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Background: Changes in sexual behaviors in frontotemporal dementia (FTD) are common and multifaceted, but not well characterized. Objective: To characterize changes in sexual behaviors and intimacy in FTD compared to corticobasal syndrome (CBS) and normal controls (NC), and to evaluate the neuroanatomical associations of these changes. Methods: Spouses of 30 FTD patients, 20 CBS patients, and 35 NC completed the Sexual Symptoms in Neurological Illness and Injury Questionnaire (SNIQ), which captures changes in sexual interest, inappropriate sexual behaviors, and prosocial sexual behaviors. 25 patients with FTD and 14 patients with CBS also received 18-flouorodeoxyglucose positron-emission topography (18FDG-PET) scans to determine the metabolic changes associated with these symptoms. Results: FTD patients showed a greater increase in inappropriate sexual behaviors than CBS patients [p = 0.009] and NC [p

Persistent fatigue is common among military servicemembers returning from deployment, especially those with a history of mild traumatic brain injury (mTBI). The purpose of this study was to characterize fatigue following deployment using the Multidimensional Fatigue Inventory (MFI), a multidimensional self-report instrument. The study was developed to test the hypothesis that if fatigue involves disrupted effort/reward processing, this should manifest as altered basal ganglia functional connectivity as observed in other amotivational states.Twenty-eight current and former servicemembers were recruited and completed the MFI. All 28 participants had a history of at least one mTBI during deployment. Twenty-six participants underwent resting-state functional MRI. To test the hypothesis that fatigue was associated with basal ganglia functional connectivity, the investigators measured correlations between MFI subscale scores and the functional connectivity of the left and right caudate, the putamen, and the globus pallidus with the rest of the brain, adjusting for the presence of depression.The investigators found a significant correlation between functional connectivity of the left putamen and bilateral superior frontal gyri and mental fatigue scores. No correlations with the other MFI subscales survived multiple comparisons correction.This exploratory study suggests that mental fatigue in military servicemembers with a history of deployment with at least one mTBI may be related to increased striatal-prefrontal functional connectivity, independent of depression. A finding of effort/reward mismatch may guide future treatment approaches.

Funder: QingLan Research Project of Jiangsu for Outstanding Young Teachers, Funder: Project funded by Postdoctoral Science Foundation of Xuzhou Medical University, Funder: Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) for Xuzhou Medical University, We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.

OBJECTIVE: To assess the effects of the common functional polymorphisms Brain-Derived Neurotrophic Factor (BDNF) val66met and Catechol O-methyltransferase (COMT) val158met on the cognitive, neuropsychiatric, motor symptoms, and MRI findings in participants with Frontotemporal Lobar Degeneration (FTLD) syndromes. METHODS: The Brain-Derived Neurotrophic Factor (BDNF) val66met and the Catechol O-methyltransferase (COMT) val158met polymorphisms were genotyped in 174 participants with FTLD syndromes including frontotemporal dementia (FTD), primary progressive aphasia (PPA) and corticobasal syndrome (CBS). Grey matter volumes, the Delis-Kaplan Executive Function System, Mattis Dementia Rating Scale, Wechsler Memory Scale, and the Neuropsychiatric Inventory were compared between allele groups. RESULTS: The BDNF met allele at position 66 was associated with a decrease in depressive symptoms [F(1, 136)=9.50, p=0.002]. The COMT val allele at position 158 was associated with impairment of executive function [F(1, 76)=6.14, p=0.015] and decreased bilateral volume of the head of the caudate among FTLD patients (uncorrected voxel-level threshold of p < 0.001). Neither polymorphism had a significant effect on motor function. CONCLUSIONS: These findings suggest that common functional polymorphisms likely contribute to the phenotypic variability seen in patients with FTLD syndromes. To our knowledge, this is the first study to implicate BDNF polymorphisms in depressive symptoms in FTLD. Our results also support an association between COMT polymorphisms and degeneration patterns and cognition in FTLD.

Objective:To assess changes in 3 clinical measures, the Revised ALS Functional Rating Scale (ALSFRS-R), letter fluency, and Frontal Behavioral Inventory (FBI), over time in C9orf72 mutation carriers (C9+) with varied clinical phenotypes.Methods:Thirty-four unrelated participants with mutations in C9orf72 were enrolled in a prospective natural history study. Participants were classified as asymptomatic, amyotrophic lateral sclerosis (ALS), ALS–familial frontotemporal dementia (FTD), or behavioral-variant FTD by clinical diagnostic criteria. Diagnostic cognitive and motor tests were repeated at 6 and 18 months. The ALSFRS-R, letter fluency, and FBI were administered at baseline and follow-up visits at 6, 12, and 18 months.Results:The clinical diagnosis of most patients did not change over the follow-up. ALSFRS-R scores correlated with measures of motor function. Letter fluency correlated with FBI and cognitive tests. ALSFRS-R, letter fluency, and FBI differed among the C9+ diagnostic subgroups at enrollment and worsened over follow-up in symptomatic patients, with different slopes among the subgroups. Most patients survived to the 6-month time point after enrollment. Survival of C9+ patients with ALS and C9+ patients with ALS-FTD declined over the 12- and 18-month follow-up.Conclusions:The pattern of scores of the ALSFRS-R, letter fluency, and FBI distinguished between ALS, ALS-FTD, and FTD presentations of C9orf72 mutation carriers and asymptomatic carriers. Longitudinal changes in these measures occurred with disease progression in a manner consistent with presenting phenotype.

There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a G(4)C(2) repeat expansion in the C9ORF72 gene as the most common genetic cause of ALS has opened up new avenues for therapeutic intervention for this form of ALS. G(4)C(2) repeat expansion RNAs and proteins of repeating dipeptides synthesized from these transcripts are believed to play a key role in C9ORF72-associated ALS (c9ALS). Therapeutics that target G(4)C(2) RNA, such as antisense oligonucleotides (ASOs) and small molecules, are thus being actively investigated. A limitation in moving such treatments from bench to bedside is a lack of pharmacodynamic markers for use in clinical trials. We explored whether poly(GP) proteins translated from G(4)C(2) RNA could serve such a purpose. Poly(GP) proteins were detected in cerebrospinal fluid (CSF) and in peripheral blood mononuclear cells from c9ALS patients and, notably, from asymptomatic C9ORF72 mutation carriers. Moreover, CSF poly(GP) proteins remained relatively constant over time, boding well for their use in gauging biochemical responses to potential treatments. Treating c9ALS patient cells or a mouse model of c9ALS with ASOs that target G(4)C(2) RNA resulted in decreased intracellular and extracellular poly(GP) proteins. This decrease paralleled reductions in G(4)C(2) RNA and downstream G(4)C(2) RNA-mediated events. These findings indicate that tracking poly(GP) proteins in CSF could provide a means to assess target engagement of G(4)C(2) RNA-based therapies in symptomatic C9ORF72 repeat expansion carriers and presymptomatic individuals who are expected to benefit from early therapeutic intervention.

Inappropriate social behaviours are early and distinctive symptoms of the temporal and frontal variants of frontotemporal lobar degeneration (FTLD). Knowledge of social behaviour is essential for appropriate social conduct. It is unknown, however, in what way this knowledge is degraded in FTLD. In a recent functional MRI study, we have identified a right-lateralized superior anterior temporal lobe (aTL) region showing selective activation for ‘social concepts’ (i.e. concepts describing social behaviour: e.g. ‘polite’, ‘stingy’) as compared with concepts describing less socially relevant animal behaviour (‘animal function concepts’: e.g. ‘trainable’, ‘nutritious’). In a further fMRI study, superior aTL activation was independent of the context of actions and feelings associated with these social concepts. Here, we investigated whether the right superior sector of the aTL is necessary for context-independent knowledge of social concepts. We assessed neuronal glucose uptake using 18-fluoro-deoxy-glucose-positron emission tomography (FDG-PET) and a novel semantic discrimination task which probed knowledge of social and animal function concepts in patients with FTLD (n = 29) and corticobasal syndrome (n = 18). FTLD and corticobasal syndrome groups performed equally poorly on animal function concepts but FTLD patients showed more pronounced impairments on social concepts than corticobasal syndrome patients. FTLD patients with right superior aTL hypometabolism, as determined on individual ROI analyses, were significantly more impaired on social concepts than on animal function concepts. FTLD patients with selective impairments for social concepts, as determined on individual neuropsychological profiles, showed higher levels of inappropriate social behaviours (‘disinhibition’) and demonstrated more pronounced hypometabolism in the right superior aTL, the left temporal pole and the right lateral orbitofrontal and dorsomedial prefrontal cortex as compared with FTLD patients showing selective impairments of animal function concepts. Combining both FTLD subgroup analyses, based on anatomical and neuropsychological criteria, by using inclusive masks, revealed the right superior aTL as associated with selective impairments of social concepts in both analyses. These results corroborate the hypothesis that the right aTL is necessary for representing conceptual social knowledge. Further, we provide first evidence for the potential importance of conceptual social knowledge impairments as contributing to behavioural symptoms of FTLD.

Although patients with frontotemporal dementia (FTD) are known to exhibit a wide range of cognitive and personality difficulties, some evidence suggests that there may be a degree of selectivity in their reasoning impairments. Based on a recent review of the neuroimaging literature on reasoning, the authors hypothesized that the presence or absence of familiar content may have a selective impact on the reasoning abilities of patients with FTD. Specifically, the authors predicted that patients with frontal-variant FTD would be more impaired when reasoning about transitive arguments involving familiar spatial environments than when reasoning about identical logical arguments involving unfamiliar spatial environments. As predicted, patients with FTD were less accurate than normal controls only when the content of arguments involved familiar spatial environments. These results indicate a degree of selectivity in the cognitive deficits of this patient population and suggest that the frontal-temporal lobe system may play a necessary role in reasoning about familiar material.

Purpose The comparative efficacy, safety, and cost-effectiveness of rapid and long-acting insulin analogs compared with regular or neutral protamine Hagedorn nonanalog insulins or with oral antidiabetic agents in hospitalized adults were evaluated. Methods A literature search was conducted to identify studies that compared the effects of rapid-acting, long-acting, or mixed insulin analogs with short- or intermediate-acting insulin or any other oral antidiabetic medication. Results Twenty-three primary studies were included in the review. Rapid-acting analogs and basal–bolus analog regimens were found to reduce the duration of hospital stay by approximately one day compared with regular insulin and basal–bolus nonanalog regimens. One large cohort study found an adjusted 48% relative risk reduction in mortality with rapid-acting analogs versus regular insulin in a heterogeneous hospitalized hyperglycemic population. A randomized controlled trial found a significant reduction in postoperative complications with basal–bolus analogs compared with basal–bolus nonanalog insulin. When compared with regular sliding-scale insulin (SSI), fixed-dose insulin glargine with or without insulin glulisine was found to reduce the blood glucose concentration in patients with type 2 diabetes and reduce postoperative complications in surgical patients with diabetes. The quality of evidence was primarily very low or low for most outcomes. Conclusion A systematic literature review revealed a very low or low quality of evidence, suggesting that, compared with nonanalog regimens, rapid-acting insulin analogs reduce the duration of hospital stay and mortality rates and that basal– bolus analog regimens may reduce the duration of hospital stay and postoperative complications. There is also a low quality of evidence to suggest that a fixed-dose analog regimen of insulin glargine with or without insulin glulisine is more effective than regular SSI for reducing blood glucose concentrations and postoperative complications.

A nonsense/protein chain-terminating mutation in the CHMP2B gene has recently been reported as a cause of frontotemporal dementia (FTD) in the single large family known to show linkage to chromosome 3. Screening for mutations in this gene in a large series of FTD families and individual patients led to the identification of a protein-truncating mutation in 2 unaffected members of an Afrikaner family with FTD, but not in their affected relatives. The putative pathogenicity of CHMP2B mutations for dementia is discussed.

Summary Background Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes— MAPT , GRN , and C9orf72 —have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p −8 ) single-nucleotide polymorphisms. Findings We identified novel associations exceeding the genome-wide significance threshold (p −8 ). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05 × 10 −8 ; odds ratio=1·204 [95% CI 1·11–1·30]), rs9268856 (p=5·51 × 10 −9 ; 0·809 [0·76–0·86]) and rs1980493 (p value=1·57 × 10 −8 , 0·775 [0·69–0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38 / CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10 −7 ; 0·814 [0·71–0·92]). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis . Interpretation Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD. Funding The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK, and Texas Tech University Health Sciences Center.

The phenotypes of the behavioral variant of frontotemporal dementia and the corticobasal syndrome present considerable clinical and anatomical overlap. The respective patterns of white matter damage in these syndromes have not been directly contrasted. Beyond cortical involvement, damage to white matter pathways may critically contribute to both common and specific symptoms in both conditions. Here we assessed patients with the behavioral variant of frontotemporal dementia and corticobasal syndrome with whole-brain diffusion tensor imaging to identify the white matter networks underlying these pathologies. Twenty patients with the behavioral variant of frontotemporal dementia, 19 with corticobasal syndrome, and 15 healthy controls were enrolled in the study. Differences in tract integrity between (i) patients and controls, and (ii) patients with the corticobasal syndrome and the behavioral variant of frontotemporal dementia were assessed with whole brain tract-based spatial statistics and analyses of regions of interest. Behavioral variant of frontotemporal dementia and the corticobasal syndrome shared a pattern of bilaterally decreased white matter integrity in the anterior commissure, genu and body of the corpus callosum, corona radiata and in the long intrahemispheric association pathways. Patients with the behavioral variant of frontotemporal dementia showed greater damage to the uncinate fasciculus, genu of corpus callosum and forceps minor. In contrast, corticobasal syndrome patients had greater damage to the midbody of the corpus callosum and perirolandic corona radiata. Whereas several compact white matter pathways were damaged in both the behavioral variant of frontotemporal dementia and corticobasal syndrome, the distribution and degree of white matter damage differed between them. These findings concur with the distinctive clinical manifestations of these conditions and may improve the in vivo neuroanatomical and diagnostic characterization of these disorders.

In the present study we aimed to determine the prevalence of C9ORF72 GGGGCC hexanucleotide expansion in our cohort of 53 frontotemporal lobar degeneration (FTLD) patients and 174 neurologically normal controls. We identified the hexanucleotide repeat, in the pathogenic range, in 4 (2 bv-frontotemporal dementia (FTD) and 2 FTD-amyotrophic lateral sclerosis [ALS]) out of 53 patients and 1 neurologically normal control. Interestingly, 2 of the C9ORF72 expansion carriers also carried 2 novel missense mutations in GRN (Y294C) and in PSEN-2(I146V). Further, 1 of the C9ORF72 expansion carriers, for whom pathology was available, showed amyloid plaques and tangles in addition to TAR (trans-activation response) DNA-binding protein (TDP)-43 pathology. In summary, our findings suggest that the hexanucleotide expansion is probably associated with ALS, FTD, or FTD-ALS and occasional comorbid conditions such as Alzheimer's disease. These findings are novel and need to be cautiously interpreted and most importantly replicated in larger numbers of samples.

Anxiety negatively affects quality of life and psychosocial functioning. Previous research has shown that anxiety symptoms in healthy individuals are associated with variations in the volume of brain regions, such as the amygdala, hippocampus, and the bed nucleus of the stria terminalis. Brain lesion data also suggests the hemisphere damaged may affect levels of anxiety. We studied a sample of 182 male Vietnam War veterans with penetrating brain injuries, using a semi-automated voxel-based lesion-symptom mapping (VLSM) approach. VLSM reveals significant associations between a symptom such as anxiety and the location of brain lesions, and does not require a broad, subjective assignment of patients into categories based on lesion location. We found that lesioned brain regions in cortical and limbic areas of the left hemisphere, including middle, inferior and superior temporal lobe, hippocampus, and fusiform regions, along with smaller areas in the inferior occipital lobe, parahippocampus, amygdala, and insula, were associated with increased anxiety symptoms as measured by the Neurobehavioral Rating Scale (NRS). These results were corroborated by similar findings using Neuropsychiatric Inventory (NPI) anxiety scores, which supports these regions' role in regulating anxiety. In summary, using a semi-automated analysis tool, we detected an effect of focal brain damage on the presentation of anxiety. We also separated the effects of brain injury and war experience by including a control group of combat veterans without brain injury. We compared this control group against veterans with brain lesions in areas associated with anxiety, and against veterans with lesions only in other brain areas.

This study aimed to evaluate genetic variability in the FUS and TDP-43 genes, known to be mainly associated with amyotrophic lateral sclerosis (ALS), in patients with the diagnoses of frontotemporal lobar degeneration (FTLD) and corticobasal syndrome (CBS). We screened the DNA of 228 patients for all the exons and flanking introns of FUS and TDP-43 genes. We identified 2 novel heterozygous missense mutations in FUS: P106L (g.22508384C>T) in a patient with behavioral variant frontotemporal dementia (bvFTD) and Q179H in several members of a family with behavioral variant FTD. We also identified the N267S mutation in TDP-43 in a CBS patient, previously only reported in 1 ALS family and 1 FTD patient. Additionally, we identified 2 previously reported heterozygous insertion and deletion mutations in Exon 5 of FUS; Gly174-Gly175 del GG (g. 4180-4185 delGAGGTG) in an FTD patient and Gly175-Gly176 ins GG (g. 4185-4186 insGAGGTG) in a patient with diagnosis of CBS. Not least, we have found a series of variants in FUS also in neurologically normal controls. In summary, we report that genetic variability in FUS and TDP-43 encompasses a wide range of phenotypes (including ALS, FTD, and CBS) and that there is substantial genetic variability in FUS gene in neurologically normal controls.

Frontotemporal dementia (FTD) is a progressive neurodegenerative disease that primarily affects the frontal and anterior temporal lobes, resulting in changes in behavior, language, and cognition.1 Corticobasal syndrome (CBS) is a disorder characterized by progressive asymmetric apraxia and rigidity with other findings of cortical (e.g., alien limb, cortical sensory loss, myoclonus) and basal ganglia (e.g., bradykinesia and increased resistance to passive movement) dysfunction.2,3 Both disorders can be associated with pathologic tau aggregation.1–5 Patients with FTD and patients with CBS often have deficits in executive function,6–9 a term that encompasses complex cognitive functions such as planning, judgment, reasoning, problem solving, organization, attention, abstraction, and mental flexibility.10 Several questions, however, remain unanswered: How do the patterns of executive dysfunction of behavioral variant FTD (bv-FTD) and CBS compare? What brain areas are associated with specific symptoms of executive dysfunction in bv-FTD and CBS? These are important questions for several reasons: executive dysfunction is a clinically important symptom in FTD11 and CBS,7 but little is known about its neurobiological basis in these disorders; and insights from patients with deficits in executive function can elucidate the neuroanatomic basis of executive function in healthy people. The distributions of atrophy observed in FTD and CBS are ideal to determine the relative contributions of regions of the frontal and parietal cortexes to executive function. A review of the brain areas involved in the performance of executive function tests is beyond the scope of this article, but in summary, while intact executive function requires more fundamental cognitive abilities in other parts of the brain (including the parietal lobe12), the prefrontal cortex, especially on the left, is prominently associated with executive functions.13 Patients with FTD had high numbers of rule violations on the Tower Test compared to patients with Alzheimer disease and healthy controls,14 and impaired performance on a sorting task associated with decreased left frontal lobe volume.15 Performance on the Twenty Questions test has been shown to be impaired in patients with prefrontal cortex lesions,16 and letter fluency is impaired in patients with left prefrontal17 lesions. Patients with FTD who had progressive disease were especially impaired on digit span and inhibition of prepotent responses.18 The Delis-Kaplan Executive Function System (D-KEFS) is a battery of nine standardized executive function tests (Trail Making, Verbal Fluency, Design Fluency, Color-Word Interference, Sorting, Twenty Questions, Word Context, Tower, and Proverb interpretation) designed to comprehensively assess higher cognitive function.19 In this study, we compared D-KEFS scores between the patients with CBS and patients with FTD and determined which areas of the brain are associated with these executive functions using voxel-based morphometry (VBM) of MRI. Based on the findings discussed above and the brain areas affected in FTD and CBS, we hypothesized that patients with FTD would show more severe executive dysfunction than the patients with CBS and that this executive dysfunction would be associated with left prefrontal atrophy in the patients with FTD and left prefrontal and parietal atrophy in the patients with CBS.

Aims: To determine areas of atrophy in patients that are associated with caregiver burden. Methods: We measured caregiver burden, dementia and neuropsychiatric scores in 22 patients with corticobasal syndrome (CBS) and 25 with frontotemporal dementia (FTD), and in 14 healthy controls. We used voxel-based morphometry to correlate caregiver burden with gray matter loss. Results: Increased dementia and behavioral disturbances contributed to higher burden scores in CBS patients, while behavioral disturbances alone significantly affected burden scores in frontal-variant FTD (FTD-fv) patients. In CBS patients, caregiver burden scores correlated with atrophy in left inferior and middle temporal gyri. Conclusions: Caregivers of FTD-fv patients had significantly higher burden scores than caregivers of CBS patients. Damage to areas important in semantic knowledge appears critical in increased burden for CBS caregivers.

Frontotemporal dementia (FTD) is an umbrella term for a set of progressive disorders affecting predominantly the frontal and/or the anterior temporal lobes of the brain. FTD usually presents clinically with behavior or language changes, or both, and is associated with atrophy and decreased metabolism of the frontal and anterior temporal lobes on imaging.1,2 The mean age of onset for FTD is in the mid-50s.3,4 It is the second most common cause of dementia in people younger than 65 (after Alzheimer’s disease), comprising approximately one third of these cases.4,5 Between 35 and 50% of cases are reported to have a family history of FTD.4–10 In the majority of these cases, the illness is inherited in a manner consistent with an autosomal dominant mechanism.5,6,9 Fourteen percent of FTD patients have clinical motor neuron disease (MND),11 and up to about 40% of patients with behavioral variant FTD show MND-type inclusions.12 Several mutations have been associated with rare cases of FTD.13 Mutations in the MAPT gene at 17q21 coding for the tau protein are the most commonly associated with FTD.14–18 More than 30 MAPT mutations associated with the development of FTD have been discovered (a list of these mutations is available online at: http://www.molgen.ua.ac.be/ADMutations/default.cfm?MT=1&ML=1&Page=MutByQuery&Query=tblContexts.GeneSymbol%20In%20('MAPT')&Selection=Gene%20In%20(MAPT)&CFID=136313&CFTOKEN=48500543). These mutations are associated with intraneuronal and/or glial deposits that are immunopositive for tau on neuropathology.6 The reported prevalence of MAPT mutations in patients with FTD has ranged from 0 to 18%.4,6,8,19–22 In several families with inherited FTD, the illness has been linked to 17q21, but no MAPT mutations have been identified, and the cases are not associated with tau-positive inclusions.6,23,24 In a recent report, cases of FTD linked to 17q21 with a DR2-DR8 haplotype were seven times more common than FTD cases with identified MAPT mutations (7 vs 1% of the sample).6 On neuropathology, one of these cases had frontotemporal lobar degeneration (FTLD) with rare tau-negative, ubiquitin-positive inclusions.6 Recent reports show that, although it appears to be an unlikely coincidence, mutations in another gene at 17q21 (Progranulin or PGRN) are also associated with FTD.14–16 PGRN is a 593-amino acid (68.5kDa) multifunctional growth factor.25 Mutations in PGRN that likely result in premature termination and null alleles segregated with illness in several large families and were absent in 550 control patients.14 RNA extracted from patient cells consisted almost entirely of wild-type RNA with little of the mutant RNA detected and with a reduction in wild-type RNA, suggesting that the mutations result in degradation of the mutant RNA and a loss of functional PGRN (haploinsufficiency).14 In the original report,14 eight mutations predicted to cause premature termination of the coding sequence of PGRN were detected in patients with familial FTD without MAPT mutations. In a series of familial FTD patients, PGRN mutations were 3.5 times more frequent than MAPT mutations.26 In this study, we serially evaluated 84 FTD patients for known MAPT and PGRN mutations and sequenced the coding exons and the flanking intronic regions of PGRN. We compared the PGRN mutation carriers with the rest of the patients for demographic characteristics, clinical presentation, imaging, neuropsychological testing, and pathology.

Serial assessment of patient MT with McLeod syndrome (MLS) and a cross-sectional study in nine patients with genetically confirmed chorea-acanthocytosis (ChAc) are presented along with a review of more than 20 case reports each from the literature. The cognitive and neuropsychiatric findings may be summarized as a “fronto-subcortical syndrome” but are not unique to either condition since a similar syndrome is also shared by other basal ganglia degenerations, most notably Huntington’s disease. Some distinction may be made on the basis of age of neuropsychiatric manifestations (MLS: fourth to fifth decade — ChAc: second to third decade) and the more pronounced features of ChAc. Correlation with the involvement of specific fronto-subcortical loops may be possible in the future.

Study Objective. To compare the cost of contemporary outpatient and historical inpatient management of proximal lower limb deep vein thrombosis (DVT) in adults. Design. Prospective, observational study with historical inpatient cases as controls. Setting. Ambulatory thrombosis clinic of a tertiary care teaching center in Canada. Patients. Forty-nine inpatients with DVT from a previous study in 1996 at the same institution who would have been eligible for outpatient therapy if this option had been available, and 51 consecutive patients referred to the ambulatory thrombosis clinic for treatment of DVT between March 2000 and January 2001. Intervention. The 49 inpatients received unfractionated heparin, and the 51 outpatients received low-molecular-weight heparin (LMWH). Measurements and Main Results. A cost-minimization analysis restricted to the hospital perspective was conducted. This design was justified based on the clinical equivalence of the two treatment strategies. All direct hospital costs for treating the 51 consecutive outpatients with LMWH were measured. These data were compared with the cost of treating the inpatients with unfractionated heparin. The analysis horizon was limited to 7 days, based on the duration of hospitalization and length of heparin therapy for DVT before conversion to oral warfarin. The mean cost (in Canadian dollars) per outpatient case was $248 (95% confidence interval $216–280) and was significantly different from the mean cost/inpatient case of $2826 (adjusted for the difference in fiscal years) (p

OBJECTIVE: To report a case of metabolic acidosis and coma in a severe acetaminophen overdose. CASE SUMMARY: A 29-year-old white woman was admitted to the emergency department with a diminished level of consciousness and metabolic acidosis. The toxicology screen revealed a serum acetaminophen concentration of 1072 μg/mL, and she was consequently treated with intravenous acetylcysteine. Despite the elevated concentration, the patient did not manifest signs of hepatotoxicity. DISCUSSION: Metabolic acidosis and coma are rare manifestations in acetaminophen overdoses. In published case reports, severe acetaminophen ingestion independently causes metabolic acidosis and coma in the absence of hepatotoxicity. The mechanism by which metabolic acidosis occurs is not clearly defined. Studies conducted on animals demonstrated that in severe overdoses, acetaminophen may cause lactic acidosis by inhibiting mitochondrial respiration. The mechanism by which acetaminophen can cause coma is still unknown. CONCLUSIONS: Severe acetaminophen overdoses can independently cause metabolic acidosis and coma in the absence of hepatotoxicity.

OBJECTIVE: To evaluate the efficacy and safety of intravenous potassium phosphate administered in a fixed-dose regimen in critically ill patients. DESIGN: Prospective, unblind study. SETTING: Surgical—medical intensive care unit (ICU). PARTICIPANTS: Patients who developed hypophosphatemia during their ICU admission. INTERVENTIONS: Patients with a serum phosphate concentration between 1.27 and 2.48 mg/dL (group 1) and those with a concentration of 1.24 mg/dL or less (group 2) received 15 and 30 mmol, respectively, of phosphate as a potassium salt via a central line over 3 hours. MAIN OUTCOME MEASURES: Normalization of serum phosphate within 6 hours of infusion, the development of arrhythmias during the infusion, and the development of hypocalcemia and hyperkalemia after the infusion were evaluated. Redevelopment of hypophosphatemia and the need for further therapy were also assessed. RESULTS: Thirty-seven episodes of hypophosphatemia were entered in this study: 27 in group 1 (17 patients) and 10 in group 2 (10 patients). The mean serum phosphate concentration increased significantly from 2.02 to 2.82 mg/dL in group 1 and from 0.83 to 2.17 mg/dL in group 2, with no change in calcium or potassium. Normalization of serum phosphate with this initial dose occurred in 81.5% of the episodes in group 1 and 30% in group 2. However, over the following 2 days, 45% of the patients in group 1 and 60% in group 2 required further phosphate supplementation. No arrhythmias occurred during the 3-hour infusion that were related to the potassium phosphate. A significant drop in total serum calcium concentrations occurred in 2 patients who were slightly hypercalcemic prior to the infusion. Serum calcium concentrations remained above normal, but this was not associated with any adverse effects. CONCLUSIONS: The administration of potassium phosphate 15 mmol to critically ill patients with mild-to-moderate hypophosphatemia over 3 hours is both effective and safe. The administration of potassium phosphate 30 mmol to severely hypophosphatemic patients was safe but achieved normalization of serum phosphate in a minority of patients. Either a higher dose or the subsequent administration of more potassium phosphate may be required to normalize serum phosphate concentrations. Once normalization has occurred, there is a high likelihood of redevelopment of hypophosphatemia over the following 2 days and supplementation should be given accordingly.

Advances in therapy have largely contributed to the increased life expectancy of patients with cystic fibrosis. Unlike children, adults with cystic fibrosis must take responsibility for their own care. We administered a questionnaire to 23 adult patients (aged 18–39 years) with cystic fibrosis to (1) determine patients' degree of compliance with medications and chest physiotherapy; (2) collect information on their self-assessment of health motivation, disease severity, and benefits of treatment; and (3) identify barriers to receiving medical care. Patients reported better compliance with medications than with chest physiotherapy. Nine percent of the patients missed at least 25 percent of prescribed medication, whereas 47 percent missed at least 25 percent of prescribed physiotherapy. We observed a trend toward better compliance in patients who were highly worried about their health, who believed their illness to be serious, and who felt that their medications were very effective. Less than half of the study participants believed physiotherapy to be effective, and that adhering to a physiotherapy schedule was very difficult. Among adults with cystic fibrosis, compliance can be a serious problem that minimizes the benefits of good medical care. We suggest that emphasizing the severity of disease and usefulness of therapy may improve compliance and requires study.

Objective: To use the Visual Object and Space Perception Battery (VOSP) to distinguish Alzheimer disease (AD) from non-AD pathology in corticobasal syndrome (CBS). Methods: This clinicopathologic study assessed 36 patients with CBS on the VOSP. All were autopsied. The primary dependent variable was a binary pathologic outcome: patients with CBS who had primary pathologic diagnosis of AD (CBS-AD, n = 10) vs patients with CBS without primary pathologic diagnosis of AD (CBS-nonAD, n = 26). We also determined sensitivity and specificity of individual VOSP subtests. Results: Patients with CBS-AD had younger onset (54.5 vs 63.6 years, p = 0.001) and lower memory scores on the Mattis Dementia Rating Scale–2 (16 vs 22 points, p = 0.003). Failure on the VOSP subtests Incomplete Letters (odds ratio [OR] 11.5, p = 0.006), Position Discrimination (OR 10.86, p = 0.008), Number Location (OR 12.27, p = 0.026), and Cube Analysis (OR 45.71 p = 0.0001) had significantly greater odds of CBS-AD than CBS-nonAD. These associations remained when adjusting for total Mattis Dementia Rating score, disease laterality, education, age, and sex. Receiver operating characteristic curves demonstrated significant accuracy for Incomplete Letters and all VOSP spatial subtests, with Cube Analysis performing best (area under the curve 0.91, p = 0.0004). Conclusions: In patients with CBS, failure on specific VOSP subtests is associated with greater odds of having underlying AD. There may be preferential involvement of the dorsal stream in CBS-AD. Classification of evidence: This study provides Class II evidence that some subtests of the VOSP accurately distinguish patients with CBS-AD from those without AD pathology (e.g., Cube Analysis sensitivity 100%, specificity 77%).