Movement Disorder Society Task Force Viewpoint: Huntington's Disease Diagnostic Categories

Ross, Christopher A.; Reilmann, Ralf; Cardoso, Francisco; McCusker, Elizabeth; Testa, Claudia; Stout, Julie C.; Leavitt, Blair R.; Pei, Zhong; Landwehrmeyer, Bernhard; Martínez, Asunción; Levey, Jamie; Srajer, Teresa; Bang, Jee; Tabrizi, Sarah J.

doi:10.1002/mdc3.12808

Cited by 79 publications

(94 citation statements)

References 41 publications

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“…19 Individuals with a UHDRS-TMS score ≥ 5, a diagnostic confidence level (DCL) score of 2 and cognitive impairments (as indicated by a composite score comprising: Hopkins Verbal Learning Test, Symbol Digit Modalities Test, Trail Making Test Part A and B, Cambridge One Touch Stockings) were classified as pro-HD and individuals with a UHDRS-TMS score < 5, a DCL score between 0 and 2 and no validated clinical signs were classified as pre-HD. 20 Individuals with pre-HD and pro-HD were excluded from the study if they had recent or ongoing substance abuse or concomitant musculoskeletal, cardiovascular, or sleep disorders. Inclusion and exclusion criteria for healthy age-and gender-matched controls were as follows: no family history of HD, no recent or ongoing substance abuse and no known neurological, musculoskeletal, cardiovascular, or sleep disorders.…”

Section: Participantsmentioning

confidence: 99%

Dual tasking impairments are associated with striatal pathology in Huntington’s disease

Reyes

Pulverenti

et al. 2020

Ann Clin Transl Neurol

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Background Recent findings suggest that individuals with Huntington’s disease (HD) have an impaired capacity to execute cognitive and motor tasks simultaneously, or dual task, which gradually worsens as the disease advances. The onset and neuropathological changes mediating impairments in dual tasking in individuals with HD are unclear. The reliability of dual tasking assessments for individuals with HD is also unclear. Objectives To evaluate differences in dual tasking performance between individuals with HD (presymptomatic and prodromal) and matched controls, to investigate associations between striatal volume and dual tasking performance, and to determine the reliability of dual tasking assessments. Methods Twenty individuals with HD (10 presymptomatic and 10 prodromal) and 20 healthy controls were recruited for the study. Individuals undertook four single and dual task assessments, comprising motor (postural stability or force steadiness) and cognitive (simple or complex mental arithmetic) components, with single and dual tasks performed three times each. Participants also undertook a magnetic resonance imaging assessment. Results Compared to healthy controls, individuals with presymptomatic and prodromal HD displayed significant deficits in dual tasking, particularly cognitive task performance when concurrently undertaking motor tasks (P < 0.05). The observed deficits in dual tasking were associated with reduced volume in caudate and putamen structures (P < 0.05),however, not with clinical measures of disease burden. An analysis of the reliability of dual tasking assessments revealed moderate to high test–retest reliability [ICC: 0.61‐0.99] for individuals with presymptomatic and prodromal HD and healthy controls. Conclusions Individuals with presymptomatic and prodromal HD have significant deficits in dual tasking that are associated with striatal degeneration. Findings also indicate that dual tasking assessments are reliable in individuals presymptomatic and prodromal HD and healthy controls.

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Section: Participantsmentioning

confidence: 99%

Dual tasking impairments are associated with striatal pathology in Huntington’s disease

Reyes

Pulverenti

et al. 2020

Ann Clin Transl Neurol

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“…Individuals in the mild–moderate HD group (n = 46) were diagnosed with definite HD on the basis of unequivocal motor signs on the UHDRS (DCL = 4), a positive family history of HD, and a CAG repeat length greater than 39. As described by Ross and colleagues 2 and as determined by a senior staff neurologist, individuals in the pre‐HD group (n = 33) had a positive family history of HD and DCL of 0 to 2. Individuals in the pro‐HD group (n = 23) had a positive family history of HD and DCL of ≥ 2 with consideration of cognitive change.…”

Section: Methodsmentioning

confidence: 96%

“…9 Several studies have suggested that measures of executive function and processing speed-such as the Symbol Digits Modality Test (SDMT), Trail Making Test Part B, and Stroop-are particularly sensitive to early impairment in HD gene carriers. 2,9,10 Using a factor analysis, Harrington and colleagues 11 found that motor planning/speed and sensoryperceptual processing were the strongest indicators of time to diagnosis, even after controlling for CAG age product and Unified Huntington's Disease Rating Scale (UHDRS) motor scores. They argued that tests representative of these 2 domains should be used in clinical trials as they may have prognostic value.…”

mentioning

confidence: 99%

“…Although the presence of the mutation can be determined using genetic testing, a diagnosis of manifest HD is made based on the existence of clinical motor symptoms (ie, chorea). In view of the potentially prolonged nature of the premanifest stage, Ross and colleagues 2 proposed that premanifest HD be composed of the following 2 stages: presymptomatic HD (pre‐HD; furthest from HD diagnosis) and prodromal HD (pro‐HD; closest to HD diagnosis). By the time individuals are diagnosed with manifest HD, many will demonstrate measurable cognitive impairment on standardized neuropsychological assessments 3–8 .…”

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confidence: 99%

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Central Cognitive Processing Speed Is an Early Marker of Huntington's Disease Onset

Corey–Bloom

Williams

Beltran‐Najera

et al. 2020

Movement Disord Clin Pract

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Background Background: Several studies have suggested that cognitive processing speed may be useful for assessing early cognitive change in premanifest Huntington's disease (HD); however, current measures lack the ability to control for the effects of motor dysfunction commonly found in HD. The Computerized Test of Information Processing (CTiP) is a rapidly administered computerized tool that allows for the examination of central cognitive processing speed by using motor-corrected scores to account for motor dysfunction. Objective Objective: To examine central cognitive processing speed as an early marker of HD onset using the CTiP. Methods Methods: The CTiP and other measures were administered to 102 HD gene carriers and 55 healthy adults (HA). Gene carriers included presymptomatic HD (pre-HD; n = 33), prodromal HD (pro-HD; ie, individuals close to disease onset; n = 23), and mild-moderate HD (HD; n = 46). Results Results: The HD group performed significantly slower than all other groups (HA, pre-HD, and pro-HD) on most subtests (Ps < .05). Moreover, the pro-HD group performed significantly slower than the HA group on both motor-corrected subtests (Ps < 0.05). Effect sizes associated with significant group differences between the pro-HD and HA groups on motor-corrected CTiP subtests (d = 0.73 and 0.84) were similar to effect sizes associated with group differences on the Symbol Digit Modalities Test (d = .82) and other traditional cognitive assessments (Montreal Cognitive Assessment, d = .75; Mini-Mental State Examination, d = .84). Conclusions Conclusions: The CTiP may be a useful marker of deficits in central cognitive processing speed in individuals close to manifest onset of HD.

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“…Anatomical images covering the entire brain were acquired using a multi-slice Rapid Acquisition using Relaxation Enhancement (RARE) sequence: resolution=0.10× 0.10 × 0.50 mm 3 , echo time (TE)/repetition time (TR)=30/3000 ms, and RARE factor = 8. A multi-slice iVASO sequence optimized for typical blood flow and vascular transit times in mice and relaxation times at 11.7T was performed for CBVa mapping: TR/inversion time (TI) = 1924/800, 1636/700, 1365/600, 1109/500, 867/400, 750/350, 636/300, 525/250, 415/200 ms, TE = 4.6 ms, resolution=0.15×0.15×0.80 mm 3 , and RARE factor=16. All mice were anesthetized with an induction of 2% isoflurane in medical air, and then 1.0-1.5% isoflurane during the MRI scan.…”

Section: Mri Acquisitionmentioning

confidence: 99%

HTTsilencing delays onset and slows progression of Huntington’s disease like phenotype: Monitoring with a novel neurovascular biomarker

Liu

Zhang

et al. 2020

Preprint

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Huntington’s disease (HD) is a dominantly inherited, fatal neurodegenerative disorder caused by a CAG expansion in the Huntingtin (HTT) gene, coding for pathologic mutant HTT protein (mHTT). Because of its gain-of-function mechanism and monogenic etiology, strategies to lower HTT are being actively investigated as disease-modifying therapies. Most approaches are currently targeted at the manifest HD stage, when clinical outcomes are used to evaluate the effectiveness of therapy. However, as almost 50% of striatal volume has been lost at the time of onset of manifest HD it would be preferable to begin therapy in the premanifest period. An unmet challenge is how to evaluate therapeutic efficacy before the presence of clinical symptoms as outcome measures. To address this, we have been developing more sensitive biomarkers such as functional neuroimaging with the goal of identifying noninvasive biomarkers that provide insight into the best time to introduce HTT-lowering treatment. In this study, we mapped the temporal trajectories of arteriolar cerebral blood volumes (CBVa) using inflow-based vascular-space-occupancy (iVASO) MRI technique in an HD mouse model. Significantly elevated CBVa was evident in premanifest zQ175 HD mice prior to motor deficits and striatal atrophy, recapitulating altered CBVa in human premanifest HD. CRISPR/Cas9-mediated non-allele-specific HTT silencing in striatal neurons restored altered CBVa in premanifest zQ175 mice, delayed onset of striatal atrophy, and slowed the progression of motor phenotype and brain pathology. This study showed the potential of CBVa as a noninvasive fMRI biomarker for premanifest HD clinical trials and demonstrates long-term benefits of introducing an HTT lowering treatment in the premanifest HD.

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Movement Disorder Society Task Force Viewpoint: Huntington's Disease Diagnostic Categories

Cited by 79 publications

References 41 publications

Dual tasking impairments are associated with striatal pathology in Huntington’s disease

Dual tasking impairments are associated with striatal pathology in Huntington’s disease

Central Cognitive Processing Speed Is an Early Marker of Huntington's Disease Onset

HTTsilencing delays onset and slows progression of Huntington’s disease like phenotype: Monitoring with a novel neurovascular biomarker

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