The Vitamin D Metabolite Ratio (VMR) is a Biomarker of Vitamin D Status That is Not Affected by Acute Changes in Vitamin D Binding Protein.

BACKGROUND: 25-hydroxyvitamin D[25(OH)D] may be a poor marker of vitamin D status due to variability in levels of vitamin D binding protein (VDBP). The vitamin D metabolite ratio (VMR) is the ratio of 24,25-dihydroxyvitamin D[24,25(OH)2D3] to 25(OH)D3 and has been postulated to reflect vitamin D sufficiency independent of variability in VDBP. Therapeutic plasma exchange (TPE) is a procedure that removes plasma, including VDBP, and may lower bound vitamin D metabolite concentrations. Effects of TPE on the VMR are unknown. METHODS: We measured 25(OH)D, free 25(OH)D, 1,25-dihydroxyvitamin D[1,25(OH)2D], 24,25(OH)2D3, and VDBP in persons undergoing TPE, before and after treatment. We used paired t-tests to assess changes in these biomarkers during a TPE procedure. RESULTS: Study participants (n = 45) had a mean age of 55 ± 16 years; 67% were female; and 76% were white. Compared to pretreatment concentrations, TPE caused a significant decrease in total VDBP by 65% (95%CI 60,70%), as well as all the vitamin D metabolites-25(OH)D by 66% (60%,74%), free 25(OH)D by 31% (24%,39%), 24,25(OH)2D3 by 66% (55%,78%) and 1,25(OH)2D by 68% (60%,76%). In contrast, there was no significant change in the VMR before and after a single TPE treatment, with an observed mean 7% (-3%, 17%) change in VMR. CONCLUSIONS: Changes in VDBP concentration across TPE parallel changes in 25(OH)D, 1,25(OH)2D, and 24,25(OH)2D3, suggesting that concentrations of these metabolites reflect underlying VDBP concentrations. The VMR is stable across a TPE session despite a 65% reduction in VDBP. These findings suggest that the VMR is a marker of vitamin D status independent of VDBP levels.

Myelin water imaging using a short-TR adiabatic inversion-recovery (STAIR) sequence.

PURPOSE: To develop a new myelin water imaging (MWI) technique using a short-TR adiabatic inversion-recovery (STAIR) sequence on a clinical 3T MR scanner. METHODS: Myelin water (MW) in the brain has both a much shorter T1 and a much shorter T2 * than intracellular/extracellular water. A STAIR sequence with a short TR was designed to efficiently suppress long T1 signals from intracellular/extracellular water, and therefore allow selective imaging of MW, which has a much shorter T1 . Numerical simulation and phantom studies were performed to investigate the effectiveness of long T1 signal suppression. TheT2 * in white matter (WM) was measured with STAIR and compared with T2 * measured with a conventional gradient recall echo in in vivo study. Four healthy volunteers and 4 patients with multiple sclerosis were recruited for qualitative and quantitative MWI. Apparent MW fraction was generated to compare MW in normal WM in volunteers to MW in lesions in patients with multiple sclerosis. RESULTS: Both simulation and phantom studies showed that when TR was sufficiently short (eg, 250 ms), the STAIR sequence effectively suppressed long T1 signals from tissues with a broad range of T1 s using a single TR/TI combination. The volunteer study showed a short T2 * of 9.5 ± 1.7 ms in WM, which is similar to reported values for MW. Lesions in patients with multiple sclerosis showed a significantly lower apparent MW fraction (4.5% ± 1.0%) compared with that of normal WM (9.2% ± 1.5%) in healthy volunteers (p < 0.05). CONCLUSIONS: The STAIR sequence provides selective MWI in brain and can quantify reductions in MW content in patients with multiple sclerosis.

The Repeatable Battery for the Assessment of Neuropsychological Status, While Useful for Measuring Cognitive Changes in Manifest Huntington Disease, May Show Limited Utility in Premanifest Disease.

BACKGROUND: The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is a brief, standardized neuropsychological test that assesses several areas of cognitive function. Recent studies, although sparse, have examined the use of the RBANS to detect cognitive deficits in individuals with manifest Huntington disease (HD); however, no studies have investigated its utility to detect cognitive deficits in individuals with premanifest HD (PreHD), where cognitive symptoms are thought to be more subtle. OBJECTIVE: To assess cognitive deficits in individuals with HD, particularly in individuals with PreHD, using an easily administered, brief but comprehensive, neuropsychological test. METHOD: We administered the RBANS to 31 individuals with HD, 29 individuals with PreHD, and 22 healthy controls (HC) at an academic HD clinical research center and collected RBANS Total, Index, and subtest scores for group comparisons. RESULTS: The HD group had significantly lower RBANS Total, Index, and subtest scores than the HC. The PreHD group had significantly lower RBANS Total scores and Coding subtest scores than the HC, but no other significant group differences were identified. CONCLUSION: Our results substantiate previous findings of significant impairment on the RBANS in individuals with HD. In addition, we are the first to demonstrate that, although the RBANS can identify deficits in psychomotor speed and information processing in individuals with PreHD, it does not appear to have the ability to detect impairment in any additional cognitive domains in individuals with PreHD.

Whole-Brain Myelin Imaging Using 3D Double-Echo Sliding Inversion Recovery Ultrashort Echo Time (DESIRE UTE) MRI.

Background Signal contamination from long T2 water is a major challenge in direct imaging of myelin with MRI. Nulling of the unwanted long T2 signals can be achieved with an inversion recovery (IR) preparation pulse to null long T2 white matter within the brain. The remaining ultrashort T2 signal from myelin can be detected with an ultrashort echo time (UTE) sequence. Purpose To develop patient-specific whole-brain myelin imaging with a three-dimensional double-echo sliding inversion recovery (DESIRE) UTE sequence. Materials and Methods The DESIRE UTE sequence generates a series of IR images with different inversion times during a single scan. The optimal inversion time for nulling long T2 signal is determined by finding minimal signal on the second echo. Myelin images are generated by subtracting the second echo image from the first UTE image. To validate this method, a prospective study was performed in phantoms, cadaveric brain specimens, healthy volunteers, and patients with multiple sclerosis (MS). A total of 20 healthy volunteers (mean age, 40 years ± 13 [standard deviation], 10 women) and 20 patients with MS (mean age, 58 years ± 8; 15 women) who underwent MRI between November 2017 and February 2019 were prospectively included. Analysis of variance was performed to evaluate the signal difference between MS lesions and normal-appearing white matter in patients with MS. Results High signal intensity and corresponding T2* and T1 of the extracted myelin vesicles provided evidence for direct imaging of ultrashort-T2 myelin protons using the UTE sequence. Gadobenate dimeglumine phantoms with a wide range of T1 values were selectively suppressed with DESIRE UTE. In the ex vivo brain study of MS lesions, signal loss was observed in MS lesions and was conformed with histologic analysis. In the human study, there was a significant reduction in normalized signal intensity in MS lesions compared with that in normal-appearing white matter (0.19 ± 0.10 vs 0.76 ± 0.11, respectively; P < .001). Conclusion The double-echo sliding inversion recovery ultrashort echo time sequence can generate whole-brain myelin images specifically with a clinical 3-T scanner. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Port in this issue.

Myelin Imaging in Human Brain Using a Short Repetition Time Adiabatic Inversion Recovery Prepared Ultrashort Echo Time (STAIR-UTE) MRI Sequence in Multiple Sclerosis.

Background Water signal contamination is a major challenge for direct ultrashort echo time (UTE) imaging of myelin in vivo because water contributes most of the signals detected in white matter. Purpose To validate a new short repetition time (TR) adiabatic inversion recovery (STAIR) prepared UTE (STAIR-UTE) sequence designed to suppress water signals and to allow imaging of ultrashort T2 protons of myelin in white matter using a clinical 3-T scanner. Materials and Methods In this prospective study, an optimization framework was used to obtain the optimal inversion time for nulling water signals using STAIR-UTE imaging at different TRs. Numeric simulation and phantom studies were performed. Healthy volunteers and participants with multiple sclerosis (MS) underwent MRI between November 2018 and October 2019 to compare STAIR-UTE and a clinical T2-weighted fluid-attenuated inversion recovery sequence for assessment of MS lesions. UTE measures of myelin were also performed to allow comparison of signals in lesions and with those in normal-appearing white matter (NAWM) in patients with MS and in normal white matter (NWM) in healthy volunteers. Results Simulation and phantom studies both suggest that the proposed STAIR-UTE technique can effectively suppress long T2 tissues with a broad range of T1s. Ten healthy volunteers (mean age, 33 years ± 8 [standard deviation]; six women) and 10 patients with MS (mean age, 51 years ± 16; seven women) were evaluated. The three-dimensional STAIR-UTE sequence effectively suppressed water components in white matter and selectively imaged myelin, which had a measured T2* value of 0.21 msec ± 0.04 in the volunteer study. A much lower mean UTE measure of myelin proton density was found in MS lesions (3.8 mol/L ± 1.5), and a slightly lower mean UTE measure was found in NAWM (7.2 mol/L ± 0.8) compared with that in NWM (8.0 mol/L ± 0.8) in the healthy volunteers (P < .001 for both comparisons). Conclusion The short repetition time adiabatic inversion recovery-prepared ultrashort echo time sequence provided efficient water signal suppression for volumetric imaging of myelin in the brain and showed excellent myelin signal contrast as well as marked ultrashort echo time signal reduction in multiple sclerosis lesions and a smaller reduction in normal-appearing white matter compared with normal white matter in volunteers. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Messina and Port in this issue.

Inversion recovery UTE based volumetric myelin imaging in human brain using interleaved hybrid encoding.

PURPOSE: Direct myelin imaging can improve the characterization of myelin-related diseases such as multiple sclerosis. In this study, we explore a novel method to directly image myelin using inversion recovery-prepared hybrid encoding (IR-HE) UTE MRI. METHODS: The IR-HE sequence uses an adiabatic inversion pulse to suppress the long T2 white matter signal, followed by 3D dual-echo HE utilizing both single point imaging and radial frequency encoding, for which the subtraction image between 2 echoes reveals the myelin signal with high contrast. To reduce scan time, it is common to obtain multiple spokes per IR. Here, we invented a novel method to improve the HE, adapted for the multi-spoke IR imaging-termed interleaved HE-for which single point imaging encoding is interleaved between radial frequency encodings near nulling point to allow more efficient IR-signal suppression. To evaluate the proposed approach, a computer simulation, myelin phantom experiment, an ex vivo experiment with a cadaveric multiple sclerosis brain, and an in vivo experiment with 8 healthy volunteers and 13 multiple sclerosis patients were performed. RESULTS: The computer simulation showed that IR-interleaved HE allows for improved contrast of myelin signal with reduced imaging artifacts. The myelin phantom experiment showed IR-interleaved HE allows direct imaging of myelin lipid with excellent suppression of water signal. In the ex vivo and in vivo experiments, the proposed method demonstrated highly specific imaging of myelin in white matter of the brain. CONCLUSION: IR-interleaved HE allows for time-efficient, high-contrast direct myelin imaging and can detect demyelinated lesions in multiple sclerosis patients.

Improved volumetric myelin imaging in human brain using 3D dual echo inversion recovery-prepared UTE with complex echo subtraction.

PURPOSE: Inversion recovery-based UTE (IR-UTE) sequences have been proposed to directly image myelin with extremely short T2∗ (~0.3 ms). In this study, we demonstrate the feasibility of complex echo subtraction to improve 3D IR-UTE imaging of myelin in white matter of the brain in vivo. METHODS: In IR-UTE imaging, long T2 components in white matter (i.e., water) are suppressed using an adiabatic inversion recovery preparation pulse. Dual echo UTE data acquisition and magnitude echo subtraction are used to suppress the residual white matter and gray matter signals, providing high myelin contrast. Complex echo subtraction may further improve the myelin contrast by reducing the residual long T2 water signal contamination caused by regional T1 variations. To verify the efficacy of the complex subtraction technique, in vivo experiments were performed with 5 non-symptomatic healthy volunteers and 5 multiple sclerosis patients on a 3T clinical MR system. Signal enhancement between the complex subtraction and the magnitude subtraction was introduced to evaluate the improvement. RESULTS: The complex subtraction improved myelin contrast over the magnitude subtraction in both healthy and patient groups, with more fine myelin structures being revealed. The foci of the demyelinated lesion were more clearly detected by complex subtraction. An average signal enhancement of up to 135.9% was achieved with the complex subtraction over the magnitude subtraction. CONCLUSION: The complex echo subtraction improves 3D IR-UTE morphologic imaging of myelin in white matter of the brain.

Volumetric imaging of myelin in vivo using 3D inversion recovery-prepared ultrashort echo time cones magnetic resonance imaging.

Direct myelin imaging is promising for characterization of multiple sclerosis (MS) brains at diagnosis and in response to therapy. In this study, a 3D inversion recovery-prepared ultrashort echo time cones (IR-UTE-Cones) sequence was used for both morphological and quantitative imaging of myelin on a clinical 3 T scanner. Myelin powder phantoms with different myelin concentrations were imaged with the 3D UTE-Cones sequence and it showed a strong correlation between concentrations and UTE-Cones signals, demonstrating the ability of the UTE-Cones sequence to directly image myelin in the brain. Quantitative myelin imaging with multi-echo IR-UTE-Cones sequences show similar T2 * values for a D2 O-exchanged myelin phantom (T2 * = 0.33 ± 0.04 ms), ex vivo brain specimens (T2 * = 0.20 ± 0.04 ms) and in vivo healthy volunteers (T2 * = 0.254 ± 0.023 ms), further confirming the feasibility of 3D IR-UTE-Cones sequences for direct myelin imaging in vivo. In ex vivo MS brain study, signal loss is observed in MS lesions, which was confirmed with histology. For the in vivo study, the lesions in MS patients also show myelin signal loss using the proposed direct myelin imaging method, demonstrating the clinical potential for MS diagnosis. Furthermore, the measured IR-UTE-Cones signal intensities show a significant difference between normal-appearing white matter in MS patients and normal white matter in volunteers, which cannot be found in clinical used T2 -FLAIR sequences. Thus, the proposed 3D IR-UTE-Cones sequence showed clinical potential for MS diagnosis with the capability of direct myelin detection of the whole brain.

Identification of Subtle Verbal Memory Deficits in Premanifest Huntington Disease Using the California Verbal Learning Test.

BACKGROUND: Verbal memory impairment in individuals with Huntington disease (HD) is well-documented; however, the nature and extent of verbal memory impairment in individuals with premanifest HD (pre-HD) are less understood. OBJECTIVE: To evaluate verbal memory function in individuals with pre-HD by comparing their performance on the California Verbal Learning Test to that of individuals with a clinical diagnosis of HD and that of a demographically similar group of adults with no family history of, or genetic risk for, HD, thereby reducing possible complications of psychiatric difficulties commonly experienced by individuals who are at risk for HD but are gene negative. METHODS: Participant groups included 77 adults with a diagnosis of HD, 23 premanifest gene carriers for HD (pre-HD), and 54 demographically similar, healthy adults. The California Verbal Learning Test-Second Edition (CVLT-II) was used to evaluate the participants' immediate and delayed recall, recognition, learning characteristics, errors, and memory retention. RESULTS: The pre-HD group performed significantly worse than the healthy group, yet significantly better than the HD group, on Short and Long Delay Recall (Free and Cued) and Recognition Discriminability. On Total Immediate Recall, Learning Slope, Semantic Clustering, and Intrusions, the pre-HD group performed similarly to the healthy group and significantly better than the HD group. None of the groups differed in their performance on Repetitions and a measure of retention. CONCLUSIONS: Subtle memory deficits can be observed during the premanifest stage of HD with use of a subset of indices from the CVLT-II.

Levels of Interleukin-6 in Saliva, but Not Plasma, Correlate with Clinical Metrics in Huntington's Disease Patients and Healthy Control Subjects.

Growing evidence suggests that inflammatory responses, in both the brain and peripheral tissues, contribute to disease pathology in Huntington's disease (HD), an inherited, progressive neurodegenerative disorder typically affecting adults in their 30-40 s. Hence, studies of inflammation-related markers in peripheral fluids might be useful to better characterize disease features. In this study, we measured levels of C-reactive protein (CRP), Interleukin-6 (IL-6), interleukin 1 beta (IL-1B), and alpha-amylase (AA) in saliva and plasma from n = 125 subjects, including n = 37 manifest HD patients, n = 36 premanifest patients, and n = 52 healthy controls, using immunoassays. We found increases in salivary levels of IL-6, IL-1B and CRP across different disease groups and increased levels of IL-6 in the plasma of HD patients as compared to premanifest patients and controls. The levels of salivary IL-6 were significantly correlated with each of the other salivary markers, as well as with IL-6 levels measured in plasma. Further, salivary IL-6 and IL-1B levels were significantly positively correlated with Total Motor Score (TMS) and chorea scores and negatively correlated with Total Functional Capacity (TFC) in HD patients, whereby in healthy control subjects, IL-6 was significantly negatively correlated with Montreal Cognitive Assessment (MoCA) and the Symbol Digit Modalities test (SDM). Interestingly, the plasma levels of IL-6 did not show similar correlations to any clinical measures in either HD or control subjects. These findings suggest that salivary IL-6 is particularly relevant as a potential non-invasive biomarker for HD symptoms. The advent of an effective, dependable salivary biomarker would meet the urgent need for a less invasive means of identifying and monitoring HD disease progression.

New Intrusion Analyses on the CVLT-3: Utility in Distinguishing the Memory Disorders of Alzheimer's versus Huntington's Disease.

OBJECTIVES: Research has shown that analyzing intrusion errors generated on verbal learning and memory measures is helpful for distinguishing between the memory disorders associated with Alzheimer's disease (AD) and other neurological disorders, including Huntington's disease (HD). Moreover, preliminary evidence suggests that certain clinical populations may be prone to exhibit different types of intrusion errors. METHODS: We examined the prevalence of two new California Verbal Learning Test-3 (CVLT-3) intrusion subtypes - across-trial novel intrusions and across/within trial repeated intrusions - in individuals with AD or HD. We hypothesized that the encoding/storage impairment associated with medial-temporal involvement in AD would result in a greater number of novel intrusions on the delayed recall trials of the CVLT-3, whereas the executive dysfunction associated with subcortical-frontal involvement in HD would result in a greater number of repeated intrusions across trials. RESULTS: The AD group generated significantly more across-trial novel intrusions than across/within trial repeated intrusions on the delayed cued-recall trials, whereas the HD group showed the opposite pattern on the delayed free-recall trials. CONCLUSIONS: These new intrusion subtypes, combined with traditional memory analyses (e.g., recall versus recognition performance), promise to enhance our ability to distinguish between the memory disorders associated with primarily medial-temporal versus subcortical-frontal involvement.

New Yes/No Recognition Memory Analysis on the California Verbal Learning Test-3: Clinical Utility in Alzheimer's and Huntington's Disease.

OBJECTIVES: The third edition of the California Verbal Learning Test (CVLT-3) includes a new index termed List A versus Novel/Unrelated recognition discriminability (RD) on the Yes/No Recognition trial. Whereas the Total RD index incorporates false positive (FP) errors associated with all distractors (including List B and semantically related items), the new List A versus Novel/Unrelated RD index incorporates only FP errors associated with novel, semantically unrelated distractors. Thus, in minimizing levels of source and semantic interference, the List A versus Novel/Unrelated RD index may yield purer assessments of yes/no recognition memory independent of vulnerability to source memory difficulties or semantic confusion, both of which are often seen in individuals with primarily frontal-system dysfunction (e.g., early Huntington's disease [HD]). METHODS: We compared the performance of individuals with Alzheimer's disease (AD) and HD in mild and moderate stages of dementia on CVLT-3 indices of Total RD and List A versus Novel/Unrelated RD. RESULTS: Although AD and HD subgroups exhibited deficits on both RD indices relative to healthy comparison groups, those with HD generally outperformed those with AD, and group differences were more robust on List A versus Novel/Unrelated RD than on Total RD. CONCLUSIONS: Our findings highlight the clinical utility of the new CVLT-3 List A versus Novel/Unrelated RD index, which (a) maximally assesses yes/no recognition memory independent of source and semantic interference; and (b) provides a greater differentiation between individuals whose memory disorder is primarily at the encoding/storage level (e.g., as in AD) versus at the retrieval level (e.g., as in early HD). (JINS, 2018, 24, 833-841).

Magnetic resonance imaging of myelin using ultrashort Echo time (UTE) pulse sequences: Phantom, specimen, volunteer and multiple sclerosis patient studies.

Clinical magnetic resonance imaging of multiple sclerosis (MS) has focused on indirect imaging of myelin in white matter by detecting signal from protons in the water associated with myelin. Here we show that protons in myelin can be directly imaged using ultrashort echo time (UTE) free induction decay (FID) and imaging sequences on a clinical 3T MR scanner. An adiabatic inversion recovery UTE (IR-UTE) sequence was used to detect signal from myelin and simultaneously suppress signal from water protons. Validation studies were performed on myelin lipid and myelin basic protein (MBP) phantoms in the forms of lyophilized powders as well as suspensions in D2O and H2O. IR-UTE sequences were then used to image MS brain specimens, healthy volunteers, and patients. The T2* of myelin was measured using a UTE FID sequence, as well as UTE and IR-UTE sequences at different TEs. T2* values of ~110-330µs were measured with UTE FID, as well as with UTE and IR-UTE sequences for myelin powders, myelin-D2O and myelin-H2O phantoms, consistent with selective imaging of myelin protons with IR-UTE sequences. Our studies showed myelin selective imaging of white matter in the brains in vitro and in vivo. Complete or partial signal loss was observed in specimens in areas of the brain with histopathologic evidence of myelin loss, and in the brain of patients with MS.

Proactive selective response suppression is implemented via the basal ganglia.

In the welter of everyday life, people can stop particular response tendencies without affecting others. A key requirement for such selective suppression is that subjects know in advance which responses need stopping. We hypothesized that proactively setting up and implementing selective suppression relies on the basal ganglia and, specifically, regions consistent with the inhibitory indirect pathway for which there is scant functional evidence in humans. Consistent with this hypothesis, we show, first, that the degree of proactive motor suppression when preparing to stop selectively (indexed by transcranial magnetic stimulation) corresponds to striatal, pallidal, and frontal activation (indexed by functional MRI). Second, we demonstrate that greater striatal activation at the time of selective stopping correlates with greater behavioral selectivity. Third, we show that people with striatal and pallidal volume reductions (those with premanifest Huntington's disease) have both absent proactive motor suppression and impaired behavioral selectivity when stopping. Thus, stopping goals are used to proactively set up specific basal ganglia channels that may then be triggered to implement selective suppression. By linking this suppression to the striatum and pallidum, these results provide compelling functional evidence in humans of the basal ganglia's inhibitory indirect pathway.

Ultrashort echo time (UTE) magnetic resonance imaging of the short T2 components in white matter of the brain using a clinical 3T scanner.

White matter of the brain contains a majority of long T2 components as well as a minority of short T2 components. These are not detectable using clinical magnetic resonance imaging (MRI) sequences with conventional echo times (TEs). In this study we used ultrashort echo time (UTE) sequences to investigate the ultrashort T2 components in white matter of the brain and quantify their T2*s and relative proton densities (RPDs) (relative to water with a proton density of 100%) using a clinical whole body 3T scanner. An adiabatic inversion recovery prepared dual echo UTE (IR-dUTE) sequence was used for morphological imaging of the ultrashort T2 components in white matter. IR-dUTE acquisitions at a constant TR of 1000 ms and a series of TIs were performed to determine the optimal TI which corresponded to the minimum signal to noise ratio (SNR) in white matter of the brain on the second echo image. T2*s of the ultrashort T2 components were quantified using mono-exponential decay fitting of the IR-dUTE signal at a series of TEs. RPD was quantified by comparing IR-dUTE signal of the ultrashort T2 components with that of a rubber phantom. Nine healthy volunteers were studied. The IR-dUTE sequence provided excellent image contrast for the ultrashort T2 components in white matter of the brain with a mean signal to noise ratio of 18.7 ± 3.7 and a contrast to noise ratio of 14.6 ± 2.4 between the ultrashort T2 white matter and gray matter in a 4.4 min scan time with a nominal voxel size of 1.25 × 1.25 × 5.0mm(3). On average a T2* value of 0.42 ± 0.08 ms and a RPD of 4.05 ± 0.88% were demonstrated for the ultrashort T2 components in white matter of the brain of healthy volunteers at 3T.

"Forgetting to remember" in Huntington's disease: a study of laboratory, semi-naturalistic, and self-perceptions of prospective memory.

Prospective memory (PM) is dependent on executive processes known to be impaired in Huntington's disease (HD); however, no study to the authors' knowledge has investigated PM in this group. We examined performance-based, semi-naturalistic, and self-reported PM in 20 individuals diagnosed with mild-moderate HD and 20 demographically similar controls. Relative to controls, HD participants demonstrated significantly lower scores in time-based PM, event-based PM (at a trend level), and the semi-naturalistic PM trial, all of which were marked by omission errors. HD participants demonstrated comparable recognition memory for the PM intentions relative to controls. HD and control participants also showed comparable scores in self-reported PM complaints. The results suggest that HD is associated with deficits in the strategic aspects of PM. HD-associated PM deficits also are evident in real-world situations, which may relate to an apparent meta-memory deficit for PM functioning as indicated by HD participants' overestimation of their PM performance on self-report.

Mapping neurodegeneration across the Huntington's disease spectrum: a five-year longitudinal analysis of plasma neurofilament light.

BACKGROUND: Neurofilament light (NfL) has previously been highlighted as a potential biomarker for Huntington's Disease (HD) using cross-sectional analyses. Our study aim was to investigate how longitudinal trajectories of plasma NfL relate to HD disease stage. METHODS: 108 participants [78 individuals with the HD mutation, and 30 healthy controls (HC)] were included in this study. Individuals with the HD mutation were categorised separately by both HD-Integrated Staging System (HD-ISS) (Study 1) and PIN score-Approximated Staging System (PASS) (Study 2) criteria. Plasma NfL trajectories were examined using Mixed Linear Modeling (MLM); associations with symptom presentation were assessed using Spearman's rho correlations. FINDINGS: The MLM coefficients for disease stage (HD-ISS ß = 32.73, p < 0.0001; PASS ß = 33.00, p < 0.0001) and disease stage∗time (HD-ISS ß = 7.85, p = 0.004; PASS ß = 6.58, p = 0.0047) suggest these are significant contributors to plasma NfL levels. In addition, the plasma NfL rate of change varied significantly across time (HD-ISS ß = 3.14, p = 0.04; PASS ß = 2.94, p = 0.050). The annualised rate of change was 8.32% for HC; 10.55%, 12.75% and 15.62% for HD-ISS Stage ≤1, Stage 2, and Stage 3, respectively; and 12.13%, 10.46%, 10.33%, 17.52%, for PASS Stage 0, Stage 1, Stage 2, and Stage 3, respectively. Plasma NfL levels correlated with the Symbol Digit Modalities Test (SDMT) in HD-ISS Stage ≤1, and both SDMT and Total Motor Score in Stage 3 (ps < 0.01). INTERPRETATION: Our findings suggest that plasma NfL levels increase linearly across earlier disease stages, correlating with the cognitive SDMT measure. Thereafter, an increase or surge in plasma NfL levels, paired with correlations with both cognitive and motor measures, suggest a late acceleration in clinical and pathological progression. FUNDING: NIH (NS111655); the UCSD HDSA CoE; the UCSD ADRC (NIH-NIA P30 AG062429).

Computer simulations predict the impact of neuronal atrophy on the calcium dynamics in Huntington's disease.

One of the early hallmarks of Huntington's disease (HD) is neuronal cell atrophy, especially in the striatum, underlying motor dysfunction in HD. Here using a computer model, we have predicted the impact of cell shrinkage on calcium dynamics at the cellular level. Our model indicates that as cytosolic volume decreases, the amplitude of calcium transients increases and the endoplasmic reticulum (ER) becomes more leaky due to calcium-induced calcium release and a "toxic" positive feedback mechanism mediated by ryanodine receptors that greatly increases calcium release into the cytosol. The excessive calcium release from ER saturates the calcium buffering capacity of calbindin and forces further accumulation of free calcium in the cytosol and cellular compartments including mitochondria. This leads to imbalance of calcium in both cytosol and ER regions. Excessive calcium accumulation in the cytosol can damage the mitochondria resulting in metabolic dysfunction in the cell consistent with the pathology of HD. Our computational model points toward potential drug targets and can accelerate and greatly help the experimental studies of HD paving the way for treatments of patients suffering from HD.

Exploring bradyphrenia in Huntington's disease using the computerized test of information processing (CTiP).

Background: Bradyphrenia, best thought of as the mental equivalent of bradykinesia, has been described in several disorders of the brain including Parkinson's disease and schizophrenia; however, little is known about this phenomenon in Huntington's Disease (HD). Objective: The aim of this study was to investigate the presence of bradyphrenia in HD using the Computerized Test of Information Processing (CTiP), an easy to administer and objective task that assesses cognitive processing speed with increasing task complexity. Methods: This study included 211 participants: Huntington's Disease Integrated Staging System (HD-ISS) Stage 0 [n = 28], Stage 1 [n = 30], Stage 2 [n = 48] and Stage 3 [n = 48], and healthy controls (HC) [n = 57]. The CTiP incorporates three subtests: Simple Reaction Time (SRT), which assesses baseline motor function; Choice Reaction Time (CRT), with an added decisional component; and Semantic Search Reaction Time (SSRT), with an added conceptual component. SRT scores were subtracted from CRT and SSRT scores to establish a motor-corrected measure of central conduction time, which was used to operationalize bradyphrenia. Results: HD-ISS and HC within-group reaction times differed significantly when comparing motor-corrected CRT vs SSRT (all ps < 0.0001). Furthermore, the magnitude of these differences increased with HD disease stage (p < 0.0001). An ROC analysis determined that motor-corrected within-subject differences significantly distinguished Stage 2 + 3 from Stage 0 + 1 (AUC = 0.72, p < 0.0001). Conclusions: We report evidence of bradyphrenia in HD that increases with disease progression. This processing deficit, which can be quantified using the CTiP, has the potential to greatly impact HD daily life and warrants additional research.

Usefulness of the Montreal Cognitive Assessment (MoCA) in Huntington's disease.

BACKGROUND: The Montreal Cognitive Assessment (MoCA) is a brief screening instrument for dementia that is sensitive to executive dysfunction. This study examined its usefulness for assessing cognitive performance in mild, moderate, and severe Huntington's disease (HD), compared with the use of the Mini-Mental State Examination (MMSE). METHODS: We compared MoCA and MMSE total scores and the number of correct answers in 5 cognitive-specific domains in 104 manifest HD patients and 100 matched controls. RESULTS: For the total HD sample, and for the moderate and severe patients, significant differences between both MoCA and MMSE total scores and almost all cognitive-specific domains emerged. Even mild HD subjects showed significant differences with regard to total score and several cognitive domains on both instruments. CONCLUSIONS: We conclude that the MoCA, although not necessarily superior to the MMSE, is a useful instrument for assessing cognitive performance over a broad level of functioning in HD.