Assessment of Fitbit Charge 4 for sleep stage and heart rate monitoring against polysomnography and during home monitoring in Huntington's disease.

STUDY OBJECTIVES: Wearable devices that monitor sleep stages and heart rate offer the potential for longitudinal sleep monitoring in patients with neurodegenerative diseases. Sleep quality reduces with disease progression in Huntington's disease (HD). However, the involuntary movements characteristic of HD may affect the accuracy of wrist-worn devices. This study compares sleep stage and heart rate data from the Fitbit Charge 4 (FB) against polysomnography (PSG) in participants with HD. METHODS: Ten participants with manifest HD wore an FB during overnight hospital-based PSG, and 9 of these participants continued to wear the FB for 7 nights at home. Sleep stages (30-second epochs) and minute-by-minute heart rate were extracted and compared against PSG data. RESULTS: FB-estimated total sleep and wake times and sleep stage times were in good agreement with PSG, with intraclass correlations of 0.79-0.96. However, poor agreement was observed for wake after sleep onset and the number of awakenings. FB detected waking with 68.6 ± 15.5% sensitivity and 93.7 ± 2.5% specificity, rapid eye movement sleep with high sensitivity and specificity (78.7 ± 31.9%, 95.6 ± 2.3%), and deep sleep with lower sensitivity but high specificity (56.4 ± 28.8%, 95.0 ± 4.8%). FB heart rate was strongly correlated with PSG, and the mean absolute error between FB and PSG heart rate data was 1.16 ± 0.42 beats/min. At home, longer sleep and shorter wake times were observed compared with hospital data, whereas percentage sleep stage times were consistent with hospital data. CONCLUSIONS: Results suggest the potential for long-term monitoring of sleep patterns using wrist-worn wearable devices as part of symptom management in HD. CITATION: Doheny EP, Renerts K, Braun A, et al. Assessment of Fitbit Charge 4 for sleep stage and heart rate monitoring against polysomnography and during home monitoring in Huntington's disease. J Clin Sleep Med. 2024;20(7):1163-1171.

Cognitive Screening Tests in Huntington Gene Mutation Carriers: Examining the Validity of the Mini-Mental State Examination and the Montreal Cognitive Assessment.

BACKGROUND: Due to high prevalence of cognitive impairment in Huntington's disease (HD) gene mutation carriers, even before onset of motor symptoms, cognitive screening is important for the optimal management of patients. The Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) are widely used, but the validity for HD has only been evaluated in few studies with important limitations. OBJECTIVE: To evaluate the discriminative validity of the MMSE and the MoCA for the assessment of cognitive dysfunction in HD gene mutation carriers, independently of motor manifestation and furthermore, to report estimated probabilities for cognitive impairment with different score ranges on the MMSE and the MoCA. METHODS: 106 pre-motor-manifest and motor-manifest HD gene mutation carriers and 40 non-HD gene mutation carriers were administered the MMSE, the MoCA, and an extensive neuropsychological battery with operationalized criteria for cognitive impairment. The same physician and the same neuropsychologist performed all examinations; blinded to one another. RESULTS: The area under the receiver operating characteristic (ROC) curve was 0.70 for the MMSE and 0.82 for the MoCA. The latter correctly diagnosed 82% of the cognitively impaired and not-impaired HD gene mutation carriers and non-HD gene mutation carriers, whereas the MMSE only diagnosed 73% correctly. CONCLUSIONS: The MMSE and the MoCA can both be used as cognitive screening tests in HD gene mutation carriers, but both have important limitations. Our results indicate that the MoCA is a better cognitive screening test for HD than the MMSE. In addition, our study provides estimated probabilities for cognitive impairment with different score ranges, which may be used as clinical guidelines in the interpretation of results from the two tests.

Health state utility values (QALY weights) for Huntington's disease: an analysis of data from the European Huntington's Disease Network (EHDN).

BACKGROUND: Huntington's Disease (HD) is a hereditary neurodegenerative disorder which affects individuals' ability to walk, talk, think, and reason. Onset is usually in the forties, there are no therapies currently available that alter disease course, and life expectancy is 10-20 years from diagnosis. The gene causing HD is fully penetrant, with a 50% probability of passing the disease to offspring. Although the impacts of HD are substantial, there has been little report of the quality of life of people with the condition in a manner that can be used in economic evaluations of treatments for HD. Health state utility values (HSUVs), used to calculate quality-adjusted life-years (QALYs), are the metric commonly used to inform such healthcare policy decision-making. OBJECTIVES: The aim was to report HSUVs for HD, with specific objectives to use European data to: (i) describe HSUVs by demographic and clinical characteristics; (ii) compare HSUVs of people with HD in the UK with population norms; (iii) identify the relative strength of demographic and clinical characteristics in predicting HSUVs. METHODS: European Huntington's Disease Network REGISTRY study data were used for analysis. This is a multi-centre, multi-national, observational, longitudinal study, which collects six-monthly demographic, clinical, and patient-reported outcome measures, including the SF-36. SF-36 scores were converted to SF-6D HSUVs and described by demographic and clinical characteristics. HSUVs from people with HD in the UK were compared with population norms. Regression analysis was used to estimate the relative strength of age, gender, time since diagnosis, and disease severity (according to the Total Function Capacity (TFC) score, and the UHDRS's Motor score, Behavioural score, and Cognition score) in predicting HSUVs. RESULTS: 11,328 questionnaires were completed by 5560 respondents with HD in 12 European countries. Women generally had lower HSUVs than men, and HSUVs were consistently lower than population norms for those with HD in the UK, and dropped with increasing disease severity. The regression model significantly accounted for the variance in SF-6D scores (n = 1939; F [7,1931] = 120.05; p < 0.001; adjusted R-squared 0.3007), with TFC score, Behavioural score, and male gender significant predictors of SF-6D values (p < 0.001). CONCLUSION: To our knowledge, this is the first report of HSUVs for HD for countries other than the UK, and the first report of SF-6D HSUVs described for 12 European countries, according to demographic and clinical factors. Our analyses provide new insights into the relationships between HD disease characteristics and assessment of health-related quality of life in a form that can be used in policy-relevant economic evaluations.

Assessment of Caregiver Burden in Huntington's Disease.

Huntington's disease (HD) is a rare neurodegenerative disease associated with disability and loss of patient independence. The caregivers of HD patients are at high risk for burnout. We aimed to identify variables that impact caregiver burden, as measured by the Modified Caregiver Strain Index (MCSI) and the Huntington's disease Quality of Life Battery for Carers Short Form (HD-SF). Total functional capacity and being sole caregiver were significantly associated with higher caregiver burden via MCSI. There was not good correlation between MCSI and HDQoLC-SF. This study highlights the need for more research to effectively identify at-risk caregivers for early intervention.

Movement Symmetry Assessment by Bilateral Motion Data Fusion.

OBJECTIVE: A new approach, named bilateral motion data fusion, was proposed for the analysis of movement symmetry, which takes advantage of cross-information between both sides of the body and processes the unilateral motion data at the same time. METHODS: This was accomplished using canonical correlation analysis and joint independent component analysis. It should be noted that human movements include many categories, which cannot be enumerated one by one. Therefore, the gait rhythm fluctuations of the healthy subjects and patients with neurodegenerative diseases were employed as an example for method illustration. In addition, our model explains the movement data by latent parameters in the time and frequency domains, respectively, which were both based on bilateral motion data fusion. RESULTS: They show that our method not only reflects the physiological correlates of movement but also obtains the differential signatures of movement asymmetry in diverse neurodegenerative diseases. Furthermore, the latent variables also exhibit the potentials for sharper disease distinctions. CONCLUSION: We have provided a new perspective on movement analysis, which may prove to be a promising approach. SIGNIFICANCE: This method exhibits the potentials for effective movement feature extractions, which might contribute to many research fields such as rehabilitation, neuroscience, biomechanics, and kinesiology.

Bayesian quantile regression joint models: Inference and dynamic predictions.

In the traditional joint models of a longitudinal and time-to-event outcome, a linear mixed model assuming normal random errors is used to model the longitudinal process. However, in many circumstances, the normality assumption is violated and the linear mixed model is not an appropriate sub-model in the joint models. In addition, as the linear mixed model models the conditional mean of the longitudinal outcome, it is not appropriate if clinical interest lies in making inference or prediction on median, lower, or upper ends of the longitudinal process. To this end, quantile regression provides a flexible, distribution-free way to study covariate effects at different quantiles of the longitudinal outcome and it is robust not only to deviation from normality, but also to outlying observations. In this article, we present and advocate the linear quantile mixed model for the longitudinal process in the joint models framework. Our development is motivated by a large prospective study of Huntington's disease where primary clinical interest is in utilizing longitudinal motor scores and other early covariates to predict the risk of developing Huntington's disease. We develop a Bayesian method based on the location-scale representation of the asymmetric Laplace distribution, assess its performance through an extensive simulation study, and demonstrate how this linear quantile mixed model-based joint models approach can be used for making subject-specific dynamic predictions of survival probability.

Automated Assessment of Movement Impairment in Huntington's Disease.

Quantitative assessment of movement impairment in Huntington's disease (HD) is essential to monitoring of disease progression. This paper aimed to develop and validate a novel low cost, objective automated system for the evaluation of upper limb movement impairment in HD in order to eliminate the inconsistency of the assessor and offer a more sensitive, continuous assessment scale. Patients with genetically confirmed HD and healthy controls were recruited to this observational study. Demographic data, including age (years), gender, and unified HD rating scale total motor score (UHDRS-TMS), were recorded. For the purposes of this paper, a modified upper limb motor impairment score (mULMS) was generated from the UHDRS-TMS. All participants completed a brief, standardized clinical assessment of upper limb dexterity while wearing a tri-axial accelerometer on each wrist and on the sternum. The captured acceleration data were used to develop an automatic classification system for discriminating between healthy and HD participants and to automatically generate a continuous movement impairment score (MIS) that reflected the degree of the movement impairment. Data from 48 healthy and 44 HD participants was used to validate the developed system, which achieved 98.78% accuracy in discriminating between healthy and HD participants. The Pearson correlation coefficient between the automatic MIS and the clinician rated mULMS was 0.77 with a p-value < 0.01. The approach presented in this paper demonstrates the possibility of an automated objective, consistent, and sensitive assessment of the HD movement impairment.

Direct assessment of presynaptic modulation of cortico-striatal glutamate release in a Huntington's disease mouse model.

Glutamate is the main excitatory neurotransmitter in the brain, and impairments in its signaling are associated with many neurological disorders, including Huntington's disease (HD). Previous studies in HD mouse models demonstrate altered glutamate receptor distribution and signaling at cortico-striatal synapses, and some studies suggest that glutamate release is altered; however, traditional methods to study synaptic glutamate release are indirect or have poor temporal resolution. Here we utilize iGluSnFR, a modified green fluorescent protein reporter for real-time imaging of glutamate transmission, to study presynaptic modulation of cortical glutamate release in the striatum of the YAC128 HD mouse model. We determined that iGluSnFR can be used to accurately measure short- and long-term changes in glutamate release caused by modulation of extracellular Ca2+ levels, activation of presynaptic receptors, and high-frequency stimulation (HFS) protocols. We also confirmed a difference in the expression of HFS-induced long-term depression in YAC128. Together, this research demonstrates the utility of iGluSnFR in studying presynaptic modulation of glutamate release in healthy mice and disease models that display impairments in glutamate signaling. NEW & NOTEWORTHY We use iGluSnFR to directly assess presynaptic modulation of cortico-striatal glutamate release in brain slice and compare changes in glutamate release between wild type and a Huntington's disease mouse model, YAC128. We observed reductions in glutamate release after low extracellular Ca2+ and activation of various presynaptic receptors. We also demonstrate a presynaptic mechanism of reduced glutamate release in high-frequency stimulation-induced long-term depression and show this to be altered in YAC128.

Vocalisation as a Viable Assessment for Phenotyping Minipigs Transgenic for the Huntington Gene?

BACKGROUND: Large animal models, such as the transgenic (tg) Huntington disease (HD) minipig, have been proposed to improve translational reliability and assessment of safety, efficacy and tolerability in preclinical studies. Minipigs are characterised by high genetic homology and comparable brain structures to humans. In addition, behavioural assessments successfully applied in humans could be explored in minipigs to establish similar endpoints in preclinical and clinical studies. Recently, analysis of voice and speech production was established to characterise HD patients. OBJECTIVE: The aim of this study was to investigate whether vocalisation could also serve as a viable marker for phenotyping minipigs transgenic for Huntington's disease (tgHD) and whether tgHD minipigs reveal changes in this domain compared to wildtype (wt) minipigs. METHODS: While conducting behavioural testing, incidence of vocalisation was assessed for a cohort of 14 tgHD and 18 wt minipigs. Statistical analyses were performed using Fisher's Exact Test for group comparisons and McNemar's Test for intra-visit differences between tgHD and wt minipigs. RESULTS: Vocalisation can easily be documented during phenotyping assessments of minipigs. Differences in vocalisation incidences across behavioural conditions were detected between tgHD and wt minipigs. Influence of the genotype on vocalisation was detectable during a period of 1.5 years. CONCLUSION: Vocalisation may be a viable marker for phenotyping minipigs transgenic for the Huntington gene. Documentation of vocalisation provides a non-invasive opportunity to capture potential disease signs and explore phenotypic development including the age of disease manifestation.

Motor Assessment in Huntington's Disease Mice.

Motor deficits are a characteristic consequence of striatal damage, whether induced by experimental lesions, or in genetic models of Huntington's disease involving polyglutamine expansion in the huntingtin protein. With the growing power of genetic models and genetic tools for analysis, mice are increasingly the animal model of choice, and objective quantitative measures of motor performance are in demand for experimental analysis of disease pathophysiology, progression, and treatment. We present methodological protocols for six of the most common tests of motor function-ranging from spontaneous activity, locomotor coordination, balance, and skilled limb use-that are simple, effective, efficient, and widely used for motor assessment in Huntington's disease research in experimental mice.

Neurophysiological Assessment of Huntington's Disease Model Mice.

Electrophysiological and cell imaging techniques are powerful tools for understanding alterations in neuronal activity in Huntington's disease (HD), a fatal neurological disorder caused by an expansion of CAG repeats in the HTT gene. Changes in neuronal activity often precede the behavioral manifestations of HD, therefore, understanding the electrophysiology of HD is critical for identifying potential prodromal markers and therapeutic targets. This chapter outlines the basic methodology behind four major electrophysiological and imaging techniques used in HD mouse models: patch clamp recordings, optogenetics, in vivo electrophysiology, and Ca2+ imaging, as well as some of the advancements in HD research using each of these techniques.

Large-Brained Animal Models of Huntington's Disease: Sheep.

The limitations of using small-brained rodents to model diseases that affect large-brain humans are becoming increasingly obvious as novel therapies emerge. Huntington's disease (HD) is one such disease. In recent years, the desirability of a large-brained, long-lived animal model of HD for preclinical testing has changed into a necessity. Treatment involving gene therapy in particular presents delivery challenges that are currently unsolved. Models using long-lived, large-brained animals would be useful, not only for refining methods of delivery (particularly for gene and other therapies that do not involve small molecules) but also for measuring long-term "off-target" effects, and assessing the efficacy of therapies. With their large brains and convoluted cortices, sheep are emerging as feasible experimental subjects that can be used to bridge the gap between rodents and humans in preclinical drug development. Sheep are readily available, economical to use, and easy to care for in naturalistic settings. With brains of a similar size to a large rhesus macaque, they have much to offer. The only thing that was missing until recently was the means of testing their neurological function and behavior using approaches and methods that are relevant to HD. In this chapter, I will outline the present and future possibilities of using sheep and testing as large animal models of HD.

Nonhuman Primate Models of Huntington's Disease and Their Application in Translational Research.

Huntington's disease (HD) is a monogenic, autosomal dominant inherited fatal disease that affects 1 in 10,000 people worldwide. Given its unique genetic characteristics, HD would appear as one of the most straightforward neurodegenerative diseases to replicate in animal models. Indeed, mutations in the HTT gene have been used to generate a variety of animal models that display differential pathologies and have significantly increased our understanding of the pathological mechanisms of HD. However, decades of efforts have also shown the complexity of recapitulating the human condition in other species. Here we describe the three different types of models that have been generated in nonhuman primate species, stating their advantages and limitations and attempt to give a critical perspective of their translational value to test the efficacy of novel therapeutic strategies. Obtaining construct, phenotypic, and predictive validity has proven to be challenging in most animal models of human diseases. In HD in particular, it is hard to assess the predictive validity of a new therapeutic strategy when no effective "benchmark" treatment is available in the clinic. In this light, only phenotypic/face validity and construct validity are discussed.

Objective assessment of gait and posture in premanifest and manifest Huntington disease - A multi-center study.

BACKGROUND: Deficits in posture and gait are known to contribute to the complex motor phenotype of Huntington disease (HD). Objective and quantitative measures of posture and gait provided by posturography and GAITRite® assessments may supplement categorical rating scales such as the UHDRS-TMS and increase power and sensitivity of clinical trials. OBJECTIVES: To investigate whether posturography and GAITRite® measures reveal (1) changes in manifest or premanifest HD mutation-carriers, (2) a correlation to the UHDRS-TMS and functional measures in manifest HD, and (3) a correlation to the disease-burden-score (based on CAG-repeat-length and age). METHODS: Posturography and GAITRite® were applied in premanifest (n = 26) and manifest HD gene-mutation-carriers (n = 40) in different paradigms compared to age-matched controls (n = 30) in a cross-sectional multi-site study conducted in three centers. Subjects were assessed clinically with the UHDRS Total-Motor-Score, Total-Functional-Capacity and Functional-Assessment-Scale. RESULTS: Several posturography measures were able to discriminate between controls, premanifest, and manifest mutation-carriers in both conditions assessed. Only one GAITRite® measure separated controls and premanifest participants, while discrimination between controls and manifest same as between premanifest and manifest participants was possible in several measures. Correlation with all clinical measures was seen in only one measure per device while correlations to the disease-burden-score seen in posturography only. CONCLUSION: Overall the results suggests that posturography detects alterations in premanifest and manifest mutation-carriers more reliably than GAITRite® measures. Correlations with clinical assessment scores are limited; correlation with disease-burden-score is seen in posturography only. Data acquisition and analysis was easier with posturography than GAITRite® assessments in out-patient settings.

The Medicinal Chemistry of Natural and Semisynthetic Compounds against Parkinson's and Huntington's Diseases.

Among the diseases affecting the central nervous system (CNS), neurodegenerations attract the interest of both the clinician and the medicinal chemist. The increasing average age of population, the growing number of patients, and the lack of long-term effective remedies push ahead the quest for novel tools against this class of pathologies. We present a review on the state of the art of the molecules (or combination of molecules) of natural origin that are currently under study against two well-defined pathologies: Parkinson's disease (PD) and Huntington's disease (HD). Nowadays, very few tools are available for preventing or counteracting the progression of such diseases. Two major parameters were considered for the preparation of this review: particular attention was reserved to these research works presenting well-defined molecular mechanisms for the studied compounds, and where available, papers reporting in vivo data were preferred. A literature search for peer-reviewed articles using PubMed, Scopus, and Reaxys databases was performed, exploiting different keywords and logical operators: 91 papers were considered (preferentially published after 2015). The review presents a brief overview on the etiology of the studied neurodegenerations and the current treatments, followed by a detailed discussion of the natural and semisynthetic compounds dividing them in different paragraphs considering their several mechanisms of action.

Quantitative biomechanical assessment of trunk control in Huntington's disease reveals more impairment in static than dynamic tasks.

Postural instability is common in individuals with Huntington's disease (HD), yet little is known about control of the trunk during static and dynamic activities. We compared the trunk motion of 41 individuals with HD and 36 controls at thoracic and pelvic levels during sitting, standing, and walking using wearable iPod sensors. We also examined the ability of individuals with HD to respond to an auditory cue to modify trunk position when the pelvis moved >8° in sagittal or frontal planes during sitting using custom software. We found that amplitude of thoracic and pelvic trunk movements was significantly greater in participants with HD, and differences were more pronounced during static (i.e. sitting, standing) than dynamic (i.e. walking) tasks. In contrast to the slow, smooth sinusoidal trunk movements of controls, individuals with HD demonstrated rapid movements with varying amplitudes that continuously increased without stabilizing. Ninety-seven percent of participants with HD were able to modify their trunk position in response to auditory cues. Our results demonstrate that wearable iPod sensors are clinically useful for rehabilitation professionals to measure and monitor trunk stability in persons with HD. Additionally, auditory cueing holds potential as a useful training tool to improve trunk stability in HD.

Everyday Functioning in Huntington's Disease: A Laboratory-Based Study of Financial Management Capacity.

One important limitation of prior studies examining functional decline in Huntington's disease (HD) has been the reliance on self-reported measures of ability. Since report-based methods can be biased by lack of insight, depression, and cognitive impairment, contrasting self-reported ability with measures that assess capacity may lead to a more comprehensive estimation of real-world functioning. The present study examined self-reported ability to perform instrumental activities of daily living (iADLs) and performance-based financial management capacity in 20 patients diagnosed with mild-moderate Huntington's disease (HD) and 20 demographically similar healthy adults. HD patients reported significantly greater declines in their ability to manage finances. On the capacity measure of financial management, HD patients performed significantly below healthy adults. Additionally, in the HD group there were no significant correlations between self-reported ability and capacity measures of financial management. HD patients endorsed declines in global iADL ability and exhibited deficits in functional capacity when performing a financial management task. Capacity measures may aid in assessing the extent to which HD patients accurately estimate real-world iADL performance, and the present findings suggest that such measures of capacity may be related to the cognitive, but not motor or affective, symptoms of HD.

Survey of the Huntington's Disease Patient and Caregiver Community Reveals Most Impactful Symptoms and Treatment Needs.

BACKGROUND: In preparation for a meeting with the U.S. Food and Drug Administration (FDA) on Patient-Focused Drug Development in Huntington's disease, the Huntington's Disease Society of America (HDSA) created and distributed two comprehensive surveys on the symptom experience and treatment approaches for Huntington's disease. OBJECTIVE: The objective of these surveys was to identify the specific symptoms that most impact the daily lives of individuals with Huntington's disease/Juvenile Huntington's disease (HD/JHD) and their caregivers and to solicit input on the types of treatments desired by HD affected families. The data were shared with the FDA to offer background and insight in preparation for the patient-focused meeting, as well as to ensure representation by the community in a manner that would complement those who attended in person. METHODS: Two distinct surveys were created using SurveyMonkey to capture patient and caregiver perspectives on HD symptoms and current treatments. HDSA distributed the surveys to the HD community in August and September 2014 and collected responses through January 2015. RESULTS: More than 3,600 responses to the two surveys were received. The data showed that both caregivers and individuals with HD were severely impacted by the cognitive and behavioral symptoms of HD with HD patients reporting problems with executive functioning and cognitive decline as most impactful to them. However, 30 percent of caregivers reported that chorea was the most impactful symptom compared to 17 percent of people with HD. Across all the symptom categories, patients reported a lower occurrence of symptoms than were reported by their caregivers. CONCLUSIONS: With only one drug approved for treatment of a symptom of Huntington's disease and no disease modifying treatments available, there is a critical need for new medicines to treat the cognitive, psychiatric and motor symptoms associated with HD. While the surveys did not capture risk/benefit data, the data collected do provide new insights around the different perspectives of patients and caregivers. We believe that industry development of treatments would be well-informed by incorporating the patient community, which is more knowledgeable and engaged than given credit, in consideration of treatment regimens, risk-benefit and priorities for therapeutic development.

A Longitudinal Operant Assessment of Cognitive and Behavioural Changes in the HdhQ111 Mouse Model of Huntington's Disease.

Huntington's disease (HD) is characterised by motor symptoms which are often preceded by cognitive and behavioural changes, that can significantly contribute to disease burden for people living with HD. Numerous knock-in mouse models of HD are currently available for scientific research. However, before their use, they must be behaviourally characterised to determine their suitability in recapitulating the symptoms of the human condition. Thus, we sought to longitudinally characterise the nature, severity and time course of cognitive and behavioural changes observed in HdhQ111 heterozygous knock-in mice.To determine changes in cognition and behaviour an extensive battery of operant tests including: fixed ratio, progressive ratio, the five choice serial reaction time task and the serial implicit learning task, were applied longitudinally to HdhQ111 and wild type mice. The operant test battery was conducted at 6, 12 and 18 months of age. Significant deficits were observed in HdhQ111 animals in comparison to wild type animals in all operant tests indicating altered cognition (attentional and executive function) and motivation. However, the cognitive and behavioural deficits observed were not shown to be progressive over time in the longitudinal testing paradigm that was utilised. The results therefore demonstrate that the HdhQ111 mouse model of HD reflects some features of the cognitive and behavioural changes shown in the human condition of HD. Although, the cognitive and behavioural deficits demonstrated were not shown to be progressive over time.