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  • Neuroscience

Current highlights, innovative findings, exciting results

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  • 11 minute read

“The Quintessence of Neuroscience for the 21st Century” was the theme of the American Academy of Neurology ‘s anniversary meeting – and the range of topics lived up to that slogan. Neurology experts from around the world were once again given the opportunity to share their latest clinical findings and patient care expertise.

Serum neurofilament light chains (sNfL) are a marker of neuronal damage in multiple sclerosis (MS). Previous studies examining the predictive value of early sNfL measurements for disability progression were limited by consideration of MRI activity. Therefore, the aim of a recent study was to evaluate the association between sNfL and disease progression in a cohort of individuals with early relapsing-remitting multiple sclerosis (RRMS), controlling for clinical and radiographic activity [1]. This cross-sectional study took the relationship between (a) the progression of disability from baseline to year three; and (b) of sNfL measured at year 3 in more detail in RADIEMS, a prospective longitudinal cohort study that enrolled participants shortly after MS diagnosis (<5 years). Progression of disability was defined by the increase in EDSS in three strata from baseline to three-year follow-up. After generalized linear modeling adjusting sNfL for age, time since diagnosis, and intermediate inflammatory activity (recurrence or MRI activity), nonparametric tests (using SPSS) assessed differences in sNfL between patients with and without disability progression. EDSS worsened in 29 (26.9%) patients. Serum NfL levels adjusted for age and time since diagnosis were higher in patients with EDSS exacerbation than in patients without EDSS exacerbation: median (IQR), 9.39 pg/mL vs. 6.81 pg/mL. Additional adjustment for intermediate inflammatory activity revealed even higher sNFL values in patients with and without EDSS exacerbation: 8.54 pg/ml vs. 6.86 pg/ml. The magnitude of raw EDSS change from baseline also correlated with higher sNfL levels, both adjusted for and unadjusted for intermediate inflammatory activity. Measurement of serum NfL early in the disease course of RRMS correlated with worsening EDSS, even when clinical and radiological activity were controlled. This suggests that sNfL plays a role in identifying patients with disability progression independent of activity in the early phase of MS.

Do not forget the iron level in MS

Iron accumulation is a key feature of chronically active lesions – a key feature of progressive MS – and can be detected by magnetic resonance imaging. In parallel, the molecular profile of microglia associated with the lesion supports the importance of genes involved in iron metabolism. However, it is still unclear what role they play in the progression of the disease. Now, the effects of single nucleotide polymorphisms (SNPs) in genes involved in iron metabolism on the risk of developing progressive MS have been studied [2]. For this, an association analysis of 37 794 SNPs in 319 genes involved in iron metabolism was performed. Benign patients with a relapsing-remitting course (RR) were compared with patients with a secondary progressive course (SP). There was a significant association with SNPs in the hypoxia inducible factor-1-alfa (HIF1A) gene. Previous studies have shown that rs11621525_A downregulates HIF1A expression in whole blood of healthy individuals. This effect was replicated in peripheral blood mononuclear cells from 78 RR-MS patients. In addition, the concentration of neurofilaments (NFL), a recognized marker of ongoing axonal injury and chronic white matter inflammation, was examined. RR-MS patients who were carriers of the A allele had lower NFL levels, both in plasma and CSF. Genetic variants in HIF1A are thus associated with the risk of progressive MS and influence NFL levels. HIF1A is a fundamental regulator of iron metabolism, response to hypoxia, and immune processes, making it a promising candidate for further investigation.

Gait assessment as screening for stroke

The National Institutes of Health Stroke Scale (NIHSS) is less meaningful in patients with posterior circulation stroke (PCS) because signs and symptoms related to the posterior fossa are not considered. The hypothesis that the association with objective gait abnormality (OGA) is greater in PCS patients than in posterior stroke patients, especially in patients with vertigo or subjective gait abnormality (SGA), was tested [3]. A case-cohort study was performed to determine the likelihood of OGA in PCS patients and mimics and to report confidence intervals (CI), sensitivity (SE), specificity (SP), positive predictive value (PPV), and negative predictive value (NPV). PCS cases were defined as acute ischemic strokes confined to the territory of the posterior cerebral artery, basilar artery, or vertebral artery. Mimics were defined as patients with acute vertigo due to other causes. Eighty-two PCS patients and 104 mimics were identified and their gait pattern was assessed on arrival. OGA was documented in 69/82 (84.1%) PCS cases versus 18/104 (17.3%) mimics. Stratified by vertigo, OGA was documented in 38/44 (86%) PCS cases versus 18/104 (17.3%) mimics. Stratified by SGA, OGA was observed in 48/52 (92%) PCS cases versus 16/74 (21.6%) mimics. Patients with PCS were 25.4 times more likely to have OGA than mimics and 30.3 and 43.5 times more likely to have OGA if they were admitted with vertigo or SGA, respectively. While SP and PPV remained low (<90%), NPV increased to 94% in patients with vertigo and SGA on admission. Gait examination can be used as a cost-effective screening tool to rule out PCS on admission.

Telemedicine for Parkinson’s disease

Falls in PD are very common, with devastating consequences, poorer quality of life, increased comorbidity, and social isolation. Telerehabilitation has shown promising effects on motor symptoms, but the efficacy of a multidisciplinary telehealth intervention in addition to standard clinical care on nonmotor symptoms (NMS), quality of life, and lifestyle have remained unclear. The aim of a study was to investigate the effectiveness of a multidisciplinary telemedicine (TM) program to improve lifestyle, motor and non-motor symptom burden, and quality of life (QoL) in patients with Parkinson’s disease (PD) at high risk for falls [4]. The study group was assigned to a multidisciplinary TM program plus standard care for four months and compared with the control group (office visits, standard care). TM included occupational therapy, nutrition, and clinical PD management. After completion of TM, both groups were compared after eight months. After four months, patients under TM showed improvement in MDS-UPDRS II, Mini-Best, FOGQ, EuroHis-QoL8, LARS, and BDI-II compared with controls. At the end of TM after eight months, FOG and Mini-Best scores were better in the TM group compared with the control subjects. Results demonstrate that a multidisciplinary TM intervention, in addition to standard care, improves gait, quality of life, and NMS in PD patients at high risk for falls.

Glioblastoma therapy in elderly patients

Older adults 65 years and older with glioblastoma (GBM) are vulnerable to overtreatment, undertreatment, and increased toxicity. Geriatric assessment predicts toxicity in cancer patients, but data in neuro-oncology are limited. A prospective study enrolled 26 elderly GBM patients [5]. They completed a geriatric G8 screening and comprehensive geriatric assessment (CGA) prior to treatment. Physicians recommended treatment and estimated toxicity based on their clinical judgment and independent of GA. 77% of patients had a G8 score ≤14, indicating the need for CGA. Disease-oriented therapy was recommended for all patients. Of patients with G8 ≤14 weeks, 5% were recommended for a clinical trial, 35% received six weeks of radiation plus chemotherapy, 35% received three weeks of radiation plus chemotherapy, and 25% received three weeks of radiation alone. There was no association between G8 score or CGA components and treatment recommendation. 54% suffered from treatment intolerances. The most common toxicity was fatigue, which required a change in chemotherapy dose. Age was predictive of treatment intolerance. Treatment recommendations based on clinical judgment were independent of geriatric assessment. This suggests that practitioners did not recognize geriatric vulnerabilities found on G8 or CGA in the majority of elderly patients with GBM. Treatment toxicity is common in elderly patients with GBM and is underestimated by physicians. Further research should be done here.

Neuroinflammation in autism spectrum disorders.

Although neuroinflammation is considered one of the major components of autism spectrum disorder (ASD) and its etiology, the molecular mechanism of the disorder is not well understood. Advances in single-cell genomics and transcriptomics have led to the identification of novel pathways controlling astrocyte functions associated with chronic neuroinflammatory disorders such as multiple sclerosis (MS). These advances provide the opportunity to investigate the common molecular mechanisms involved in both ASD and MS and ultimately to elucidate the etiology of ASD. One paper analyzed and characterized the common astrocyte subpopulations found in both ASD and MS [6]. For this, large-scale single-cell RNA-seq expression data collected from postmortem brain samples of individuals with ASD and MS were used. Analysis revealed that oxidative stress-mediated ferroptosis plays a distinct role in pathological astrocyte subpopulations. This discovery allows hypothesizing that FTH1, SLC7A11, SAT1, CP, FTL, and MAPK signaling may be involved in ASD pathophysiology, which could be further explored as new targets for intervention.

Development of somatosensory neurons

The sense of touch is vital and relies on low-threshold mechanoreceptors (LTMRs). LTMR subtypes characterized by early embryonic expression of Ntrk2 (TrkB) and Ret exhibit different properties depending on which skin region they innervate-hairy skin or glabrous (hairless) skin. In glabrous skin, TrkB+ and Ret+ LTMRs form Meissner bodies, whereas in hairy skin they form elongated-lanceolate terminals around hair follicles. These morphological features reflect the physiological properties and specialized functions of these neurons. The developmental steps leading to the LTMR properties of glabrous and hairy skin are largely unknown, particularly whether they are genetically prespecified or whether interactions with different target skin regions determine their unique characteristics. Single genetic labeling experiments show that morphological specialization of TrkB+ and Ret+ LTMRs occurs at nearly identical time points during postnatal development. Interestingly, one study found that single neurons terminating along the boundary between glabrous and hairy skin, termed “boundary neurons,” have branches that form both lanceolate terminals and terminals of Meissner bodies [7].

Furthermore, transcriptomic profiling and RNAscope experiments show that neonatal glabrous skin and hairy skin-innervating TrkB+ and Ret+ neurons are transcriptionally similar, although distinct from other DRG neuron types. Finally, using mouse mutants that have either ectopic glabrous skin or ectopic hairy skin, it was found that neurons innervating ectopic skin regions of these mutants form terminal types (either lanceolate or Meissner corpuscle terminals) consistent with ectopic skin type.

These results support a working model in which embryonic TrkB+ and Ret+ LTMRs can form either Meissner bodies or lanceolate terminals, and that the target skin region differentially controls the morphological maturation of these LTMR types.

The role of neck pain in migraine patients

Neck pain (NP) has been documented as a migraine symptom associated with increased disability. However, there is limited data on the experience of NP from the perspective of people with episodic migraine (EP). A targeted PubMed literature search examined the relationship between NP and EM [8]. Adults with clinically diagnosed EM (5-14 days/month) were recruited to participate in conceptual survey interviews. Trained researchers used a semi-structured interview guide based on the results of the literature review. Open-ended questions were asked to elicit spontaneous reports of NP experiences associated with migraine and their temporal occurrence. When concepts were not addressed spontaneously, specific questions were asked. The results of the literature review showed that NP is very common before, during, and after the headache phase of migraine and is associated with an increased Neck Disability Index. Twenty participants completed the qualitative interviews; 65.0% reported NP related to migraine. The duration of the NP ranged from a few hours to 1 day. Most participants described their NP as tight, stiff, or firm. These findings confirm that NP is a troublesome symptom for individuals with EM and can be an important outcome of effective treatment.

Impairments in Lewy body dementia

Understanding the specific cognitive domains associated with impairment in activities of daily living (ADLs) in Lewy body dementia (LBD) (Fig. 1) can help identify patients who need additional support and who would benefit from targeted therapeutic interventions. For this purpose, neuropsychological test data from 207 LBD patients (including dementia with Lewy bodies and Parkinson’s dementia) in a clinical neuropsychological registry were analyzed [9]. All patients were assessed for impairments in eight ADLs. Patients were classified as either mild, moderate, or severe. Neuropsychological test performance differed significantly among the three groups. Especially in tests of global cognition, accelerated visuospatial processing, accelerated executive function, and psychomotor processing speed. Post-hoc comparisons revealed that the group with severe ADL limitations performed significantly worse on these measures than the other ADL groups. Impairments in driving a vehicle and self-care were associated with poorer performance on course construction part A, course construction part B, and psychomotor processing speed compared with patients without impairments in these activities. Processing speed performance may be useful in predicting limitations in ADLs in LBD.

PML in focus

Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease caused by JC virus reactivation and oligodendrocyte destruction. JC virus has a high prevalence of over 80% in the adult population. Most infections are asymptomatic, with the virus lying dormant in the kidney and lymph organs. In immunosuppression, the virus can replicate in glial cells and spread to the brain. Most cases are fatal, although progression can be slowed by immune reconstitution. A study now described a case of rapidly progressive PML and the differential diagnosis in isolated brainstem involvement [10]. A patient in his 60s presented with four weeks of increasing cognitive decline and gait difficulties. Over the next ten days, the patient became increasingly drowsy and developed generalized myoclonus and bulbar symptoms. A JCV titer of 478 000 copies/mL was detected in the CSF, confirming PML. Because of the unusually rapid progression, a superimposed process such as PRES or osmotic demyelination syndrome was considered. This differential diagnosis was supported by initial MRI without contrast. MRI with contrast showed conspicuous patchy pontine enhancement. Tacrolimus was discontinued without improvement, and sodium levels were stable throughout the admission.

PML is classically seen in patients with hematopoietic cancers, HIV infection, and immunosuppressive therapy in transplant recipients. It has also been reported in association with the use of monoclonal therapies, autoimmune diseases, and primary immunodeficiencies. The classic presentation is characterized by subacute deterioration of cognitive abilities, gait and limb ataxia, and visual and motor deficits. Imaging typically shows confluent white matter lesions in the cerebral hemispheres with or without contrast enhancement. In rare cases, PML may be confined to the brainstem, and other causes must be excluded. An atypical clinical presentation and the absence of classic WM lesions should trigger additional investigations in patients with suspected PML to rule out other diagnoses. PML is becoming more common as the prevalence increases in immunocompromised patients.

Congress: 75th Annual Meeting of the American Academy of Neurology (AAN)

Literature:

  1. Satyanarayan S, Sand IK, Sumowski J: Serum neurofilament light chain association with progression independent of activity in people with early RRMS. Poster S9.005. American Academy of Neurology (AAN) Annual Meeting; 22.-27.04.2023.
  2. Giordano A, Santoro S, Sorosina M, et al.: Genetic Variants in Iron Metabolism impact Disease Progression in MS through HIF1A. Poster S9.006. American Academy of Neurology (AAN) Annual Meeting; 22.–27.04.2023.
  3. Smith I, Valdes E, Torres J, Melmed K: Walk Your Dizzy Patients! Gait Assessment as a Screening Tool for Posterior Circulation Stroke. Poster S3.001. American Academy of Neurology (AAN) Annual Meeting; 22.–27.04.2023.
  4. Cubo Delgado E, Garcia-Bustillo A, Arnaiz A, et al.: Efficacy on Non-motor and Motor symptoms and Quality of Life using a multidisciplinary telemedicine program in high-risk fall patients with Parkinson’s disease. Poster S32.003. American Academy of Neurology (AAN) Annual Meeting; 22.–27.04.2023.
  5. Hemminger L, Whitt W, Cawley S, et al.: Treatment Recommendations and Estimation of Toxicity in Older Patients with Glioblastoma. Poster P3.001. American Academy of Neurology (AAN) Annual Meeting; 22.–27.04.2023.
  6. Zhang V: Cross-disease Transcriptomic Analysis Elucidating the Roles of Astrocytic Signaling Pathways Regulating Neuroinflammation in Autism Spectrum Disorder. Poster S2.003. American Academy of Neurology (AAN) Annual Meeting; 22.–27.04.2023.
  7. Koutsioumpa C, Santiago C, Jacobs K, et al.: Skin-dependent morphological and molecular maturation of specialized mechanosensory neurons. Poster S34.005. American Academy of Neurology (AAN) Annual Meeting; 22.–27.04.2023.
  8. Blumenfeld A, Mordin M, Kosa K, et al.: Exploring the Experience of Neck Pain in Individuals With Episodic Migraine. Poster P3.004. American Academy of Neurology (AAN) Annual Meeting; 22.–27.04.2023.
  9. Desai N, Nawaz H, Mukhopadhyay N, et al.: Cognitive correlates of ADL impairment in Lewy body dementia. Poster P13.005. American Academy of Neurology (AAN) Annual Meeting; 22.–27.04.2023.
  10. Gates J, Izurieta MS: Fatal Isolated Brainstem Lesion in a Patient With Progressive Multifocal Leukoencephalopathy. Poster P13.005. American Academy of Neurology (AAN) Annual Meeting; 22.–27.04.2023.

InFo NEUROLOGIE & PSYCHIATRIE 2023; 21(3): 20–23

Autoren
  • Leoni Burggraf
Publikation
  • InFo NEUROLOGIE & PSYCHIATRIE
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