EEG instrumentation and methods ensured few test failures. The automated data analysis pipeline allowed for near real-time analysis with no human intervention. Test-retest reliability was fair-to-excellent for most of the outcome measures. SZ subjects showed significant deficits in ERP and QEEG measures consistent with published academic literature. A subset of ERP and QEEG measures correlated with functional assessments administered to the SZ subjects. CONCLUSIONS: With standardized instrumentation and methods, complex ERP/EEG testing sessions can be reliably performed at clinical and commercial trial sites to produce high-quality data in near real-time.

Comparison of BKV quantification using a single automated nucleic acid extraction platform and 3 real-time PCR assays.

Monitoring peripheral blood for evidence of BK viremia through quantitative real-time PCR testing is an important management tool that allows for interventions that prevent nephropathy in renal allograft patients. This study compared the performance of 3 different real-time PCR assays for BKV quantification including 2 noncommercial tests (a historical assay "PEP" and 1 with improved genotypic inclusivity "V3T3") and 1 using commercial reagents (Qiagen/artus, "artus") after nucleic acid extraction of plasma with a single automated instrument (QIAsymphony). The measurable ranges (log10 copies/mL) were 2.7 to at least 8.0 for PEP and 2.0 to at least 8.0 for artus and V3T3 assays. Limits of detection (copies/mL) were 189, 56, and 28 for PEP, V3T3, and artus, respectively. Correlation experiments demonstrated linearity with original quantification results, although values obtained for the PEP assay were generally lower than those obtained for the V3T3 or artus assay across the measuring range. V3T3 and artus values were more closely related, although artus values were generally lower. The 3 assays returned different values from clinical plasma samples, likely due in part to variances in calibration. Low BKV concentrations were quantifiable by V3T3 and artus assays in plasmas that were previously deemed negative by PEP. These data underscore the need for monitoring with a single test to enable appropriate management decisions, and they suggest that an international preparation would be useful in harmonizing quantification of BKV viremia.

Longitudinal decline in autopsy-defined frontotemporal lobar degeneration.

BACKGROUND: The natural history of patients with pathologically proven frontotemporal lobar degeneration (FTLD) is important from clinical and biologic perspectives, but is not well documented quantitatively. METHODS: We examine longitudinal decline in cognitive functioning in an autopsy-proven cohort of patients with the clinical diagnosis of a FTLD spectrum disorder or FTLD pathology using a panel of neuropsychological measures. Patients are categorized according to findings at autopsy into tau-positive FTLD, tau-negative FTLD, and frontal variant-Alzheimer disease (fvAD) subgroups. RESULTS: Patients decline significantly over time on all neuropsychological measures. Moreover, several measures differentiate between histopathologically distinct subgroups throughout the course of the disease process. This includes a significant double dissociation involving relative difficulty on a visual constructional measure in tau-positive patients compared to relatively impaired visual confrontation naming in tau-negative patients. Longitudinal measures of FAS naming fluency and animal naming fluency also distinguish tau-positive patients and tau-negative patients with FTLD from patients with fvAD. Other measures show significant decline but do not distinguish between histopathologic groups longitudinally. CONCLUSION: Our findings suggest different longitudinal patterns of cognitive decline in pathologically defined subgroups of patients. Measures consistently distinguishing between patient subgroups can be used to bolster diagnostic accuracy throughout the course of these diseases, while measures demonstrating undifferentiated longitudinal decline may serve as useful endpoints in treatment trials.

Multicenter comparison of different real-time PCR assays for quantitative detection of Epstein-Barr virus.

Quantification of Epstein-Barr virus (EBV) in peripheral blood is important for the diagnosis and management of serious EBV diseases, including posttransplant lymphoproliferative disorder. A variety of PCR-based methods are currently in use; however, there is little information on their comparability. This study assessed the relative performance of different quantitative assays. A multicenter comparative study was performed at eight sites using three panels consisting of serial dilutions of quantified EBV DNA and extracts from a total of 19 whole-blood specimens. Samples were distributed and tested blindly. Instrumentation, probe chemistries, amplification targets, and other test-related aspects varied considerably between laboratories. Each laboratory's calibration curve indicated strong evidence of a consistent log-linear relationship between viral load and cycle threshold, suggesting that intralaboratory tracking of a given patient would yield similar relative quantitative trends among the participating test sites. There was strong concordance among laboratories with respect to qualitative test results; however, marked quantitative discordance was seen. For most samples, the across-laboratory interquartile range of the reported viral load (in copies/microl) was roughly 0.6 log-units, and for one sample the overall range was approximately 4.2 log-units. While intralaboratory tracking of patients may yield similar results, these data indicate a need for caution when attempting to compare clinical results obtained at different institutions and suggest the potential value to be gained by more standardized testing methodology.

Factors associated with survival probability in autopsy-proven frontotemporal lobar degeneration.

OBJECTIVE: To examine the clinical and pathological factors associated with survival in autopsy-confirmed frontotemporal lobar degeneration (FTLD). METHODS: The final analysis cohort included 71 patients with pathologically proven FTLD, excluding patients with clinical motor neuron disease (MND), evaluated at the University of Pennsylvania or at the University of California, San Francisco. We assessed clinical and demographic features; cognitive functioning at presentation; genetic markers of disease; and graded anatomical distribution of tau, ubiquitin and amyloid pathology. RESULTS: The tau-negative group (n = 35) had a median survival time of 96 months (95% CI: 72-114 months), whereas the tau-positive group (n = 36) had a median survival time of 72 months (95% CI: 60-84 months). Patients with tau-positive pathology across all brain regions had shorter survival than those with tau-negative pathology in univariate Cox regression analyses (Hazard ratio of dying = 2.003, 95% CI = 1.209-3.318, p = 0.007). CONCLUSIONS: Tau-positive pathology represents a significant risk to survival in FTLD, whereas tau-negative pathology is associated with a longer survival time when clinical MND is excluded.

Cognitive and motor assessment in autopsy-proven corticobasal degeneration.

OBJECTIVE: To investigate the clinical features of autopsy-proven corticobasal degeneration (CBD). METHODS: We evaluated symptoms, signs, and neuropsychological deficits longitudinally in 15 patients with autopsy-proven CBD and related these observations directly to the neuroanatomic distribution of disease. RESULTS: At presentation, a specific pattern of cognitive impairment was evident, whereas an extrapyramidal motor abnormality was present in less than half of the patients. Follow-up examination revealed persistent impairment of apraxia and executive functioning, worsening language performance, and preserved memory. The motor disorder emerged and worsened as the condition progressed. Statistical analysis associated cognitive deficits with tau-immunoreactive pathology that is significantly more prominent in frontal and parietal cortices and the basal ganglia than temporal neocortex and the hippocampus. CONCLUSION: The clinical diagnosis of corticobasal degeneration should depend on a specific pattern of impaired cognition as well as an extrapyramidal motor disorder, reflecting the neuroanatomic distribution of disease in frontal and parietal cortices and the basal ganglia.

Cortical biochemistry in MCI and Alzheimer disease: lack of correlation with clinical diagnosis.

OBJECTIVE: Mild cognitive impairment, hypothesized to be prodromal Alzheimer disease (AD), shows abundant senile plaques and neurofibrillary tangles, but its biochemical correlates remain undefined. METHODS: Biochemical profiles of Abeta, tau, alpha-synuclein, and oxidative pathologies were characterized in middle frontal gyrus, inferior parietal cortex, and entorhinal cortex in postmortem frozen brains from subjects diagnosed antemortem with no cognitive impairment, mild cognitive impairment, or AD. RESULTS: Insoluble Abeta and tau, as well as tissue isoprostanes, from each brain region analyzed did not correlate with the clinical diagnosis proximate to death, but insoluble Abeta and 8,12-iso-iPF(2alpha)-VI levels from gray matter of all brain regions correlated strongly with the burden of AD pathology, whereas insoluble tau did not. CONCLUSIONS: The biochemical alterations in cortical tau, Abeta, and isoprostane do not reflect the onset of clinical dementia.

Distinct MRI atrophy patterns in autopsy-proven Alzheimer's disease and frontotemporal lobar degeneration.

To better define the anatomic distinctions between Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD), we retrospectively applied voxel-based morphometry to the earliest magnetic resonance imaging scans of autopsy-proven AD (N = 11), FTLD (N = 18), and controls (N = 40). Compared with controls, AD patients showed gray matter reductions in posterior temporoparietal and occipital cortex; FTLD patients showed atrophy in medial prefrontal and medial temporal cortex, insula, hippocampus, and amygdala; and patients with both disorders showed atrophy in dorsolateral and orbital prefrontal cortex and lateral temporal cortex (P(FWE-corr) < .05). Compared with FTLD, AD patients had decreased gray matter in posterior parietal and occipital cortex, whereas FTLD patients had selective atrophy in anterior cingulate, frontal insula, subcallosal gyrus, and striatum (P < .001, uncorrected). These findings suggest that AD and FTLD are anatomically distinct, with degeneration of a posterior parietal network in AD and degeneration of a paralimbic fronto-insular-striatal network in FTLD.

From progressive nonfluent aphasia to corticobasal syndrome: a case report of corticobasal degeneration.

In a previous report, we presented longitudinal clinical, cognitive and anatomical data of a right-handed woman, whose clinical picture evolved from progressive nonfluent aphasia with apraxia of speech to corticobasal syndrome (CBS) in the last stage of the disease. The patient died at age 57 and pathological examination revealed severe atrophy in the left frontal operculum and left premotor area. On histological examination, there was diffuse tau-positive pathology in gray and white cortical hemispheric gray and white matter, basal ganglia and substantia nigra, compatible with corticobasal degeneration (CBD). This case demonstrates the clinical overlap between frontotemporal lobar degeneration and CBD. In this case, early motor speech impairment predicted earlier and more accurately than CBS the presence of underlying tau-pathology and CBD.

Frontotemporal dementia progresses to death faster than Alzheimer disease.

BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a common cause of non-Alzheimer dementia, but its natural history and the factors related to mortality in affected patients are not well understood. METHODS: This retrospective, longitudinal study compared survival in FTLD (n = 177) with Alzheimer disease (AD; n = 395). Hazards analysis investigated the contribution of various demographic, neuropsychiatric, and neuropsychological variables and associated neurologic and neuropathologic findings. RESULTS: The frontotemporal dementia (FTD) subtype of FTLD progressed faster than AD (median survival from retrospectively determined symptom onset, 8.7 +/- 1.2 vs 11.8 +/- 0.6 years, p < 0.0001; median survival from initial clinic presentation, 3.0 +/- 0.5 vs 5.7 +/- 0.1 years, p < 0.0001). Survival was similarly reduced in the related conditions corticobasal degeneration and progressive supranuclear palsy. Survival in the semantic dementia subtype of FTLD (11.9 +/- 0.2 years from onset and 5.3 +/- 0.4 years from presentation), however, was significantly longer than in FTD and did not differ from AD. Hazards analysis to determine factors affecting survival in FTLD showed no effect of age at onset, sex, education, family history, or neuropsychiatric profile. Among neuropsychological measures examined, impaired letter fluency had a significant association with reduced survival. Associated ALS significantly reduced survival in FTLD. The presence of tau-positive inclusions was associated with the slowest progression. CONCLUSIONS: Frontotemporal lobar degeneration progresses more rapidly than Alzheimer disease, and the fastest-progressing cases are those with the frontotemporal dementia clinical subtype, coexisting motor neuron disease, or tau-negative neuropathology.

Multiple pathologies in a patient with a progressive neurodegenerative syndrome.

A woman presenting with levodopa responsive Parkinsonism developed rapidly progressive bulbar signs, quadriparesis, and upper and lower motor neurone signs. At necropsy, she was found to have three pathological diagnoses: amyotrophic lateral sclerosis, Parkinson's disease, and abundant tau-positive argyrophilic neuritic pathology, known as argyrophilic grain disease. This case raises the possibility that three distinct neuropathological diagnoses share a common aetiology.

Longitudinal observations on mutations conferring ganciclovir resistance in patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis: The Cytomegalovirus and Viral Resistance Study Group Report Number 8.

PURPOSE: Cytomegalovirus retinitis is the most common intraocular infection in patients with acquired immunodeficiency syndrome (AIDS). With prolonged suppressive anticytomegalovirus maintenance therapy, resistance occurs in over 25% of patients. We evaluated longitudinal changes in the cytomegalovirus genotype in patients with cytomegalovirus retinitis who developed ganciclovir resistance that was demonstrated in either the blood or urine. METHODS: Patients with AIDS and previously untreated cytomegalovirus retinitis were followed prospectively for the occurrence of resistance while on treatment. Blood and urine specimens were obtained periodically for cytomegalovirus culture according to a predetermined schedule. Positive isolates were tested for phenotypic susceptibility and for mutations in the UL97 and UL54 genes. RESULTS: A mutation conferring resistance to ganciclovir in either the UL97 or UL54 gene was detected in 18 patients. In general, patients with a genotypically resistant virus developed increasing phenotypic resistance over time. There was a suggestion that unless therapy was changed, UL97 mutations tended to persist. In seven of eight patients, the mutations identified in isolates from the blood and urine were identical. In selected patients, there was a suggestion that a mixed population of cytomegalovirus might be present. Progression of the retinitis in an involved eye (15 of 18), contralateral eye retinitis (10 of 11), and extraocular cytomegalovirus disease (5 of 18) occurred commonly among patients with resistant virus. CONCLUSION: Resistance-conferring mutations in the cytomegalovirus genome emerge and may persist when the selective pressure for resistance is maintained. Some patients appear to harbor complex subpopulations of virus with different mutations and different levels of phenotypic resistance. Changes in therapy may result in a shift in virus population and changes in the cytomegalovirus genotype identified.

Prominent perikaryal expression of alpha- and beta-synuclein in neurons of dorsal root ganglion and in medullary neurons.

Synucleins (syns) are a family of small, highly conserved proteins expressed predominantly in neurons. Although the normal function of syns is unknown, alpha-syn plays a pivotal role in several neurodegenerative diseases. The expression patterns of syns have been described in several studies, but much of this information was obtained before the cloning of all four members of this family of proteins and previous studies were limited to the analysis of single species. Here, we used antibodies specific for alpha-, beta-, and gamma-syn to study the patterns of expression in human, mouse, and rat nervous systems. Significant species-specific differences were detected in the expression of all three syns throughout the neuraxis. For example, gamma-syn is highly expressed in human cortex, while it is present only at low levels in mouse and rat cortex. Moreover, in contrast to previous reports that alpha- and beta-syns are normally localized predominantly at presynaptic terminals, we demonstrate that these proteins also are abundant in the perikarya of some neurons, such as in dorsal root ganglion. Intense alpha-syn immunoreactivity also was detected in the perikarya of human neurons in raphe, hypoglossal, and arcuate nuclei. These data underscore the need for additional studies to better understand the fundamental biological mechanism(s) targeting specific proteins to axonal terminals, as disruption of this process may be involved in the formation of pathological lesions.

Delivery of human vascular endothelial growth factor with platinum coils enhances wall thickening and coil impregnation in a rat aneurysm model.

BACKGROUND AND PURPOSE: Histopathologic studies indicate that aneurysms treated with Guglielmi detachable coils (GDCs) have avascular centers with fibrosis mostly at the aneurysm periphery. We hypothesized that vascular endothelial growth factor (VEGF) released from a coil promotes clot organization, hyperplasia, and endothelial proliferation to facilitate closure of the aneurysm neck. METHODS: GDC segments were inserted into ligated common carotid arteries (CCAs) of adult male rats for 14 days. Coil segments (4-mm) were unmodified, modified with type I collagen (2.4 mg/mL), or modified with type I collagen and recombinant human VEGF-165 (rhVEGF; 500 microg/mL). CCA segments were harvested and coils removed for scanning electron microscopy (SEM). RESULTS: Collagen/rhVEGF coils (n = 11) resulted in marked reductions in CCA lumen area (0.03 mm(2)) compared with coils (n = 9, 0.21 mm(2), P <.001) and collagen coils (n = 5, 0.13 mm(2), P <.001). Collagen/rhVEGF coils (n = 11) also resulted in marked reductions in CCA diameter (0.19 mm) compared with coils (n = 9, 0.50 mm, P <.001) and collagen coils (n = 5, 0.40 mm, P <.001). Wall thickness was greater for the collagen/rhVEGF coil segments (0.22 mm) compared with coils (0.09 mm, P <.001), and the collagen coils (0.15 mm, P =.06). CCA segments containing collagen/rhVEGF coils also displayed Factor VIII positivity and were completely encapsulated in fibrotic tissue, while the unmodified and collagen coils were essentially smooth, as seen by SEM. CONCLUSION: These results suggest that rhVEGF may be beneficial in promoting endothelialization, clot organization, and tissue integration of the coils. This is the first study to hypothesize that rhVEGF may be useful as a surface modification to GDCs for enhancing their therapeutic effects in the treatment of cerebral aneurysms.

Retinal findings in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (cadasil).

We describe a 45-year-old man with biopsy proven cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). This patient demonstrated unique retinal findings, including arteriole narrowing and sheathing, irregular choroidal filling on fluorescein angiography, and patchy visual field loss. CADASIL is a hereditary, nonamyloid, nonathersclerotic microangiopathy. This disorder has been mapped to chromosome 19 with mutations in the Notch 3 gene. Deposits of granular osmiophilic material in the basal lamina of the smooth muscle cells of small vessels are considered pathognomonic for CADASIL and are typically seen only on electron microscopy. Although CADASIL is a systemic vascular disease affecting the entire arteriole tree, we are unaware of other reports describing the retinal findings observed in our patient.

July 2000: A 70 year old with rigidity, decreased ocular movements, and dementia.

The July Case of the Month (COM): A 70 year old male presented with a four year history of cognitive decline, difficulty expressing himself, and an increasingly unsteady gait with numerous falls. At presentation he was wheel-chair bound. Examination showed some slowing of speech, mild memory impairment, but normal cranial nerves. Spastic weakness and brisk reflexes were also noted, with bilateral ankle clonus. MRI scans were normal. Four years later he was admitted with a urinary tract infection and was mute with severely impaired ocular motility. He died 18 months later and autopsy showed the classic neuropathological findings of typical Progressive supranuclear palsy, including tau-positive glial inclusions.

Successful treatment of enterovirus infection with the use of pleconaril in 2 infants with severe combined immunodeficiency.

Two patients with severe combined immunodeficiency and enterovirus infections were successfully treated with pleconaril. There were no adverse affects.

Mutations conferring ganciclovir resistance in a cohort of patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis.

Cytomegalovirus (CMV) retinitis is among the most common opportunistic infections in patients with acquired immunodeficiency syndrome. In a prospective study of 210 patients with CMV retinitis, 26 were identified as having either a phenotypic or a genotypic ganciclovir-resistant isolate from either blood or urine cultures. For blood culture isolates with an IC(50) >6.0 microm for ganciclovir, the sensitivity and specificity for detecting a UL97 mutation were 95% and 98%, respectively, whereas for an IC(50) >8.0 microM they were 79% and 99%, respectively. Although there were trade-offs between the 2 thresholds for blood culture isolates, for urine culture isolates an IC(50) >8.0 microM appeared to be better at identifying genotypic resistance. UL97 mutations identified in both the blood and urine cultures of individual patients were identical in 87.5% of cases. High-level ganciclovir resistance (IC(50), >30 microM) typically, but not invariably, was associated with a mutation in both the UL97 and UL54 genes.

Biodegradable polyglycolide endovascular coils promote wall thickening and drug delivery in a rat aneurysm model.

OBJECTIVE: We designed biodegradable polyglycolide coils (BPCs) and compared the histopathological response to the coils with that to platinum Guglielmi detachable coils (GDCs), after insertion into ligated common carotid arteries (CCAs) of adult rats. BPCs were also tested for use in local drug delivery. METHODS: Segments (4-mm) of unmodified BPCs, unmodified GDCs, or BPCs coated with Type I bovine collagen and recombinant human vascular endothelial growth factor-165 (500 microg/ml) were inserted into ligated CCAs of adult rats for 14 days, and specimens were compared with contralateral CCA control specimens. RESULTS: Arterial segments with BPCs exhibited substantially increased wall thickening, compared with GDCs (0.33 mm versus 0.10 mm, P < 0.005), which reduced the luminal diameter by 40%, relative to untreated contralateral control specimens (P < 0.05, n = 6). Arterial segments with BPCs also exhibited a marked reduction (P < 0.05, n = 6) in luminal area (0.72 +/- 0.93 mm(2)), with marked cellular proliferation within the coil diameter, indicating coil integration. Arterial segments with collagen/recombinant human vascular endothelial growth factor-coated BPCs also exhibited a marked 2.9-fold increase (P < 0.005, n = 5) in wall thickness (0.29 +/- 0.11 mm) and a 34% reduction in luminal diameter, compared with contralateral control vessels. There was marked proliferation of cells within the coil lumen of vessels treated with BPCs with collagen/recombinant human vascular endothelial growth factor. CONCLUSION: In this feasibility study, BPCs enhanced the vascular response of CCA segments, compared with GDCs, and were also suitable for local protein delivery to the vessel lumen, under conditions of stasis and arterial pressurization of vascular cells.

Symptomatic lateral ventricular ependymal cysts: criteria for distinguishing these rare cysts from other symptomatic cysts of the ventricles: case report.

OBJECTIVE AND IMPORTANCE: Symptomatic lateral ventricular ependymal cysts are rare. Two previous cases of this lesion have been reported in the literature. We report a third case and provide radiological and histopathological criteria for differentiating this entity from common intracranial cysts. CLINICAL PRESENTATION: A 43-year-old man presented with a 6-year history of seizures and progressive right occipitoparietal headaches. Computed tomography and magnetic resonance imaging demonstrated a 4- x 3- x 3-cm nonenhancing cystic mass, expanding the trigone of the right lateral ventricle. INTERVENTION: The patient underwent a right occipital craniotomy. The cyst was opened, fluid was aspirated, the cyst wall was biopsied, and a cyst-subarachnoid communication was established. The patient did well postoperatively, with no seizures and with resolution of headaches. CONCLUSION: Lateral ventricular ependymal cysts are a rare cause of neurological symptoms, including headache and seizure. Distinctive radiographic characteristics distinguish these cysts at preoperative evaluation. Careful analysis of the histopathology and immunohistochemistry studies correctly identifies these lesions, gives insight into the natural history of ependymal cysts, and guides clinical management decisions.