Apathy predicts rate of cognitive decline over 24 months in premanifest Huntington's disease.

BACKGROUND: Cognitive impairment is a core feature of Huntington's disease (HD), however, the onset and rate of cognitive decline is highly variable. Apathy is the most common neuropsychiatric symptom of HD, and is associated with cognitive impairment. The aim of this study was to investigate apathy as a predictor of subsequent cognitive decline over 2 years in premanifest and early HD, using a prospective, longitudinal design. METHODS: A total of 118 premanifest HD gene carriers, 111 early HD and 118 healthy control participants from the multi-centre TRACK-HD study were included. Apathy symptoms were assessed at baseline using the apathy severity rating from the Short Problem Behaviours Assessment. A composite of 12 outcome measures from nine cognitive tasks was used to assess cognitive function at baseline and after 24 months. RESULTS: In the premanifest group, after controlling for age, depression and motor signs, more apathy symptoms predicted faster cognitive decline over 2 years. In contrast, in the early HD group, more motor signs, but not apathy, predicted faster subsequent cognitive decline. In the control group, only older age predicted cognitive decline. CONCLUSIONS: Our findings indicate that in premanifest HD, apathy is a harbinger for cognitive decline. In contrast, after motor onset, in early diagnosed HD, motor symptom severity more strongly predicts the rate of cognitive decline.

Early deficits in olfaction are associated with structural and molecular alterations in the olfactory system of a Huntington disease mouse model.

Olfactory dysfunction and altered neurogenesis are observed in several neurodegenerative disorders including Huntington disease (HD). These deficits occur early and correlate with a decline in global cognitive performance, depression and structural abnormalities of the olfactory system including the olfactory epithelium, bulb and cortices. However, the role of olfactory system dysfunction in the pathogenesis of HD remains poorly understood and the mechanisms underlying this dysfunction are unknown. We show that deficits in odour identification, discrimination and memory occur in HD individuals. Assessment of the olfactory system in an HD murine model demonstrates structural abnormalities in the olfactory bulb (OB) and piriform cortex, the primary cortical recipient of OB projections. Furthermore, a decrease in piriform neuronal counts and altered expression levels of neuronal nuclei and tyrosine hydroxylase in the OB are observed in the YAC128 HD model. Similar to the human HD condition, olfactory dysfunction is an early phenotype in the YAC128 mice and concurrent with caspase activation in the murine HD OB. These data provide a link between the structural olfactory brain region atrophy and olfactory dysfunction in HD and suggest that cell proliferation and cell death pathways are compromised and may contribute to the olfactory deficits in HD.

The reliability of commonly used electrophysiology measures.

BACKGROUND: Electrophysiological measures can help understand brain function both in healthy individuals and in the context of a disease. Given the amount of information that can be extracted from these measures and their frequent use, it is essential to know more about their inherent reliability. OBJECTIVE/HYPOTHESIS: To understand the reliability of electrophysiology measures in healthy individuals. We hypothesized that measures of threshold and latency would be the most reliable and least susceptible to methodological differences between study sites. METHODS: Somatosensory evoked potentials from 112 control participants; long-latency reflexes, transcranial magnetic stimulation with resting and active motor thresholds, motor evoked potential latencies, input/output curves, and short-latency sensory afferent inhibition and facilitation from 84 controls were collected at 3 visits over 24 months at 4 Track-On HD study sites. Reliability was assessed using intra-class correlation coefficients for absolute agreement, and the effects of reliability on statistical power are demonstrated for different sample sizes and study designs. RESULTS: Measures quantifying latencies, thresholds, and evoked responses at high stimulator intensities had the highest reliability, and required the smallest sample sizes to adequately power a study. Very few between-site differences were detected. CONCLUSIONS: Reliability and susceptibility to between-site differences should be evaluated for electrophysiological measures before including them in study designs. Levels of reliability vary substantially across electrophysiological measures, though there are few between-site differences. To address this, reliability should be used in conjunction with theoretical calculations to inform sample size and ensure studies are adequately powered to detect true change in measures of interest.

Routine CT angiography to detect severe coronary artery disease prior to transcatheter aortic valve replacement.

Patients undergoing TAVR undergo routine CT angiography (CTA) to assess aorto-iliac pathology and annular dimensions. While coronary CTA may exclude severe CAD in younger patients, its efficacy in defining CAD severity prior to TAVR may be limited. We retrospectively studied 50 consecutive patients undergoing both invasive coronary angiography (ICA) and routine pre-TAVR CTA. Severe CAD was defined as ≥50% stenosis by quantitative coronary angiography and compared to a blinded CTA visual estimation of ≥50% stenosis. The analysis was confined to four segments: left main and three proximal to mid major coronaries to maximize myocardial territory at risk. Coronary assessment was performed using standard reconstructed ECG phases from pre-TAVR chest CTA on a Philips 256 iCT scanner. Nearly ¾ of patients were ≥75 years old, 57% were female, half were diabetic and 45% had prior PCI. By ICA, 49% had significant coronary calcification. The incidence of severe proximal to mid vessel CAD by ICA was 39%. Similarly, a third of patients required PCI prior to TAVR. CTA was unable to exclude severe proximal to mid vessel CAD in 88% of patients in all four segments: non-diagnostic CTA readings were mainly due to calcification (60%) or motion artifact (28%). Non-diagnostic coronary CTA readings ranged from 25 to 72% according to segment analyzed: only the left main segment had diagnostic quality CTA in the majority of patients (p < 0.01). PCI is performed frequently prior to TAVR based upon invasive coronary angiographic assessment. Routine chest CTA algorithms do not provide adequate diagnostic information to exclude severe CAD, primarily due to severe coronary calcification in the TAVR population.

Enhanced immune response to MMP3 stimulation in microglia expressing mutant huntingtin.

Huntington's Disease (HD) is an inherited neurodegenerative disease caused by a polyglutamine expansion in the huntingtin protein. The YAC128 mouse model of HD expresses the full-length human huntingtin protein with 128 CAG repeats and replicates the phenotype and neurodegeneration that occur in HD. Several studies have implicated a role for neuroinflammation in HD pathogenesis. Studies on presymptomatic HD patients have illustrated microgliosis (activated microglia) in brain regions affected in HD. Mutant huntingtin expressing isolated primary monocytes (human HD patients) and primary macrophages (YAC128) are overactive in response to lipopolysaccharide (LPS) stimulation. In this study we demonstrate that cultured primary microglia (the resident immune cells of the brain cells) from YAC128 mice differentially express a wide number of cytokines compared to wildtype microglia cultures in response to LPS. Furthermore, this study outlines a direct interaction between mutant huntingtin and cytokine secretion in HD microglia. Increased cytokine release in YAC128 microglia can be blocked by cannabinoid activation or by mutant huntingtin knockdown with anti-sense oligonucleotide treatment. Matrix metalloprotease 3 (MMP3), an endogenous neuronal activator of microglia, also induces increased cytokine release from YAC128 microglia compared to wildtype microglia. We found elevated MMP levels in HD CSF, and MMP levels correlate with disease severity in HD. These data support a novel role for MMPs and microglial activation in HD pathogenesis. With an improved understanding of the specific cellular processes involved in HD neuroinflammation, novel therapeutic agents targeting these processes can be developed and hold great promise in the treatment of HD.

Core neuropathological abnormalities in progranulin-deficient mice are penetrant on multiple genetic backgrounds.

Loss-of-function mutations in the progranulin gene (GRN) are a common cause of familial frontotemporal lobar degeneration (FTLD). A high degree of heterogeneity in the age-of-onset, duration of disease, and clinical presentation of FTLD, even among families carrying the same GRN mutation, suggests that additional modifying genes may be important to pathogenesis. Progranulin-knockout mice display subtle behavioral abnormalities and progressive neuropathological changes, as well as altered dendritic morphology and synaptic deficits in the hippocampus. In this study we evaluated multiple neuropathological endpoints in aged progranulin knockout mice and their wild-type littermates on two different genetic backgrounds: C57Bl/6 and 129/SvImJ. We find that in most brain regions, both strains are susceptible to progranulin-mediated neuropathological phenotypes, including astrogliosis, microgliosis, and highly accelerated deposition of the aging pigment lipofuscin. Neuroinflammation due to progranulin deficiency is exaggerated in the B6 strain and present, but less pronounced, in the 129 strain. Differences between the strains in hippocampal neuron counts and neuronal morphology suggest a complex role for progranulin in the hippocampus. We conclude that core progranulin-mediated neurodegenerative phenotypes are penetrant on multiple inbred mouse strains, but that genetic background modulates progranulin's role in neuroinflammation and hippocampal biology.

The absence of indoleamine 2,3-dioxygenase expression protects against NMDA receptor-mediated excitotoxicity in mouse brain.

We previously showed that the expression and activity of indoleamine 2,3-dioxygenase (Ido1) are chronically elevated in the striatum of YAC128 mouse model of HD. This was followed by increased production of neurotoxic metabolite hydroxykynurenine (3-HK) in the striatum of symptomatic mice. We therefore hypothesized that the chronic Ido1 induction in the striatum of YAC128 mice leads to increased neurotoxicity in this mouse model; based on this hypothesis, we predicted that the absence of Ido1 expression would result in decreased sensitivity to neurotoxicity in mice. The work described in this brief communication will include the characterization of Ido(-/-) striatum in terms of enzymatic expression and activity in the first step of the pathway. Additionally, we assessed the sensitivity of the striatum to excitotoxic insult in the absence of Ido1 expression in the striatum of constitutive Ido1 null mice (Ido(-/-)) and demonstrated that Ido(-/-) mice are less sensitive to QA-induced striatal neurotoxicity. Finally, through measurement of kynurenine pathway (KP) metabolites in Ido(-/-) mice, we showed decreased levels of 3-HK in the striatum of these mice. This study suggests that the inhibition of the first step in the KP may be neuroprotective and should be considered as a potential therapeutic target in HD and other neurodegenerative diseases.

Tapping linked to function and structure in premanifest and symptomatic Huntington disease.

OBJECTIVE: Motor signs are functionally disabling features of Huntington disease. Characteristic motor signs define disease manifestation. Their severity and onset are assessed by the Total Motor Score of the Unified Huntington's Disease Rating Scale, a categorical scale limited by interrater variability and insensitivity in premanifest subjects. More objective, reliable, and precise measures are needed which permit clinical trials in premanifest populations. We hypothesized that motor deficits can be objectively quantified by force-transducer-based tapping and correlate with disease burden and brain atrophy. METHODS: A total of 123 controls, 120 premanifest, and 123 early symptomatic gene carriers performed a speeded and a metronome tapping task in the multicenter study TRACK-HD. Total Motor Score, CAG repeat length, and MRIs were obtained. The premanifest group was subdivided into A and B, based on the proximity to estimated disease onset, the manifest group into stages 1 and 2, according to their Total Functional Capacity scores. Analyses were performed centrally and blinded. RESULTS: Tapping variability distinguished between all groups and subgroups in both tasks and correlated with 1) disease burden, 2) clinical motor phenotype, 3) gray and white matter atrophy, and 4) cortical thinning. Speeded tapping was more sensitive to the detection of early changes. CONCLUSION: Tapping deficits are evident throughout manifest and premanifest stages. Deficits are more pronounced in later stages and correlate with clinical scores as well as regional brain atrophy, which implies a link between structure and function. The ability to track motor phenotype progression with force-transducer-based tapping measures will be tested prospectively in the TRACK-HD study.

Magnetic resonance spectroscopy biomarkers in premanifest and early Huntington disease.

OBJECTIVES: To evaluate in vivo brain metabolite differences in control subjects, individuals with premanifest Huntington disease (pre-HD), and individuals with early HD using ¹H magnetic resonance spectroscopy (MRS) and to assess their relationship with motor performance. METHODS: Eighty-five participants (30 controls, 25 pre-HD, and 30 early HD) were recruited as part of the TRACK-HD study. Eighty-four were scanned at 3 T with single-voxel spectroscopy in the left putamen. Disease burden score was >220 among pre-HD individuals. Subjects underwent TRACK-HD motor assessment including Unified Huntington's Disease Rating Scale (UHDRS) motor scoring and a novel quantitative motor battery. Statistical analyses included linear regression and one-way analysis of variance. RESULTS: Total N-acetylaspartate (tNAA), a neuronal integrity marker, was lower in early HD (∼15%) vs controls (p < 0.001). N-acetylaspartate (NAA), a constituent of tNAA, was lower in pre-HD (∼8%) and early HD (∼17%) vs controls (p < 0.05). The glial cell marker, myo-inositol (mI), was 50% higher in early HD vs pre-HD (p < 0.01). In early HD, mI correlated with UHDRS motor score (R² = 0.23, p < 0.05). Across pre-HD and early HD, tNAA correlated with performance on a tongue pressure task (R² = 0.30, p < 0.0001) and with disease burden score (R² = 0.17, p < 0.005). CONCLUSIONS: We demonstrate lower putaminal tNAA in early HD compared to controls in a cross-section of subjects. A novel biomarker role for mI in early HD was also identified. These findings resolve disagreement in the literature about the role of MRS as an HD biomarker. We conclude that putaminal MRS measurements of NAA and mI are promising potential biomarkers of HD onset and progression.

Progranulin expression in the developing and adult murine brain.

Frontotemporal lobar degeneration (FTLD) is a neurodegenerative condition characterized by focal degeneration of the frontal and temporal lobes of the brain. Autosomal dominantly inherited mutations of the progranulin gene (GRN) have been identified as the cause of a subset of cases of familial FTLD. In order to better understand the function of progranulin in the central nervous system (CNS), we have assessed the spatiotemporal expression pattern of both the murine progranulin gene (Grn) and the protein (Grn) by using transgenic knock-in mice expressing a reporter gene from the Grn locus and by immunohistochemistry, respectively. We compared Grn expression with a panel of established markers for distinct neuronal developmental stages and specific cell lineages at time points ranging from embryonic day 13.5 through to the mature adult. We find that Grn is expressed in both neurons and microglia within the CNS, but that it shows a different developmental expression pattern in each cell type. Grn expression in neurons increases as the cells mature, whereas expression in microglia varies with the cells' state of activation, being specifically upregulated in microglia in response to excitotoxic injury. Our results suggest that progranulin plays distinct roles in neurons and microglia, both of which likely contribute to overall neuronal health and function.

Ataxia and the role of antigliadin antibodies.

BACKGROUND: Although it is acknowledged that patients with celiac disease can develop neurological complications such as ataxia, the association of antigliadin antibodies in the etiology of sporadic ataxia and the usefulness of this testing in diagnosis of ataxia is controversial. METHODS: We investigated this association by testing for the presence of IgG and IgA antigliadin antibodies in 56 ataxic patients and 59 controls. The ataxia patients were subsequently classified into three groups: sporadic, hereditary and MSA. RESULTS: Of the total ataxic patients, 6/56 (11%) were positive for either IgG or IGA antigliadin antibodies compared to the controls of which 5/59 (8%) were positive (p = 0.68). In a subgroup analysis, 4/29 (14%) of the samples in the sporadic ataxic subgroup were positive for antigliadin antibodies (IgG or IgA) compared to control (p = 0.44). Similar negative results were found in the remaining subgroup analyses. CONCLUSIONS: These results do not support an association between antigliadin antibodies and sporadic ataxias.

Als2-deficient mice exhibit disturbances in endosome trafficking associated with motor behavioral abnormalities.

ALS2 is an autosomal recessive form of spastic paraparesis (motor neuron disease) with juvenile onset and slow progression caused by loss of function of alsin, an activator of Rac1 and Rab5 small GTPases. To establish an animal model of ALS2 and derive insights into the pathogenesis of this illness, we have generated alsin-null mice. Cytosol from brains of Als2(-/-) mice shows marked diminution of Rab5-dependent endosome fusion activity. Furthermore, primary neurons from Als2(-/-) mice show a disturbance in endosomal transport of insulin-like growth factor 1 (IGF1) and BDNF receptors, whereas neuronal viability and endocytosis of transferrin and dextran seem unaltered. There is a significant decrease in the size of cortical motor neurons, and Als2(-/-) mice are mildly hypoactive. Altered trophic receptor trafficking in neurons of Als2(-/-) mice may underlie the histopathological and behavioral changes observed and the pathogenesis of ALS2.

Ethyl-EPA in Huntington disease: a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Preliminary evidence suggests beneficial effects of pure ethyl-eicosapentaenoate (ethyl-EPA) in Huntington disease (HD). METHODS: A total of 135 patients with HD were randomized to enter a multicenter, double-blind, placebo-controlled trial on the efficacy of 2 g/d ethyl-EPA vs placebo. The Unified Huntington's Disease Rating Scale (UHDRS) was used for assessment. The primary end point was outcome at 12 months on the Total Motor Score 4 subscale (TMS-4). Analysis of covariance (ANCOVA) and a chi2 test on response, defined as absence of increase in the TMS-4, were performed. RESULTS: A total of 121 patients completed 12 months, and 83 did so without protocol violations (PP cohort). Intent-to-treat (ITT) analysis revealed no significant difference between ethyl-EPA and placebo for TMS-4. In the PP cohort, ethyl-EPA proved better than placebo on the chi2 test on TMS-4 (p < 0.05), but missed significance on ANCOVA (p = 0.06). Secondary end points (ITT cohort) showed no benefit of ethyl-EPA but a significantly worse outcome in the behavioral severity and frequency compared with placebo. Exploring moderators of the efficacy of ethyl-EPA on TMS-4 showed a significant interaction between treatment and a factor defining patients with high vs low CAG repeats. Reported adverse events were distributed equally between treatment arms. CONCLUSIONS: Ethyl-eicosapentaenoate (ethyl-EPA) (purity > 95%) had no benefit in the intent-to-treat cohort of patients with Huntington disease, but exploratory analysis revealed that a significantly higher number of patients in the per protocol cohort, treated with ethyl-EPA, showed stable or improved motor function. Further studies of the potential efficacy of ethyl-EPA are warranted.

The effect of not using an internal mammary artery as a conduit for coronary artery bypass grafting.

When presented with a high risk case for coronary bypass surgery, the surgeon can confidently use an internal mammary artery as a conduit for that patient.

Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation.

We describe five female carriers of the FMR1 premutation who presented with symptoms of tremor and ataxia and who received a diagnosis of definite or probable fragile-X-associated tremor/ataxia syndrome (FXTAS). Unlike their male counterparts with FXTAS, none of the women had dementia. Females had not been reported in previous studies of FXTAS, suggesting that they may be relatively protected from this disorder. Brain tissue was available from one of the five subjects, a women who died at age 85 years; microscopic examination revealed intranuclear neuronal and astrocytic inclusions, in accord with the findings previously reported in males with FXTAS. The work-up of families with the FMR1 mutation should include questions regarding neurological symptoms in both older male and female carriers, with the expectation that females may also manifest the symptoms of FXTAS, although more subtly and less often than their male counterparts.

Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease.

Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder resulting in selective neuronal loss and dysfunction in the striatum and cortex. The molecular pathways leading to the selectivity of neuronal cell death in HD are poorly understood. Proteolytic processing of full-length mutant huntingtin (Htt) and subsequent events may play an important role in the selective neuronal cell death found in this disease. Despite the identification of Htt as a substrate for caspases, it is not known which caspase(s) cleaves Htt in vivo or whether regional expression of caspases contribute to selective neuronal cells loss. Here, we evaluate whether specific caspases are involved in cell death induced by mutant Htt and if this correlates with our recent finding that Htt is cleaved in vivo at the caspase consensus site 552. We find that caspase-2 cleaves Htt selectively at amino acid 552. Further, Htt recruits caspase-2 into an apoptosome-like complex. Binding of caspase-2 to Htt is polyglutamine repeat-length dependent, and therefore may serve as a critical initiation step in HD cell death. This hypothesis is supported by the requirement of caspase-2 for the death of mouse primary striatal cells derived from HD transgenic mice expressing full-length Htt (YAC72). Expression of catalytically inactive (dominant-negative) forms of caspase-2, caspase-7, and to some extent caspase-6, reduced the cell death of YAC72 primary striatal cells, while the catalytically inactive forms of caspase-3, -8, and -9 did not. Histological analysis of post-mortem human brain tissue and YAC72 mice revealed activation of caspases and enhanced caspase-2 immunoreactivity in medium spiny neurons of the striatum and the cortical projection neurons when compared to controls. Further, upregulation of caspase-2 correlates directly with decreased levels of brain-derived neurotrophic factor in the cortex and striatum of 3-month YAC72 transgenic mice and therefore suggests that these changes are early events in HD pathogenesis. These data support the involvement of caspase-2 in the selective neuronal cell death associated with HD in the striatum and cortex.

Alterations of myocardial dynamic stiffness implicating abnormal crossbridge function in human mitral regurgitation heart failure.

Mitral regurgitation (MR) causes ventricular dilation, a blunted myocardial force-frequency relation, and increased crossbridge force-time integral (FTI). The mechanism of FTI increase was investigated using sinusoidal length perturbation analysis to compare crossbridge function in skinned left ventricular (LV) epicardial muscle strips from 5 MR and 5 nonfailing (NF) control hearts. Myocardial dynamic stiffness was modeled as 3 parallel viscoelastic processes. Two processes characterize intermediate crossbridge cycle transitions, B (work producing) and C (work absorbing) with Q(10)s of 4 to 5. No significant differences in moduli or kinetic constants of these processes were observed between MR and NF. The third process, A, characterizes a nonenzymatic (Q(10)=0.9) work-absorbing viscoelasticity, whose modulus increases sigmoidally with [Ca(2+)]. Effects of temperature, crossbridge inhibition, or variation in [MgATP] support associating the calcium-dependent portion of A with the structural "backbone" of the myosin crossbridge. Extension of the conventional sinusoidal length perturbation analysis allowed using the A modulus to index the lifetime of the prerigor, AMADP crossbridge. This index was 75% greater in MR than in NF (P=0.02), suggesting a mechanism for the previously observed increase in crossbridge FTI. Notably, the A-process modulus was inversely correlated (r(2)=0.84, P=0.03) with in vivo LV ejection fraction in MR patients. The longer prerigor dwell time in MR may be clinically relevant not only for its potential role as a compensatory mechanism (increased economy of tension maintenance and increased resistance to ventricular dilation) but also for a potentially deleterious effect (reduced elastance and ejection fraction).

NMDA receptor function in mouse models of Huntington disease.

Huntington disease (HD) is an autosomal dominant disorder in which degeneration of medium-sized spiny striatal neurons occurs. The HD gene and the protein it encodes, huntingtin, have been identified but their functions remain unknown. Transgenic mouse models for HD have been developed and we examined responses of medium-sized striatal neurons recorded in vitro to application of N-methyl-D-aspartate (NMDA) in two of these. The first model (R6/2) expresses exon 1 of the human HD gene with approximately 150 CAG repeats. In the R6/2 an enhancement of currents induced by selective activation of NMDA receptors as well as an enhancement of intracellular Ca(2+) flux occurred in both presymptomatic and symptomatic mice. These alterations appeared specific for the NMDA receptor because alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-mediated currents were reduced in symptomatic R6/2s. In R6/2 animals there were parallel increases in NMDA-R1 and decreases in NMDA-R2A/B subunit proteins as established by immunohistochemistry. The second model (YAC72) contains human genomic DNA spanning the full-length gene and all its regulatory elements with 72 CAG repeats. The phenotypical expression of the disorder develops more gradually than in the R6/2. In YAC72 mice we found similar but less marked increases in responses of medium-sized striatal neurons to NMDA. These findings indicate that alterations in NMDA receptor function may predispose striatal neurons to excitotoxic damage, leading to subsequent neuronal degeneration and underscore the functional importance of NMDA receptors in HD.

Metastatic serous borderline ovarian tumor in an internal mammary lymph node: a case report and review of the literature.

Background. Reports of supradiaphragmatic involvement of lymph nodes by serous borderline ovarian tumors are rare. Case. We describe the finding of metastatic tumor involving an internal mammary lymph node in a 74-year-old patient with serous borderline ovarian tumor. The positive lymph node was found incidentally during cardiac surgery 7 years after excision of the patient's serous borderline ovarian tumor. The incidence and significance of pelvic, paraaortic, and supradiaphragmatic lymph node involvement among women with borderline ovarian tumors is discussed. Conclusion. Supradiaphragmatic lymph node involvement can occur among women with serous borderline ovarian tumors. Borderline ovarian tumors should be included in the differential diagnosis of metastatic adenocarcinoma involving the supradiaphragmatic lymph nodes.