Sensorimotor outcomes in adrenomyeloneuropathy show significant disease progression.

Current outcomes used to evaluate adrenomyeloneuropathy are limited by rater bias, not sensitive to preclinical changes, and require years to decades to detect disease progression. Quantitative outcomes are needed that detect meaningful change in a short time period over a broad range of disability. The study aim was to track sensorimotor outcomes in adults with adrenomyeloneuropathy and evaluate differences in progression between men and women. This prospective observational cohort study analyzes data collected annually in the Phase III study of adults with adrenomyeloneuropathy. Outcomes include postural sway in four static standing conditions, great-toe vibration, hip strength, walking velocity, timed up-and-go, and 6-minute walk distance. Linear mixed model analysis was used to detect change in the outcomes in 2 years, correcting for age, sex, disability, symptom duration, and treatment across the cohort. Modeling was repeated for each sex to evaluate differences. Power computations were carried out by sex and for the full dataset. Sixty-one men and 87 women participated. Average age, 46 ± 12 years; Expanded Disability Status Scale, 3 (1-6.5); symptom duration, 10.8 ± 9.4 years. The cohort showed significant worsening in all standing conditions (P < .001), sensation (P = .0223) and strength (P = .001); but more stability in walking with only velocity (P < .0337) significantly declining. For each sex, postural sway declines significantly in all conditions (P < .01) except for eyes closed feet together for women. Strength declines significantly by sex for hip flexion (P < .03). Sex-specific significant decline is seen in walking (velocity P = .0276; distance P = .0072) for men only. Quantitative measures of postural sway, sensation strength, and walking are effective measures of adrenomyeloneuropathy progression in 2 years.

Cerebellar Contributions to Motor and Cognitive Control in Multiple Sclerosis✰✰✰.

OBJECTIVE: To evaluate relationships between specific cerebellar regions and common clinical measures of motor and cognitive function in persons with multiple sclerosis (PwMS). DESIGN: Cross-sectional. SETTING: Laboratory. PARTICIPANTS: Twenty-nine PwMS and 28 age- and sex-matched controls without multiple sclerosis (MS) (N=57). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Both diffusion and lobule magnetic resonance imaging analyses and common clinical measures of motor and cognitive function were used to examine structure-function relationships in the cerebellum. RESULTS: PwMS demonstrate significantly worse motor and cognitive function than controls, including weaker strength, slower walking, and poorer performance on the Symbol Digit Modalities Test, but demonstrate no differences in cerebellar volume. However, PwMS demonstrate significantly worse diffusivity (mean diffusivity: P=.0003; axial diffusivity: P=.0015; radial diffusivity: P=.0005; fractional anisotropy: P=.016) of the superior cerebellar peduncle, the primary output of the cerebellum. Increased volume of the motor lobules (I-V, VIII) was significantly related to better motor (P<.022) and cognitive (P=.046) performance, and increased volume of the cognitive lobules (VI-VII) was also related to better motor (P<.032) and cognitive (P=.008) performance, supporting the role of the cerebellum in both motor and cognitive functioning. CONCLUSIONS: These data highlight the contributions of the cerebellum to both motor and cognitive function in PwMS. Using novel neuroimaging techniques to examine structure-function relationships in PwMS improves our understanding of individualized differences in this heterogeneous group and may provide an avenue for targeted, individualized rehabilitation aimed at improving cerebellar dysfunction in MS.

Prioritizing progressive MS rehabilitation research: A call from the International Progressive MS Alliance.

BACKGROUND: People with multiple sclerosis (MS) experience myriad symptoms that negatively affect their quality of life. Despite significant progress in rehabilitation strategies for people living with relapsing-remitting MS (RRMS), the development of similar strategies for people with progressive MS has received little attention. OBJECTIVE: To highlight key symptoms of importance to people with progressive MS and stimulate the design and implementation of high-quality studies focused on symptom management and rehabilitation. METHODS: A group of international research experts, representatives from industry, and people affected by progressive MS was convened by the International Progressive MS Alliance to devise research priorities for addressing symptoms in progressive MS. RESULTS: Based on information from the MS community, we outline a rationale for highlighting four symptoms of particular interest: fatigue, mobility and upper extremity impairment, pain, and cognitive impairment. Factors such as depression, resilience, comorbidities, and psychosocial support are described, as they affect treatment efficacy. CONCLUSIONS: This coordinated call to action-to the research community to prioritize investigation of effective symptom management strategies, and to funders to support them-is an important step in addressing gaps in rehabilitation research for people affected by progressive MS.

Gait and Balance Assessment.

Gait and balance deficits are commonly experienced by individuals with a variety of neurologic disorders. These deficits can be particularly frustrating because they often profoundly impact a person's quality of life. The author applies information about gait and balance based on the neurologic examination and summarizes important relationships among common impairment measures of gait and balance deficits. She also provides an interpretation of these relationships to assist the clinician in how to identify and manage gait and balance deficits.

Utility of the Six-Spot Step Test as a Measure of Walking Performance in Ambulatory Individuals With Multiple Sclerosis.

OBJECTIVE: To examine the concurrent validity of the Six-Spot Step Test (SSST) with clinical measures of walking and spatiotemporal measures of gait in multiple sclerosis (MS), and to understand the utility of the SSST in individuals with both low and high levels of disability. DESIGN: Cross-sectional study. SETTING: Laboratory. PARTICIPANTS: Individuals with relapsing-remitting MS (N=29). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: In a single visit, demographic information (age, sex, Expanded Disability Status Scale [EDSS], symptom duration) and functional measures (SSST, timed Up and Go [TUG] test, timed 25-foot walk [T25FW] test, spatiotemporal measures of walking) were collected. RESULTS: The SSST demonstrates concurrent validity with the TUG test, T25FW test, and 2-minute walk test (2MWT) (P≤.0002). Both spatial and temporal measures of gait are significantly related to SSST performance (P<.004). In individuals with lower disability (EDSS score 1-3.5), the SSST remains strongly related to the TUG test and T25FW test performances, whereas it fails to relate to any other measures. However, in the higher disability group (EDSS score 4-6), the SSST is significantly related to the TUG test, T25FW test, 2MWT, walk velocity, and both temporal and spatial measures of gait. CONCLUSIONS: The SSST is an alternative test for lower-extremity function in the clinical setting that may useful in both higher and lower EDSS groups. The SSST requires minimal training to administer and may be a time-efficient measure of real-life functional performance that would be useful in large clinical trials.

Cerebellar volume measures may differentiate multiple sclerosis fallers from non-fallers.

Introduction: The cerebellum is a common lesion site in persons with multiple sclerosis (PwMS). Physiologic and anatomic studies have identified a topographic organization of the cerebellum including functionally distinct motor and cognitive areas. This study implemented a recent parcellation algorithm developed by Han et al., 2020 to a sample of PwMS and healthy controls to examine relationships among specific cerebellar regions, fall status, and common clinical measures of motor and cognitive functions. Methods: Thirty-one PwMS and 29 age and sex-matched controls underwent an MRI scan and motor and cognitive testing. The parcellation algorithm was applied to all images and divided the cerebellum into 28 regions. Mann-Whitney U tests were used to compare cerebellar volumes among PwMS and controls, and MS fallers and MS non-fallers. Relationships between cerebellar volumes and motor and cognitive function was evaluated using Spearman correlations. Results: PwMS performed significantly worse on functional measures compared to controls. We found significant differences in volumetric measures between PwMS and controls in the corpus medullare, lobules I-III, and lobule V. Volumetric differences seen between PwMS and controls were primarily driven by the MS fallers. Finally, functional performance on motor and cognitive tasks was associated with cerebellar volumes. Conclusions: Using the parcellation tool, our results showed that volumes of motor and cognitive lobules impact both motor and cognitive performance, and that functional performance and cerebellar volumes distinguishes MS fallers from non-fallers. Future studies should explore the potential of cerebellar imaging to predict falls in PwMS.

Adrenoleukodystrophy in female heterozygotes: underrecognized and undertreated.

X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disease resulting from mutations in the gene ABCD1 and alterations in peroxisomal beta-oxidation of long chain fatty acids. As it has been frequently discussed, it manifests a wide range of phenotypes in male, with progressive myelopathy being the most common. Even though the gene is localized to the X-chromosome and a region subject to X-inactivation, female carriers still are affected significantly by this condition. It has been stated that between 20 and 50% of women who are carriers may manifest some symptoms and recent evidence has suggested the differences in disease manifestations and relative rates of progression between men and women. However there have been only limited studies specifically addressing this and to date there has been no comprehensive review discussing the different phenotypes in female carriers, as well as the differences in disease onset, progression, disability, nervous system pathology and neuroimaging patterns compared to affected males. This is of key importance as similarities and differences between genders will assist in determining how best to target therapies in all affected individuals as opportunities for treatment present themselves. As will be further addressed in this review, we need to improve our understanding of the associations of emergent neuroimaging techniques to physical disability in this population. We reviewed the clinical presentations in the carrier population, the distinct disability profile and neuroimaging findings in order to put together pieces of this neglected segment in X-ALD and give direction to further studies.

Lessons learned from clinical trials of exercise and physical activity in people with MS - guidance for improving the quality of future research.

The body of research on exercise and physical activity among persons with multiple sclerosis(MS) has expanded rapidly in quantity, but not necessarily quality, over the past 20+ years. There is evidence for beneficial effects of exercise and physical activity on immune cells and neurotrophic factors, brain structure and function, walking and cognitive performance, fatigue, depression, and pain, and quality of life among persons with MS. Nevertheless, there is heterogeneity in the outcomes of exercise and physical activity, and a recognition of substantial challenges for improving the effectiveness of those behaviors in MS. To move the field forward, members of the National MS Society physical wellness research working-group pooled collective experiences for identifying challenges, logistic complexities, and opportunities for researchers in designing and conducting interventions of exercise and physical activity among persons with MS. We examined the scope of our experiences and identified collective "lessons learned" regarding the behaviors themselves; study design features and stage of research; study setting, safety, and sample selection; and implementation of randomized controlled trials(RCTs) and treatment fidelity. This paper provides a resource that can inform researchers, particularly new investigators or established investigators transitioning into MS, on conducting high-quality RCTs on exercise and physical activity in MS.

From the prodromal stage of multiple sclerosis to disease prevention.

A prodrome is an early set of signs or symptoms that indicate the onset of a disease before more typical symptoms develop. Prodromal stages are well recognized in some neurological and immune-mediated diseases such as Parkinson disease, schizophrenia, type 1 diabetes mellitus and rheumatoid arthritis. Emerging evidence indicates that a prodromal stage exists in multiple sclerosis (MS), raising the possibility of intervention at this stage to delay or prevent the development of classical MS. However, much remains unclear about the prodromal stage of MS and considerable research is needed to fully characterize the prodrome and develop standardized criteria to reliably identify individuals with prodromal MS who are at high risk of progressing to a diagnosis of MS. In this Roadmap, we draw on work in other diseases to propose a disease framework for MS that incorporates the prodromal stage, and set out key steps and considerations needed in future research to fully characterize the MS prodrome, identify early disease markers and develop standardized criteria that will enable reliable identification of individuals with prodromal MS, thereby facilitating trials of interventions to slow or stop progression beyond the prodrome.

Longitudinal tracking of gait and balance impairments in cerebellar disease.

Cerebellar damage typically results in ataxia and can be caused by stroke, tumor, or one of many forms of degenerative disease. Since few pharmacological options are available, most treatments rely heavily on rehabilitation therapy. Little data exist on methods for tracking the progression of ataxia, which is critical for assessing the efficacy of current and newly developing treatments. Here, we tracked the severity of ataxia, with a particular emphasis on gait and balance dysfunction, in a group of individuals with cerebellar damage using the International Cooperative Ataxia Rating Scale (ICARS) and several instrumented laboratory measures of gait and balance impairments over 1 year. We found that the ICARS was able to distinguish between subjects with static lesions and those with degenerative disorders, was sensitive to increases in ataxia severity occurring over 1 year, and correlated well with specific instrumented measures of gait in persons with cerebellar degeneration. These results suggest the ICARS is a valuable tool for clinicians and investigators to document and track long-term changes in gait and balance performance in individuals with cerebellar degenerative disorders.

Sensorimotor dysfunction in multiple sclerosis and column-specific magnetization transfer-imaging abnormalities in the spinal cord.

The human spinal cord contains segregated sensory and motor pathways that have been difficult to quantify using conventional magnetic resonance imaging (MRI) techniques. Multiple sclerosis is characterized by both focal and spatially diffuse spinal cord lesions with heterogeneous pathologies that have limited attempts at linking MRI and behaviour. We used a novel magnetization-transfer-weighted imaging approach to quantify damage to spinal white matter columns and tested its association with sensorimotor impairment. We studied 42 participants with multiple sclerosis who each underwent MRI at 3 Tesla and quantitative tests of sensorimotor function. We measured cerebrospinal-fluid-normalized magnetization-transfer signals in the dorsal and lateral columns and grey matter of the cervical cord. We also measured brain lesion volume, cervical spinal cord lesion number and cross-sectional area, vibration sensation, strength, walking velocity and standing balance. We used linear regression to assess the relationship between sensorimotor impairment and MRI abnormalities. We found that the dorsal column cerebrospinal-fluid-normalized magnetization-transfer signal specifically correlated with vibration sensation (R = 0.58, P < 0.001) and the lateral column signal with strength (R = -0.45, P = 0.003). Spinal cord signal measures also correlated with walking and balance dysfunction. A stepwise multiple regression showed that the dorsal column signal and diagnosis subtype alone explained a significant portion of the variance in sensation (R(2) = 0.54, P < 0.001), whereas the lateral column signal and diagnosis subtype explained a significant portion of the variance in strength (R(2) = 0.30, P < 0.001). These results help to understand the anatomic basis of sensorimotor disability in multiple sclerosis and have implications for testing the effects of neuroprotective and reparative interventions.

Combining Magnetization Transfer Ratio MRI and Quantitative Measures of Walking Improves the Identification of Fallers in MS.

Multiple sclerosis (MS) impacts balance and walking function, resulting in accidental falls. History of falls and clinical assessment are commonly used for fall prediction, yet these measures have limited predictive validity. Falls are multifactorial; consideration of disease-specific pathology may be critical for improving fall prediction in MS. The objective of this study was to examine the predictive value of clinical measures (i.e., walking, strength, sensation) and corticospinal tract (CST) MRI measures, both discretely and combined, to fall status in MS. Twenty-nine individuals with relapsing-remitting MS (mean ± SD age: 48.7 ± 11.5 years; 17 females; Expanded Disability Status Scale (EDSS): 4.0 (range 1-6.5); symptom duration: 11.9 ± 8.7 years; 14 fallers) participated in a 3T brain MRI including diffusion tensor imaging and magnetization transfer ratio (MTR) and clinical tests of walking, strength, sensation and falls history. Clinical measures of walking were significantly associated with CST fractional anisotropy and MTR. A model including CST MTR, walk velocity and vibration sensation explained >31% of the variance in fall status (R2 = 0.3181) and accurately distinguished 73.8% fallers, which was superior to stand-alone models that included only MRI or clinical measures. This study advances the field by combining clinical and MRI measures to improve fall prediction accuracy in MS.

Longitudinal assessment of hand function in individuals with multiple sclerosis.

OBJECTIVE: Little is known about the frequency and severity of hand dysfunction in individuals with multiple sclerosis (MS). Hence, we sought to determine the extent that quantitative tests of hand function detect changes over time, evaluate their relationship to global disability measures, and identify predictors of hand function. METHODS: One-hundred and forty-seven individuals with MS were included (96 women, 84 relapsing-remitting MS [RRMS]) along with 35 age-and-sex matched controls. Quantitative tests of hand function (grip strength, pinch strength, 9 hole peg test [9HPT], finger tapping) and leg strength were acquired and normalized to age and sex. Expanded Disability Status Scale (EDSS) and timed 25 foot walk were also obtained. Spearman correlations, multivariate regression models and mixed effects linear regression were used for analysis. RESULTS: Our cohort had an EDSS of 3.6 ±â€¯2.2 (median ± SD) and age 44.6 ±â€¯11.9 years. Follow up time was up to 5 years. At baseline, 14/63 individuals with progressive MS (PMS) required more than twice as much time to complete the 9HPT using their dominant hand, compared to controls. Similarly, 11 individuals with PMS had less than 50% of grip strength and 6 had less than 50% of pinch strength, compared to controls. Additionally, 7 individuals with PMS were found to be at least 50% slower than controls in finger tapping. Over two years, 27/85 individuals with MS had more than 20% worsening in their 9HPT results from baseline (17 RRMS, 10 PMS) and 37/74 (20 RRMS, 17 PMS) had more than 20% worsening in their grip strength compared to baseline. CONCLUSIONS: Hand function is commonly impaired in individuals with MS. Assessing hand dysfunction with dynamometry and the 9HPT could help improve the precision of detecting changes in hand function over time in MS, and may be more sensitive in detecting changes in PMS. These quantitative tests may be useful as outcome measures in clinical trials using neuroprotective or reparative therapies and rehabilitative interventions.

Quantitative vibratory sensation measurement is related to sensory cortical thickness in MS.

Objective: Vibratory sensation is a quantifiable measure of physical dysfunction and is often related to spinal cord pathology; however, its association with relevant brain areas has not been fully explored. Our objective was to establish a cortical structural substrate for vibration sensation. Methods: Eighty-four individuals with multiple sclerosis (MS) (n = 54 relapsing, n = 30 progressive) and 28 controls participated in vibratory sensation threshold quantification at the great toe and a 3T MRI evaluating volume of the thalamus and cortical thickness primary and secondary sensory cortices. Results: After controlling for age, sex, and disability level, vibratory sensation thresholds were significantly related to cortical thickness of the anterior cingulate (P = 0.041), parietal operculum (P = 0.022), and inferior frontal gyrus pars operculum (P = 0.044), pars orbitalis (P = 0.007), and pars triangularis (P = 0.029). Within the progressive disease subtype, there were significant relationships between vibratory sensation and thalamic volume (P = 0.039) as well as reduced inferior frontal gyrus pars operculum (P = 0.014) and pars orbitalis (P = 0.005) cortical thickness. Conclusions: The data show significant independent relationships between quantitative vibratory sensation and measures of primary and secondary sensory cortices. Quantitative clinical measurement of vibratory sensation reflects pathological changes in spatially distinct brain areas and may supplement information captured by brain atrophy measures. Without overt relapses, monitoring decline in progressive forms of MS has proved challenging; quantitative clinical assessment may provide a tool to examine pathological decline in this cohort. These data suggest that quantitative clinical assessment may be a reliable way to examine pathological decline and have broader relevance to progressive forms of MS.

Distinguishing among multiple sclerosis fallers, near-fallers and non-fallers.

BACKGROUND: Fall rates among adults with multiple sclerosis are consistently greater than 50%, but near-falls (i.e. a trip or stumble) are often undocumented. Furthermore, little is known about the circumstances surrounding fall and near-fall events. The purpose of this study was to examine the similarities and differences among non-fallers, near-fallers and fallers with multiple sclerosis, including the circumstances that surround falls and near-falls. METHODS: In a single visit, 135 multiple sclerosis participants completed the Hopkins Falls Grading Scale, a custom questionnaire investigating circumstances surrounding falls and near-falls, and performed the Timed Up and Go and Timed 25-Foot Walk tests. Mann-Whitney tests were used to examine differences between fallers, near-fallers and non-fallers. Multiple logistic regression with AIC criterion was used to examine associations of circumstances with the odds of falling vs. near-falling. Cumulative odds ordinal logistic regression was used to analyze the association between each of the walking tests and the susceptibility of the individual for falls or near-falls. RESULTS: 30% of individuals reported falls, while 44% reported near-falls over a 1-year period. Non-fallers completed the walking tests more quickly than near-fallers (p < 0.0045), and fallers (p < 0.0001); near-fallers and fallers demonstrated similar motor profiles. Individuals were more likely to sustain a fall rather than a near-fall under the following circumstances: transferring outside the home (p = 0.015) and tripping over an obstacle (p = 0.025). Performing 1-second slower on the walking tests increased the odds of a history of a fall by 6-20%. CONCLUSION: Near-falls occur commonly in individuals with MS; near-fallers and fallers reported similar circumstances surrounding fall events and demonstrated similar performance on standard timed walking tests. Clinicians monitoring individuals with MS should consider evaluation of the circumstances surrounding falls in combination with quantitative walking measures to improve determination of fall risk and appropriate rehabilitation interventions.

Quantitative measures of walking and strength provide insight into brain corticospinal tract pathology in multiple sclerosis.

At least 85% of individuals with multiple sclerosis report walking dysfunction as their primary complaint. Walking and strength measures are common clinical measures to mark increasing disability or improvement with rehabilitation. Previous studies have shown an association between strength or walking ability and spinal cord MRI measures, and strength measures with brainstem corticospinal tract magnetization transfer ratio. However, the relationship between walking performance and brain corticospinal tract magnetization transfer imaging measures and the contribution of clinical measurements of walking and strength to the underlying integrity of the corticospinal tract has not been explored in multiple sclerosis. The objectives of this study were explore the relationship of quantitative measures of walking and strength to whole-brain corticospinal tract-specific MRI measures and to determine the contribution of quantitative measures of function in addition to basic clinical measures (age, gender, symptom duration and Expanded Disability Status Scale) to structural imaging measures of the corticospinal tract. We hypothesized that quantitative walking and strength measures would be related to brain corticospinal tract-specific measures, and would provide insight into the heterogeneity of brain pathology. Twenty-nine individuals with relapsing-remitting multiple sclerosis (mean(SD) age 48.7 (11.5) years; symptom duration 11.9(8.7); 17 females; median[range] Expanded Disability Status Scale 4.0 [1.0-6.5]) and 29 age and gender-matched healthy controls (age 50.8(11.6) years; 20 females) participated in clinical tests of strength and walking (Timed Up and Go, Timed 25 Foot Walk, Two Minute Walk Test ) as well as 3 T imaging including diffusion tensor imaging and magnetization transfer imaging. Individuals with multiple sclerosis were weaker (p = 0.0024) and walked slower (p = 0.0013) compared to controls. Quantitative measures of walking and strength were significantly related to corticospinal tract fractional anisotropy (r > 0.26; p < 0.04) and magnetization transfer ratio (r > 0.29; p < 0.03) measures. Although the Expanded Disability Status Scale was highly correlated with walking measures, it was not significantly related to either corticospinal tract fractional anisotropy or magnetization transfer ratio (p > 0.05). Walk velocity was a significant contributor to magnetization transfer ratio (p = 0.006) and fractional anisotropy (p = 0.011) in regression modeling that included both quantitative measures of function and basic clinical information. Quantitative measures of strength and walking are associated with brain corticospinal tract pathology. The addition of these quantitative measures to basic clinical information explains more of the variance in corticospinal tract fractional anisotropy and magnetization transfer ratio than the basic clinical information alone. Outcome measurement for multiple sclerosis clinical trials has been notoriously challenging; the use of quantitative measures of strength and walking along with tract-specific imaging methods may improve our ability to monitor disease change over time, with intervention, and provide needed guidelines for developing more effective targeted rehabilitation strategies.

Sensorimotor function and axonal integrity in adrenomyeloneuropathy.

BACKGROUND: Gait abnormalities and sensorimotor disturbances are principal defects in adrenomyeloneuropathy (AMN). However, to our knowledge, their association with overall impairment and neuroanatomical changes has not been defined. OBJECTIVES: To understand how sensorimotor impairments create mobility deficits and to analyze how these impairments are related to specific metrics of axonal integrity. DESIGN: Cross-sectional study assessing impairments, including vibration sensation, strength, spasticity, and global measures of walking and balance. Fractional anisotropy was measured to evaluate the integrity of the corresponding brainstem tracts. PARTICIPANTS: Men with AMN and healthy control subjects. RESULTS: Individuals with sensory loss only showed minimal walking deficits. Concomitant strength and sensory loss resulted in slower walking, with abnormal knee control; increased spasticity led to an exaggerated trunk motion and a knee-flexed (crouched) posture. Hip strength was an independent predictor of walking velocity in subjects with AMN. Subjects with sensory loss only had greater sway amplitudes during standing balance testing, which did not worsen with additional impairments. There were significant associations among sway amplitude, great toe vibration sense, and dorsal column fractional anisotropy. Brainstem fractional anisotropy in AMN was significantly negatively correlated with impairment, indicating that overall tract integrity is associated with sensorimotor abnormalities in AMN. CONCLUSIONS: Impairment measures capture specific abnormalities in walking and balance that can be used to direct rehabilitation therapy in AMN. Tract-specific magnetic resonance imaging metrics, such as fractional anisotropy (used herein to evaluate structure-function relationships), significantly reflect disease severity in AMN.