Comparison of sporadic and familial behavioral variant frontotemporal dementia (FTD) in a North American cohort.

INTRODUCTION: Behavioral variant frontotemporal dementia (bvFTD) may present sporadically or due to an autosomal dominant mutation. Characterization of both forms will improve understanding of the generalizability of assessments and treatments. METHODS: A total of 135 sporadic (s-bvFTD; mean age 63.3 years; 34% female) and 99 familial (f-bvFTD; mean age 59.9; 48% female) bvFTD participants were identified. f-bvFTD cases included 43 with known or presumed chromosome 9 open reading frame 72 (C9orf72) gene expansions, 28 with known or presumed microtubule-associated protein tau (MAPT) mutations, 14 with known progranulin (GRN) mutations, and 14 with a strong family history of FTD but no identified mutation. RESULTS: Participants with f-bvFTD were younger and had earlier age at onset. s-bvFTD had higher total Neuropsychiatric Inventory Questionnaire (NPI-Q) scores due to more frequent endorsement of depression and irritability. DISCUSSION: f-bvFTD and s-bvFTD cases are clinically similar, suggesting the generalizability of novel biomarkers, therapies, and clinical tools developed in either form to the other.

Analysis of monitored ground support and rock mass response in a longwall tailgate entry.

A comprehensive monitoring program was conducted to measure the rock mass displacements, support response, and stress changes at a longwall tailgate entry in West Virginia. Monitoring was initiated a few days after development of the gateroad entries and continued during passage of the longwall panels on both sides of the entry. Monitoring included overcore stress measurements of the initial stress within the rock mass, changes in cable bolt loading, standing support pressure, roof deformation, rib deformation, stress changes in the coal pillar, and changes in the full three-dimensional stress tensor within the rock mass at six locations around the monitoring site. During the passage of the first longwall, stress measurements in the rock and coal detected minor changes in loading while minor changes were detected in roof deformation. As a result of the relatively favorable stress and geological conditions, the support systems did not experience severe loading or rock deformation until the second panel approached within 10-15 m of the instrumented locations. After reaching the peak loading at about 50-75 mm of roof sag, the cable bolts started to unload, and load was transferred to the standing supports. The standing support system was able to maintain an adequate opening inby the shields to provide ventilation to the first crosscut inby the face, as designed. The results were used to calibrate modeled cable bolt response to field data, and to validate numerical modeling procedures that have been developed to evaluate entry support systems. It is concluded that the support system was more than adequate to control the roof of the tailgate up to the longwall face location. The monitoring results have provided valuable data for the development and validation of support design strategies for longwall tailgate entries.

Analysis of global and local stress changes in a longwall gateroad.

A numerical-model-based approach was recently developed for estimating the changes in both the horizontal and vertical loading conditions induced by an approaching longwall face. In this approach, a systematic procedure is used to estimate the model's inputs. Shearing along the bedding planes is modeled with ubiquitous joint elements and interface elements. Coal is modeled with a newly developed coal mass model. The response of the gob is calibrated with back analysis of subsidence data and the results of previously published laboratory tests on rock fragments. The model results were verified with the subsidence and stress data recently collected from a longwall mine in the eastern United States.

Repeated, intermittent exposures to diisopropylfluorophosphate in rats: protracted effects on cholinergic markers, nerve growth factor-related proteins, and cognitive function.

Organophosphates (OPs) pose a constant threat to human health due to their widespread use as pesticides and their potential employment in military and terrorist attacks. The acute toxicity of OPs has been extensively studied; however, the consequences of prolonged or repeated exposure to levels of OPs that produce no overt signs of acute toxicity (i.e. subthreshold levels) are poorly understood. Further, there is clinical evidence that such repeated exposures to OPs lead to prolonged deficits in cognition, although the mechanism for this effect is unknown. In this study, the behavioral and neurochemical effects of repeated, intermittent, and subthreshold exposures to the alkyl OP, diisopropylfluorophosphate (DFP) were investigated. Rats were injected with DFP s.c. (dose range, 0.25-1.0 mg/kg) every other day over the course of 30 days, and then given a 2 week, DFP-free washout period. In behavioral experiments conducted at various times during the washout period, dose dependent decrements in a water maze hidden platform task and a spontaneous novel object recognition (NOR) procedure were observed, while prepulse inhibition of the acoustic startle response was unaffected. There were modest decreases in open field locomotor activity and grip strength (particularly during the DFP exposure period); however, rotarod performance and water maze swim speeds were not affected. After washout, DFP concentrations were minimal in plasma and brain, however, cholinesterase inhibition was still detectable in the brain. Moreover, the 1.0 mg/kg dose of DFP was associated with (brain region-dependent) alterations in nerve growth factor-related proteins and cholinergic markers. The results of this prospective animal study thus provide evidence to support two novel hypotheses: (1) that intermittent, subthreshold exposures to alkyl OPs can lead to protracted deficits in specific domains of cognition and (2) that such cognitive deficits may be related to persistent functional changes in brain neurotrophin and cholinergic pathways.

Protracted effects of chronic oral haloperidol and risperidone on nerve growth factor, cholinergic neurons, and spatial reference learning in rats.

The primary therapeutic agents used for schizophrenia, antipsychotic drugs, ameliorate psychotic symptoms; however, their chronic effects on cognition (or the physiologic processes of the brain that support cognition) are largely unknown. The purpose of this rodent study was to extend our previous work on this subject by investigating persistent effects (i.e. during a 14 day drug-free washout period) of chronic treatment (i.e. ranging from 45 days to 6 months) with a representative first and second generation antipsychotic. Drug effects on learning and memory and important neurobiological substrates of memory, the neurotrophin, nerve growth factor (NGF) and its receptors, and certain components of the basal forebrain cholinergic system were investigated. Behavioral effects of oral haloperidol (2.0 mg/kg/day), or risperidone (2.5 mg/kg/day) were assessed in an open field, a water maze task, and a radial arm maze procedure and neurochemical effects in brain tissue were subsequently measured by enzyme-linked immunosorbent assays (ELISAs). The results indicated that both antipsychotics produced time-dependent and protracted deficits in the performance of a water maze procedure when compared with vehicle-treated controls, while neither drug was associated with significant alterations in radial arm maze performance. Interestingly, haloperidol, but not risperidone, was detectible in the rodent brain in appreciable levels for up to 2 weeks after drug discontinuation. Both antipsychotics were also associated with reduced levels of NGF protein in the basal forebrain and prefrontal cortex and significant (or nearly significant) decreases in phosphorylated tropomyosin-receptor kinase A (TrkA) protein and the vesicular acetylcholine transporter (depending on the brain region analyzed). Neither antipsychotic markedly affected TrkA or p75 neurotrophin receptor levels. These data in rats indicate that chronic treatment with either haloperidol or risperidone may be associated with protracted negative effects on cognitive function as well as important neurotrophin and neurotransmitter pathways that support cognition.

Oral haloperidol or risperidone treatment in rats: temporal effects on nerve growth factor receptors, cholinergic neurons, and memory performance.

First and second generation antipsychotics (FGAs and SGAs) ameliorate psychotic symptoms of schizophrenia, however, their chronic effects on information processing and memory function (i.e. key determinants of long term functional outcome) are largely unknown. In this rodent study the effects of different time periods (ranging from 2 weeks to 6 months) of oral treatment with the FGA, haloperidol (2.0 mg/kg/day), or the SGA, risperidone (2.5 mg/kg/day) on a water maze repeated acquisition procedure, the levels of nerve growth factor receptors, and two important cholinergic proteins, the vesicular acetylcholine transporter and the high affinity choline transporter were evaluated. The effects of the antipsychotics on a spontaneous novel object recognition procedure were also assessed during days 8-14 and 31-38 of treatment. Haloperidol (but not risperidone) was associated with impairments in water maze hidden platform trial performance at each of the time periods evaluated up to 45 days, but not when tested during days 83-90. In contrast, risperidone did not impair water maze task performance at the early time periods and it was actually associated with improved performance during the 83-90 day period. Both antipsychotics, however, were associated with significant water maze impairments during the 174-180 day period. Further, haloperidol was associated with decrements in short delay performance in the spontaneous novel object recognition task during both the 8-14 and 31-38 day periods of treatment, while risperidone was associated with short delay impairment during the 31-38 day time period. Both antipsychotics were also associated with time dependent alterations in the vesicular acetylcholine transporter, the high affinity choline transporter, as well as tyrosine kinase A, and p75 neurotrophin receptors in specific brain regions. These data from rats support the notion that while risperidone may hold some advantages over haloperidol, both antipsychotics can produce time-dependent alterations in neurotrophin receptors and cholinergic proteins as well as impairments in the performance of tasks designed to assess spatial learning and episodic memory.

Microtubule-associated targets in chlorpyrifos oxon hippocampal neurotoxicity.

Prolonged exposure to organophosphate (OP) pesticides may produce cognitive deficits reflective of hippocampal injury in both humans and rodents. Recent work has indicated that microtubule trafficking is also adversely affected by exposure to the OP pesticide chlorpyrifos, suggesting a novel mode of OP-induced neurotoxicity. The present studies examined effects of prolonged exposure to chlorpyrifos oxon (CPO) on acetylcholinesterase (AChE) activity, immunoreactivity (IR) of microtubule-associated proteins, neuronal injury, and tubulin polymerization using in vitro organotypic slice cultures of rat hippocampus and bovine tubulin. Cultures were exposed to CPO (0.1-10 microM) in cell culture medium for 1-7 days, a regimen producing progressive reductions in AChE activity of 15-60%. Cytotoxicity (somatic uptake of the non-vital marker propidium iodide), as well as IR of alpha-tubulin and microtubule-associated protein-2 (a/b) [MAP-2], was assessed 1, 3, and 7 days after the start of CPO exposure. As early as 24 h after the start of exposure, CPO-induced deficits in MAP-2 IR were evident and progressive in each region of slice cultures at concentrations as low as 0.1 microM. CPO exposure did not alter alpha-tubulin IR at any time point. Concentration-dependent injury in the cornu ammonis (CA)1 pyramidal cell layer and to a lesser extent, CA3 and dentate cells, was evident 3 days after the start of CPO exposure (>or=0.1 microM) and was greatest after 7 days. Tubulin polymerization assays indicated that CPO (>or=0.1 microM) markedly inhibited the polymerization of purified tubulin and MAP-rich tubulin, though effects on MAP-rich tubulin were more pronounced. These data suggest that exposure to CPO produces a progressive decrease in neuronal viability that may be associated with impaired microtubule synthesis and/or function.

Chronic treatment with first or second generation antipsychotics in rodents: effects on high affinity nicotinic and muscarinic acetylcholine receptors in the brain.

Several postmortem and neuroimaging studies suggest that central nicotinic and muscarinic acetylcholine receptors are important in both the pathophysiology and pharmacotherapy of schizophrenia. However, while antipsychotic drugs are routinely used in the therapeutics of schizophrenia, little is known about their effects on the densities of these receptors when they are administered for extended periods of time (a common practice in the clinical setting). In the present study in rats, the residual effects of prior chronic exposure to representative first generation antipsychotics and second generation antipsychotics on the densities of high affinity nicotinic acetylcholine receptors and muscarinic acetylcholine receptor in the brain were investigated. Test subjects were treated with the first generation antipsychotics, haloperidol (2.0 mg/kg/day) or chlorpromazine (10.0 mg/kg/day) or the second generation antipsychotics, risperidone (2.5 mg/kg/day) or olanzapine (10.0 mg/kg/day) in drinking water for periods of 90 or 180 days, given a drug-free washout period (i.e. returned to normal drinking water) for two weeks and then killed. Quantitative receptor autoradiography was subsequently performed using 16 mum sagittal slices of whole brain incubated with [3H]-epibatidine, [3H]-pirenzepine or [3H]-AFDX-384 to measure high affinity nicotinic acetylcholine receptors, M1 and M2 muscarinic acetylcholine receptors, respectively. The most notable experimental result was a moderate, but significant (P<0.01) increase in [3H]-AFDX-384 binding sites in a number of brain regions (including cortex, hippocampus, subiculum, substantia innominata, and thalamus) associated with prior exposure to olanzapine for 90, but not 180 days. Olanzapine was also associated with a significantly higher density of [3H]-pirenzepine binding sites in cortex lamina I after 90 days of prior drug exposure. These data indicate that chronic treatment with a commonly used second generation antipsychotic, olanzapine is associated with modest increases in M2 muscarinic acetylcholine receptors in memory-related brain regions that may eventually abate with longer periods of chronic drug exposure.

Comparison of galantamine and donepezil for effects on nerve growth factor, cholinergic markers, and memory performance in aged rats.

This study was designed to determine 1) whether repeated exposures to the acetylcholinesterase inhibitors (AChEIs) galantamine (GAL) or donepezil (DON) resulted in positive effects on nerve growth factor (NGF) and its receptors, cholinergic proteins, and cognitive function in the aged rat, and 2) whether GAL had any advantages over DON given its allosteric potentiating ligand (APL) activity at nicotinic acetylcholine receptors. Behavioral tests (i.e., water maze and light/dark box) were conducted in aged Fisher 344 rats during 15 days of repeated (subcutaneous) exposure to either GAL (3.0 or 6.0 mg/kg/day) or DON (0.375 or 0.75 mg/kg/day). Forty-eight hours after the last drug injection, cholinergic receptors were measured by [(125)I]-(+/-)-exo-2-(2-iodo-5-pyridyl)-7-azabicyclo[2.2.1]heptane ([(125)I]IPH; epibatidine analog), (125)I-alpha-bungarotoxin ((125)I-BTX), [(3)H]pirenzepine ([(3)H]PRZ), and [(3)H]-5,11-dihydro-11-[((2-(2-((dipropylamino)methyl)-1-piperidinyl)ethyl)amino)carbonyl]-6H-pyrido(2,3-b)(1,4)-benzodiazepin-6-one methanesulfonate ([(3)H]AFDX-384, or [(3)H]AFX) autoradiography. Immunochemical methods were used to measure NGF, high (TrkA and phospho-TrkA)- and low (p75 neurotrophin receptor)-affinity NGF receptors, choline acetyltransferase (ChAT), and the vesicular acetylcholine transporter (VAChT) in memory-related brain regions. Depending on dose, both GAL and DON enhanced spatial learning (without affecting anxiety levels) and increased [(125)I]IPH, [(3)H]PRZ, and [(3)H]AFX (but decreased (125)I-BTX) binding in some cortical and hippocampal brain regions. Neither AChEI was associated with marked changes in NGF, NGF receptors, or VAChT, although DON did moderately increase ChAT in the basal forebrain and hippocampus. The results suggest that repeated exposures to either GAL or DON results in positive (and sustained) behavioral and cholinergic effects in the aged mammalian brain but that the APL activity of GAL may not afford any advantage over acetylcholinesterase inhibition alone.

Chronic exposure to typical or atypical antipsychotics in rodents: temporal effects on central alpha7 nicotinic acetylcholine receptors.

A decrease in alpha7 nicotinic acetylcholine receptors in the hippocampus has been hypothesized to contribute to alterations in auditory gating and other behavioral impairments in schizophrenia. However, while both typical and atypical neuroleptics are routinely used in the therapeutics of schizophrenia, little is known about their effects on auditory gating or alpha7 nicotinic acetylcholine receptor expression particularly when they are administered for extended periods of time (which is common in the clinical setting). In the present study in normal rats, the residual effects of prior chronic treatment (90 or 180 days) with representative typical and atypical neuroleptics (oral haloperidol, 2.0 mg/kg/day; chlorpromazine, 10.0 mg/kg/day, risperidone, 2.5 mg/kg/day; or olanzapine, 10.0 mg/kg/day) on prepulse inhibition of the auditory gating response were investigated. The densities of alpha7 nicotinic acetylcholine receptors were subsequently measured using [125I]-alpha-bungarotoxin autoradiography. The results indicated that none of the compounds significantly altered the startle amplitude or prepulse inhibition response either during drug treatment (day 60) or after 90 or 180 days of treatment (i.e. during a drug free washout). However, prior exposure to chlorpromazine, risperidone and olanzapine for 90 days resulted in modest but significant (P<0.01) decreases in [125I]-alpha-bungarotoxin binding sites in some brain regions (e.g. posterior cortical amygdala). After 180 days of treatment, decreases in [(125I]-alpha-bungarotoxin binding ranging from approximately 12% (lateral dentate gyrus) up to 24% (e.g. CA1 hippocampal region) were evident in the risperidone group in 13 of the 36 regions analyzed while decreases associated with the other neuroleptics agents were still present, but not statistically significant. These data indicate that the commonly used atypical neuroleptic, risperidone is associated with time dependent and persistent negative effects on an important biological substrate of memory (i.e. the alpha7 nicotinic receptor), but that the magnitude of the deficits was not sufficient to impair auditory gating.

Increased beta-carboline 9N-methyltransferase activity in the frontal cortex in Parkinson's disease.

Enzymatic beta-carboline N-methyltransferase activities generate N-methylated beta-carbolinium cations that are analogs of the parkinsonian-producing neurotoxin MPP+. We measured beta-carboline-2N-methyltransferase and beta-carboline-9N-methyltransferase activities in the supernatant and particulate fractions from postmortem human brains. These N-methyltransferase activities were assessed in the substantia nigra, putamen, and frontal cortex from control and Parkinson's disease cases. No significant differences were measured in any brain region in particulate and supernatant fraction beta-carboline 2N-methyltransferase activity or particulate fraction beta-carboline 9N-methyltransferase activity. Likewise, supernatant fraction beta-carboline 9N-methyltransferase activity was similar in the putamen and substantia nigra from Parkinson's disease and control cases. Unexpectedly, supernatant fraction beta-carboline 9N-methyltransferase activity was increased fourfold in Parkinson's disease frontal cortex (P < 0.05), suggesting that beta-carboline N-methylation may play a role in Parkinson's disease.

Characterization of brain beta-carboline-2-N-methyltransferase, an enzyme that may play a role in idiopathic Parkinson's disease.

The activity of beta-carboline-2-N-methyltransferase results in the formation of neurotoxic N-methylated beta-carbolinium compounds. We have hypothesized that these N-methylated beta-carbolinium cations may contribute to the development of idiopathic Parkinson's disease. This report describes experiments undertaken to optimize assay conditions for bovine brain beta-carboline-2-N-methyltransferase activity. The activity of beta-carboline-2-N-methyltransferase is primarily localized in the cytosol, has a pH optimum of 8.5-9, and obeys Michaelis-Menten kinetics with respect to its substrates, 9-methylnorharman (9-MeNH) and S-adenosyl-L-methionine (SAM). Kinetic constants, KM and Vmax, with respect to 9-MeNH, are 75 microM and 48 pmol/h/mg protein, respectively. The KM for SAM is 81 microM and the Vmax is 53 pmol/h/mg protein. In addition, enzyme activity is inhibited by S-adenosyl-L-homocysteine (SAH) or zinc, and is increased 2-fold in the presence of iron or manganese. Enzyme characterization is a prerequisite to the purification of this N-methyltransferase from bovine brain as well as comparison of its activity in human brain from control and Parkinson's disease individuals.

Methyl-beta-carbolinium analogs of MPP+ cause nigrostriatal toxicity after substantia nigra injections in rats.

Eleven beta-carbolinium compounds (beta C+s) and MPP+ were stereotaxically injected (40-200 nmol in 5 microliter of vehicle) unilaterally into the substantia nigra of anesthetized adult male Sprague-Dawley rats. The rats were sacrificed after three weeks. The ipsilateral striatum was analyzed for dopamine and DOPAC levels with HPLC. The brainstem injection site was fixed and cut coronally. The largest lesion area in each animal was measured using NIH IMAGE. Three beta C+s produced lesions whose mean areas were nearly as large as that produced by MPP+ (defined as 100%): 2,9-Me2-harman (94%), 2-Me-harmol (74%), and 2,9-Me2-norharman (57%). Three other compounds produced somewhat smaller lesions: 2-Me-harmaline (34%), 6-MeO-2-Me-harman (29%), and 2-Me-harmine (25%). The remaining compounds were ineffective (< or = 12%): norharman, 2-Me-norharman, 2-Me-harman, harmine, and 2-Me-6-MeO-harmalan. A 40 nmol dose of MPP+ reduced ipsilateral striatal dopamine to 0.6% of control. None of the beta C+s approached this, although several did significantly reduce striatal dopamine at doses of either 40 nmol (2,9-Me2-harman (37%), 2,9-Me2-norharman (42%), and 2-Me-harman (63%)) or 200 nmol (2-Me-harmaline (23%), norharman (63%), and 2-Me-norharman (64%)). There was a moderate negative correlation between lesion size and dopamine level (r = -0.65). There were also moderately strong correlation between lesion size and dopamine level (r = -0.65). There were also moderately strong correlations (r = 0.39-0.78) between the beta C+ nigral lesion area or striatal dopamine level potencies and their previously described IC50 values for inhibiting mitochondrial respiration or their toxicity to PC12 cells in culture. Interestingly, our correlation analysis revealed a remarkably strong correlation between beta C+ Ki MAO-A values and their toxicity to PC12 LDH release (r = -0.84) or PC12 protein loss (r = 0.79). Although beta C+s appear to be less specific toxins than MPP+, their levels in human substantia nigra are 8-20-fold higher than in cortex, making their role as relatively selective nigral toxins in Parkinson's disease plausible.