Journal of Huntington's Disease - Volume 6, issue 4

Authors: Dubinsky, Janet M.

Article Type: Review Article

Abstract: This review systematically examines the evidence for shifts in flux through energy generating biochemical pathways in Huntington’s disease (HD) brains from humans and model systems. Compromise of the electron transport chain (ETC) appears not to be the primary or earliest metabolic change in HD pathogenesis. Rather, compromise of glucose uptake facilitates glucose flux through glycolysis and may possibly decrease flux through the pentose phosphate pathway (PPP), limiting subsequent NADPH and GSH production needed for antioxidant protection. As a result, oxidative damage to key glycolytic and tricarboxylic acid (TCA) cycle enzymes further restricts energy production so that while basal needs may …be met through oxidative phosphorylation, those of excessive stimulation cannot. Energy production may also be compromised by deficits in mitochondrial biogenesis, dynamics or trafficking. Restrictions on energy production may be compensated for by glutamate oxidation and/or stimulation of fatty acid oxidation. Transcriptional dysregulation generated by mutant huntingtin also contributes to energetic disruption at specific enzymatic steps. Many of the alterations in metabolic substrates and enzymes may derive from normal regulatory feedback mechanisms and appear oscillatory. Fine temporal sequencing of the shifts in metabolic flux and transcriptional and expression changes associated with mutant huntingtin expression remain largely unexplored and may be model dependent. Differences in disease progression among HD model systems at the time of experimentation and their varying states of metabolic compensation may explain conflicting reports in the literature. Progressive shifts in metabolic flux represent homeostatic compensatory mechanisms that maintain the model organism through presymptomatic and symptomatic stages. Show more

Keywords: Huntington’s Disease, homeostasis, intermediate metabolism, flux analysis, mitochondrial dysfunction

DOI: 10.3233/JHD-170264

Citation: Journal of Huntington's Disease, vol. 6, no. 4, pp. 267-302, 2017

Authors: Simmons, Danielle A.

Article Type: Review Article

Abstract: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansions in the IT15 gene which encodes the huntingtin (HTT) protein. Currently, no treatments capable of preventing or slowing disease progression exist. Disease modifying therapeutics for HD would be expected to target a comprehensive set of degenerative processes given the diverse mechanisms contributing to HD pathogenesis including neuroinflammation, excitotoxicity, and transcription dysregulation. A major contributor to HD-related degeneration is mutant HTT-induced loss of neurotrophic support. Thus, neurotrophin (NT) receptors have emerged as therapeutic targets in HD. The considerable overlap between NT signaling networks and those dysregulated by …mutant HTT provides strong theoretical support for this approach. This review will focus on the contributions of disrupted NT signaling in HD-related neurodegeneration and how targeting NT receptors to augment pro-survival signaling and/or to inhibit degenerative signaling may combat HD pathologies. Therapeutic strategies involving NT delivery, peptidomimetics, and the targeting of specific NT receptors (e.g., Trks or p75NTR ), particularly with small molecule ligands, are discussed. Show more

Keywords: BDNF, neurotrophin, p75NTR, small molecule

DOI: 10.3233/JHD-170275

Citation: Journal of Huntington's Disease, vol. 6, no. 4, pp. 303-325, 2017

Authors: Kringlen, Gabe | Kinsley, Lisa | Aufox, Sharon | Rouleau, Gerald | Bega, Danny

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder. In most cases the disease is inherited from a parent, although a considerable number of affected persons have no reported family history of the disease. While CAG repeat length is negatively correlated with age of symptom onset, variability exists suggesting that other variables may influence symptom onset. Objectives: The objective of this study is to determine whether awareness of a family history of HD has an impact on symptom onset and disease manifestations. Methods: Data were obtained from Enroll-HD to compare subjects with a family history …of HD to subjects without on various key clinical outcomes. In addition, multiple regressions were performed to investigate the impact of family history on the age at onset of depression and motor symptoms. Results: 4,285 mutation positive subjects were included in the analysis, of which 4.81% had a negative family history. Controlling for CAG repeat length, a positive family history predicted an onset of depression 11.438 years earlier and an onset of motor symptoms 6.681 years earlier when compared to having a negative family history. Subjects with a positive family history were more likely to report behavioral manifestations as the initial major symptom of HD (38.6% vs. 29.6%, p  = 0.023), and were more likely to report previous suicidal ideation/attempts (26.2% vs. 20.3%, p  = 0.046). Conclusions: A positive family history of HD appears to be associated with an earlier onset of depression and overall disease manifestations. Implications regarding the role of genetic versus environmental contributions to symptom onset in HD are discussed. Show more

Keywords: Age at onset, depression, family history, Huntington’s disease, motor symptoms

DOI: 10.3233/JHD-170256

Citation: Journal of Huntington's Disease, vol. 6, no. 4, pp. 327-335, 2017

Authors: Latimer, Caitlin S. | Flanagan, Margaret E. | Cimino, Patrick J. | Jayadev, Suman | Davis, Marie | Hoffer, Zachary S. | Montine, Thomas J. | Gonzalez-Cuyar, Luis F. | Bird, Thomas D. | Keene, C. Dirk

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by a trinucleotide (CAG) repeat expansion in huntingtin (HTT ) on chromosome 4. Anticipation can cause longer repeat expansions in children of HD patients. Juvenile Huntington’s disease (JHD), defined as HD arising before age 20, accounts for 5–10% of HD cases, with cases arising in the first decade accounting for approximately 1%. Clinically, JHD differs from the predominately choreiform adult onset Huntington’s disease (AOHD) with variable presentations, including symptoms such as myoclonus, seizures, Parkinsonism, and cognitive decline. Objective: The neuropathologic changes of AOHD are well characterized, …but there are fewer reports that describe the neuropathology of JHD. Here we report a case of a six-year-old boy with paternally-inherited JHD caused by 169 CAG trinucleotide repeats who presented at age four with developmental delay, dysarthria, and seizures before dying at age 6. The boy’s clinical presentation and neuropathological findings are directly compared to those of his father, who presented with AOHD and 54 repeats. Methods: A full autopsy was performed for the JHD case and a brain-only autopsy was performed for the AOHD case. Histochemically- and immunohistochemically-stained slides were prepared from formalin-fixed, paraffin-embedded tissue sections. Results: Both cases had neuropathology corresponding to Vonsattel grade 3. The boy also had cerebellar atrophy with huntingtin-positive inclusions in the cerebellum, findings not present in the father. Conclusions: Autopsies of father and son provide a unique opportunity to compare and contrast the neuropathologic findings of juvenile and adult onset HD while also providing the first immunohistochemical evidence of cerebellar involvement in JHD. Additionally this is the first known report to include findings from peripheral tissue in a case of JHD. Show more

Keywords: Autopsy, huntingtin protein, Huntington’s disease, immunohistochemistry, juvenile Huntington’s disease, literature review, neuropathology

DOI: 10.3233/JHD-170261

Citation: Journal of Huntington's Disease, vol. 6, no. 4, pp. 337-348, 2017

Authors: Fodale, Valentina | Boggio, Roberto | Daldin, Manuel | Cariulo, Cristina | Spiezia, Maria Carolina | Byrne, Lauren M. | Leavitt, Blair R. | Wild, Edward J. | Macdonald, Douglas | Weiss, Andreas | Bresciani, Alberto

Article Type: Research Article

Abstract: Background: The measurement of disease-relevant biomarkers has become a major component of clinical trial design, but in the absence of rigorous clinical and analytical validation of detection methodology, interpretation of results may be misleading. In Huntington’s disease (HD), measurement of the concentration of mutant huntingtin protein (mHTT) in cerebrospinal fluid (CSF) of patients may serve as both a disease progression biomarker and a pharmacodynamic readout for HTT-lowering therapeutic approaches. We recently published the quantification of mHTT levels in HD patient CSF by a novel ultrasensitive immunoassay-based technology and here analytically validate it for use. Objective: This work aims …to analytically and clinically validate our ultrasensitive assay for mHTT measurement in human HD CSF, for application as a pharmacodynamic biomarker of CNS mHTT lowering in clinical trials. Methods: The single molecule counting (SMC) assay is an ultrasensitive bead-based immunoassay where upon specific recognition, dye-labeled antibodies are excited by a confocal laser and emit fluorescent light as a readout. The detection of mHTT by this technology was clinically validated following established Food and Drug Administration and European Medicine Agency guidelines. Results: The SMC assay was demonstrated to be accurate, precise, specific, and reproducible. While no matrix influence was detected, a list of interfering substances was compiled as a guideline for proper collection and storage of patient CSF samples. In addition, a set of recommendations on result interpretation is provided. Conclusions: This SMC assay is a robust and ultrasensitive method for the relative quantification of mHTT in human CSF. Show more

Keywords: Assay validation, biomarker, cerebrospinal fluid, huntingtin protein, Huntington’s disease, immunoassay, mutant huntingtin, polyglutamine, ultrasensitive assay

DOI: 10.3233/JHD-170269

Citation: Journal of Huntington's Disease, vol. 6, no. 4, pp. 349-361, 2017

Authors: Kloos, Anne D. | Kegelmeyer, Deb A. | Fritz, Nora E. | Daley, Allison M. | Young, Gregory S. | Kostyk, Sandra K.

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is a progressive neurodegenerative disorder that results in a gradual decline in mobility and balance. Increasing evidence has documented an important role of executive function in the safe ambulation of the elderly and people with a variety of neurological disorders. Little is known about the contribution of cognitive deficits to decline in mobility over time in HD. Objective: This study examined the relationships of mobility, motor and cognitive function measures at baseline, and of mobility and cognitive measures over four years. Methods: A retrospective chart review was performed on 70 patients with …genetically confirmed HD (age 20–75 years old) across 121 HD clinic visits. Correlations between Unified Huntington’s Disease Rating Scale – Total Motor, Tinetti Mobility Test (TMT), and cognitive measures (Letter Verbal Fluency, Symbol Digit Modalities Test (SDMT), and Stroop Test) were analyzed. Longitudinal relationships between TMT and cognitive measures were examined using mixed effect regression models. Results: Gait and balance measures representing domains of mobility (TMT scores) were significantly correlated with each of the cognitive measures with the exception of the Verbal Fluency score. Mixed effects regression modeling showed that the Stroop Interference sub-test and SDMT were significant predictors (p -values <0.01) of TMT total scores. Conclusions: Impairments in executive function measures correlate highly with measures of gait, balance and mobility in individuals with HD. Interventions designed to improve mobility and decrease fall risk should also address issues of cognitive impairments with particular consideration given to interventions that may focus on motor-cognitive dual task training. Show more

Keywords: Tinetti mobility test, cognition, stroop, symbol digit modalities test, motor function, Huntington’s disease

DOI: 10.3233/JHD-170279

Citation: Journal of Huntington's Disease, vol. 6, no. 4, pp. 363-370, 2017

Authors: Banno, Haruhiko | Andrzejewski, Kelly L. | McDermott, Michael P. | Murphy, Alyssa | Majumder, Madhurima | de Blieck, Elisabeth A. | Auinger, Peggy | Cudkowicz, Merit E. | Atassi, Nazem

Article Type: Correction

DOI: 10.3233/JHD-179002

Citation: Journal of Huntington's Disease, vol. 6, no. 4, pp. 371-371, 2017

Article Type: Meeting Report

DOI: 10.3233/JHD-179005

Citation: Journal of Huntington's Disease, vol. 6, no. 4, pp. 373-373, 2017