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Predicting the Evolution of Neurological Diseases: The Role of Biomarkers in 2022 and Beyond

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Clinical Neurology".

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 14776

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Dr. Cristoforo Comi

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Department of Translational Medicine, Section of Neurology, University of Piemonte Orientale, 28100 Novara, Italy
Interests: neurodegenerative diseases including Parkinson\'s disease, Huntington disease, other movement disorders, Alzheimer\'s disease; neuroimmune diseases including: multiple sclerosis, inflammatory neuropathies, myasthenia gravis
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Special Issue Information

Dear Colleagues,

Modern medicine is heading toward a personalized approach, and the definition of prognosis is a fundamental aspect of this strategy. The ability to predict disease evolution allows allocating the right therapy to the right patient, but also preparing the patient and the caregiver for the challenges that they will have to face. There are still several neurological conditions lacking a disease-modifying therapy, but this is expected to change in the near future, thus opening the way to a new era of disease management.

According to the World Health Organization (WHO), a biomarker is “any substance, structure, or process that can be measured in the body or its products and influence or predict the incidence of outcome or disease”.

In this Special Issue, I would like to invite authors to submit studies focusing on prognostic biomarkers of neurological diseases. Authors are welcome to cover all areas of clinical neurology, including, but not limited to neurodegenerative diseases, neuroimmune/neuroinflammatory diseases, cerebrovascular diseases, brain tumors, and neuromuscular diseases.

Dr. Cristoforo Comi
Guest Editor

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Keywords

Parkinson’s disease
Alzheimer’s disease
cerebrovascular disease
multiple sclerosis
amyotrophic lateral sclerosis
disease progression
disability
neurodegeneration

Published Papers (10 papers)

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12 pages, 1445 KiB

Open AccessArticle

APOE ε4 Gene Carriers Demonstrate Reduced Retinal Capillary Densities in Asymptomatic Older Adults

by Ziyi Zhang, William Robert Kwapong, Le Cao, Zijuan Feng, Bo Wu, Junfeng Liu and Shuting Zhang

J. Clin. Med. 2023, 12(17), 5649; https://doi.org/10.3390/jcm12175649 - 30 Aug 2023

Cited by 2 | Viewed by 817

Abstract

Early identification of Apolipoprotein E (APOE)-related microvascular pathology will help to study the microangiopathic contribution to Alzheimer’s disease and provide a therapeutic target for early intervention. To evaluate the differences in retinal microvasculature parameters between APOE ε4 carriers and non-carriers, asymptomatic older adults aged ≥ 55 years underwent APOE ε4 genotype analysis, neuropsychological examination, and optical coherence tomography angiography (OCTA) imaging. One hundred sixty-three older adults were included in the data analysis. Participants were also defined as cognitively impaired (CI) and non-cognitively impaired (NCI) according to their MoCA scores and educational years. APOE ε4 carriers demonstrated reduced SVC (p = 0.023) compared to APOE ε4 non-carriers. Compared to NCI, CI participants showed reduced SVC density (p = 0.006). In the NCI group, no significant differences (p > 0.05) were observed in the microvascular densities between APOE ε4 carriers and non-carriers. In the CI group, APOE ε4 carriers displayed reduced microvascular densities compared to non-carriers (SVC, p = 0.006; DVC, p = 0.048). We showed that CI and APOE ε4 affect retinal microvasculature in older adults. Quantitative measures of the retinal microvasculature could serve as surrogates for brain microcirculation, providing an opportunity to study microvascular contributions to AD. Full article

(This article belongs to the Special Issue Predicting the Evolution of Neurological Diseases: The Role of Biomarkers in 2022 and Beyond)

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10 pages, 947 KiB

Open AccessArticle

Lymphocyte Count and Neutrophil-to-Lymphocyte Ratio Are Associated with Mild Cognitive Impairment in Parkinson’s Disease: A Single-Center Longitudinal Study

by Elena Contaldi, Luca Magistrelli, Marco Cosentino, Franca Marino and Cristoforo Comi

J. Clin. Med. 2022, 11(19), 5543; https://doi.org/10.3390/jcm11195543 - 22 Sep 2022

Cited by 10 | Viewed by 1979

Abstract

Lymphocyte count and neutrophil-to-lymphocyte ratio (NLR) may represent useful biomarkers of Parkinson’s disease (PD), but their role in PD-related mild cognitive impairment (MCI) has not been fully elucidated. The present study aimed to confirm whether these immunological measures can discriminate PD patients from healthy controls (HC) and establish their feasibility as prognostic biomarkers of MCI in PD. Immunological data at baseline were analyzed in 58 drug-naïve PD patients and 58 HC matched 1:1 for age, sex, and cardiovascular comorbidities. We selected a subgroup of 51 patients from this initial cohort who underwent longitudinal neuropsychological assessments through the Addenbrooke’s Cognitive Examination Revised (ACE-R) test. We considered the last examination available to analyze the relationship between ACE-R test scores and immunological measures. We found that lymphocyte count was lower and NLR higher in PD than HC (p = 0.006, p = 0.044), with AUC = 0.649 and 0.608, respectively. Secondly, in PD-MCI there were significantly higher levels of circulating lymphocytes (p = 0.002) and lower NLR (p = 0.020) than PD with normal cognitive status (PD-NC). Correlations between lymphocyte count and ACE-R total score and memory subitem (r = −0.382, p = 0.006; r = −0.362, p = 0.01), as well as between NLR and ACE-R total score and memory subitem (r = 0.325, p = 0.02; r = 0.374, p = 0.007), were also found. ROC curve analysis showed that lymphocyte count and NLR displayed acceptable discrimination power of PD-MCI with AUC = 0.759 and 0.691, respectively. In conclusion, we suggest that an altered peripheral immune phenotype could foster cognitive decline development in PD, thus opening the possibility of immune-targeting strategies to tackle this disabling non-motor feature. Full article

(This article belongs to the Special Issue Predicting the Evolution of Neurological Diseases: The Role of Biomarkers in 2022 and Beyond)

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12 pages, 1547 KiB

Open AccessArticle

Comparative Analysis of Neurodegeneration and Axonal Dysfunction Biomarkers in the Cerebrospinal Fluid of Patients with Multiple Sclerosis

by Agnieszka Kulczyńska-Przybik, Maciej Dulewicz, Julia Doroszkiewicz, Renata Borawska, Ala Litman-Zawadzka, Daria Arslan, Alina Kułakowska, Jan Kochanowicz and Barbara Mroczko

J. Clin. Med. 2022, 11(14), 4122; https://doi.org/10.3390/jcm11144122 - 15 Jul 2022

Cited by 2 | Viewed by 1589

Abstract

Background: Given the significant role of neurodegeneration in the progression of multiple sclerosis (MS) and insufficient therapies, there is an urgent need to better understand this pathology and to find new biomarkers that could provide important insight into the biological mechanisms of the disease. Thus, the present study aimed to compare different neurodegeneration and axonal dysfunction biomarkers in MS and verify their potential clinical usefulness. Methods: A total of 59 patients, who underwent CSF analysis during their diagnostics, were enrolled in the study. Quantitative analysis of neurodegeneration biomarkers was performed through immunological tests. Oligoclonal bands were detected by isoelectric focusing on agarose gel, whereas the concentrations of immunoglobulins and albumin were measured using nephelometry. Results: Our studies showed that NfL, RTN4, and tau protein enabled the differentiation of MS patients from the control group. Additionally, the baseline CSF NfL levels positively correlated with the tau and MRI results, whereas the RTN4 concentrations were associated with the immunoglobulin quotients. The AUC for NfL was the highest among the tested proteins, although the DeLong test of the ROC curves showed no significant difference between the AUCs for NfL and RTN4. Conclusion: The CSF NfL, RTN-4, and tau levels at the time of diagnosis could be potential diagnostic markers of multiple sclerosis, although NfL seems to have the best clinical value. Full article

(This article belongs to the Special Issue Predicting the Evolution of Neurological Diseases: The Role of Biomarkers in 2022 and Beyond)

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18 pages, 3413 KiB

Open AccessArticle

Retinal Vascular Study Using OCTA in Subjects at High Genetic Risk of Developing Alzheimer’s Disease and Cardiovascular Risk Factors

by Inés López-Cuenca, Elena Salobrar-García, Lidia Sánchez-Puebla, Eva Espejel, Lucía García del Arco, Pilar Rojas, Lorena Elvira-Hurtado, José A. Fernández-Albarral, Federico Ramírez-Toraño, Ana Barabash, Juan J. Salazar, José M. Ramírez, Rosa de Hoz and Ana I. Ramírez

J. Clin. Med. 2022, 11(11), 3248; https://doi.org/10.3390/jcm11113248 - 06 Jun 2022

Cited by 6 | Viewed by 2509

Abstract

In 103 subjects with a high genetic risk of developing Alzheimer’s disease (AD), family history (FH) of AD and ApoE ɛ4 characterization (ApoE ɛ4) were analyzed for changes in the retinal vascular network by OCTA (optical coherence tomography angiography), and AngioTool and Erlangen-Angio-Tool (EA-Tool) as imaging analysis software. Retinal vascularization was analyzed by measuring hypercholesterolemia (HCL) and high blood pressure (HBP). Angio-Tool showed a statistically significant higher percentage of area occupied by vessels in the FH+ ApoE ɛ4- group vs. in the FH+ ApoE ɛ4+ group, and EA-Tool showed statistically significant higher vascular densities in the C3 ring in the FH+ ApoE ɛ4+ group when compared with: i)FH- ApoE ɛ4- in sectors H3, H4, H10 and H11; and ii) FH+ ApoE ɛ4- in sectors H4 and H12. In participants with HCL and HBP, statistically significant changes were found, in particular using EA-Tool, both in the macular area, mainly in the deep plexus, and in the peripapillary area. In conclusion, OCTA in subjects with genetic risk factors for the development of AD showed an apparent increase in vascular density in some sectors of the retina, which was one of the first vascular changes detectable. These changes constitute a promising biomarker for monitoring the progression of pathological neuronal degeneration. Full article

(This article belongs to the Special Issue Predicting the Evolution of Neurological Diseases: The Role of Biomarkers in 2022 and Beyond)

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15 pages, 1792 KiB

Open AccessArticle

Circulating Growth Differentiation Factor 15 Is Associated with Diabetic Neuropathy

by Shao-Wen Weng, Wen-Chieh Chen, Feng-Chih Shen, Pei-Wen Wang, Jung-Fu Chen and Chia-Wei Liou

J. Clin. Med. 2022, 11(11), 3033; https://doi.org/10.3390/jcm11113033 - 27 May 2022

Cited by 2 | Viewed by 1549

Abstract

Background: Growth differentiation factor (GDF15) is a superfamily of transforming growth factor-beta which has been suggested to be correlated with various pathological conditions. The current study aimed to investigate the predicted role of circulating GDF15 in diabetic metabolism characteristics and diabetic neuropathy. Methods: 241 diabetic patients and 42 non-diabetic subjects were included to participate in the study. The plasma GDF15 levels were measured using ELISA. Chronic kidney disease and albuminuria were defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) guideline. The nerve conductive study (NCS) was performed with measurement of distal latency, amplitude, nerve conduction velocity (NCV), H-reflex, and F-wave studies. Results: The diabetic group had a significantly higher prevalence of chronic kidney disease and higher plasma GDF15 level. After adjusting for age and BMI, GDF15 was significantly positively correlated with waist circumference (r = 0.332, p = <0.001), hip circumference (r = 0.339, p < 0.001), HbA1c (r = 0.302, p < 0.001), serum creatine (r = 0.146, p = 0.017), urine albumin/creatinine ratio (r = 0.126, p = 0.040), and HOMA-IR (r = 0.166, p = 0.007). As to NCS, GDF15 was significantly correlated with all latency and amplitude of sensory and motor nerves, as well as F-wave and H-reflex latencies. The area under the curve (AUC) in predicting tibial motor nerve neuropathy (MNCV) in all subjects and in the diabetic group for GDF15 was 0.646 (p = 0.001) and 0.610 (p = 0.012), respectively; for HbA1c was 0.639 (p = 0.001) and 0.604 (p = 0.018), respectively. Predicting ulnar sensory nerve neuropathy for GDF15 was 0.639 (p = 0.001) and 0.658 (p = 0.001), respectively; for HbA1c was 0.545 (p = 0.307) and 0.545 (p = 0.335), respectively. Predicting median sensory nerve neuropathy for GDF15 was 0.633 (p = 0.007) and 0.611 (p = 0.032), respectively; for HbA1c was 0.631 (p = 0.008) and 0.607 (p = 0.038), respectively. Predicting CKD for GDF15 was 0.709 (95% CI, 0.648–0.771), p < 0.001) and 0.676 (95% CI, 0.605–0.746), p < 0.001), respectively; for HbA1c was 0.560 (95% CI, 0.493–0.627); p = 0.080) and 0.515 (95% CI, 0.441–0.588); p = 0.697), respectively. Conclusions: We suggest that there is a significant association between the increased serum GDF-15 level and metabolic parameters and diabetic neuropathy. Plasma GDF15 may be an independent predictor of diabetic neuropathy. Full article

(This article belongs to the Special Issue Predicting the Evolution of Neurological Diseases: The Role of Biomarkers in 2022 and Beyond)

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Review

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18 pages, 887 KiB

Open AccessFeature PaperReview

Biological and Physical Performance Markers for Early Detection of Cognitive Impairment in Older Adults

by Hanna Kerminen, Emanuele Marzetti and Emanuela D’Angelo

J. Clin. Med. 2024, 13(3), 806; https://doi.org/10.3390/jcm13030806 - 30 Jan 2024

Viewed by 1209

Abstract

Dementia is a major cause of poor quality of life, disability, and mortality in old age. According to the geroscience paradigm, the mechanisms that drive the aging process are also involved in the pathogenesis of chronic degenerative diseases, including dementia. The dissection of such mechanisms is therefore instrumental in providing biological targets for interventions and new sources for biomarkers. Within the geroscience paradigm, several biomarkers have been discovered that can be measured in blood and that allow early identification of individuals at risk of cognitive impairment. Examples of such markers include inflammatory biomolecules, markers of neuroaxonal damage, extracellular vesicles, and DNA methylation. Furthermore, gait speed, measured at a usual and fast pace and as part of a dual task, has been shown to detect individuals at risk of future dementia. Here, we provide an overview of available biomarkers that may be used to gauge the risk of cognitive impairment in apparently healthy older adults. Further research should establish which combination of biomarkers possesses the highest predictive accuracy toward incident dementia. The implementation of currently available markers may allow the identification of a large share of at-risk individuals in whom preventive interventions should be implemented to maintain or increase cognitive reserves, thereby reducing the risk of progression to dementia. Full article

(This article belongs to the Special Issue Predicting the Evolution of Neurological Diseases: The Role of Biomarkers in 2022 and Beyond)

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21 pages, 1425 KiB

Open AccessReview

The Interplay between Cannabinoid Receptors and Microglia in the Pathophysiology of Alzheimer’s Disease

by Rebecca Ferrisi, Francesca Gado, Caterina Ricardi, Beatrice Polini, Clementina Manera and Grazia Chiellini

J. Clin. Med. 2023, 12(23), 7201; https://doi.org/10.3390/jcm12237201 - 21 Nov 2023

Viewed by 979

Abstract

Alzheimer’s disease (AD) is characterized by massive neuronal death, brain atrophy, and loss of neurons and synapses, which all lead to a progressive cognitive decline. Neuroinflammation has been recently identified as one of the main causes of AD progression, and microglia cells are considered to have a central role in this process. Growing evidence suggests that cannabinoids may be used as preventive treatment for AD. An altered expression of the endocannabinoids (eCBs) and their receptors (CBRs) is reported in several neurodegenerative disorders, including AD. Moreover, the modulation of CBRs demonstrated neuroprotective effects in reducing aggregated protein deposition, suggesting the therapeutic potential of natural and synthetic CBR ligands in the treatment of neurodegenerative proteinopathies. Here, we review the current knowledge regarding the involvement of CBRs in the modulation of microglia activation phenotypes, highlighting the role of neuroinflammation in the pathogenesis of neurodegenerative diseases, like AD. We also provide an overview of recently developed candidate drugs targeting CBRs that may afford a new innovative strategy for the treatment and management of AD. Full article

(This article belongs to the Special Issue Predicting the Evolution of Neurological Diseases: The Role of Biomarkers in 2022 and Beyond)

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15 pages, 651 KiB

Open AccessReview

Protein Biomarkers Shared by Multiple Neurodegenerative Diseases Are Calmodulin-Binding Proteins Offering Novel and Potentially Universal Therapeutic Targets

by Danton H. O’Day

J. Clin. Med. 2023, 12(22), 7045; https://doi.org/10.3390/jcm12227045 - 11 Nov 2023

Cited by 1 | Viewed by 1218

Abstract

Seven major neurodegenerative diseases and their variants share many overlapping biomarkers that are calmodulin-binding proteins: Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTD), Huntington’s disease (HD), Lewy body disease (LBD), multiple sclerosis (MS), and Parkinson’s disease (PD). Calcium dysregulation is an early and persistent event in each of these diseases, with calmodulin serving as an initial and primary target of increased cytosolic calcium. Considering the central role of calcium dysregulation and its downstream impact on calcium signaling, calmodulin has gained interest as a major regulator of neurodegenerative events. Here, we show that calmodulin serves a critical role in neurodegenerative diseases via binding to and regulating an abundance of biomarkers, many of which are involved in multiple neurodegenerative diseases. Of special interest are the shared functions of calmodulin in the generation of protein biomarker aggregates in AD, HD, LBD, and PD, where calmodulin not only binds to amyloid beta, pTau, alpha-synuclein, and mutant huntingtin but also, via its regulation of transglutaminase 2, converts them into toxic protein aggregates. It is suggested that several calmodulin binding proteins could immediately serve as primary drug targets, while combinations of calmodulin binding proteins could provide simultaneous insight into the onset and progression of multiple neurodegenerative diseases. Full article

(This article belongs to the Special Issue Predicting the Evolution of Neurological Diseases: The Role of Biomarkers in 2022 and Beyond)

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10 pages, 242 KiB

Open AccessCase Report

Case Series: Vestibular Migraines in Fragile X Premutation Carriers

by YeEun Tak, Flora Tassone and Randi J. Hagerman

J. Clin. Med. 2024, 13(2), 504; https://doi.org/10.3390/jcm13020504 - 16 Jan 2024

Viewed by 796

Abstract

Background: Vestibular migraine (VM) is one of the most common causes of recurrent vertigo and presents with a history of spontaneous or positional vertigo with a history of migraine headaches. While research has identified a high prevalence of migraine headaches and vestibular deficits among fragile X premutation carriers, there has been no discussion about VM within this population. Objective: This case series and review seeks to describe the clinical characteristics and pathophysiology of VM among individuals with the fragile X premutation. We also seek to discuss treatment and future steps in addressing VM in this population. Methods: A review of the literature regarding vestibular migraine and presentation of migraine headaches and vestibular deficits among premutation carriers was performed. A detailed clinical history of migraine headaches and vertigo was obtained from three patients with the fragile X premutation seen by the senior author (RJH). Results: All three cases first developed symptoms of migraine headaches earlier in life, with the development of VM near menopause. Two of the three cases developed progressive balance issues following the development of VM. All three cases found that their VM episodes were improved or resolved with pharmacological and/or lifestyle interventions. Conclusions: It is important to recognize VM among premutation carriers because beneficial treatments are available. Future studies are needed regarding the prevalence of VM and the relationship to subsequent FXTAS. The pathophysiology of VM remains uncertain but possibilities include mitochondrial abnormalities, cranial nerve VIII toxicity secondary to neurotoxic protein accumulation, and calcitonin gene-related peptide (CGRP) signaling dysfunction due to altered levels of fragile X messenger ribonucleoprotein (FMRP). Full article

(This article belongs to the Special Issue Predicting the Evolution of Neurological Diseases: The Role of Biomarkers in 2022 and Beyond)

7 pages, 539 KiB

Open AccessBrief Report

Prognostic Role of Visual Evoked Potentials in Non-Neuritic Eyes at Multiple Sclerosis Diagnosis

by Domizia Vecchio, Paolo Barbero, Giulia Galli, Eleonora Virgilio, Paola Naldi, Cristoforo Comi and Roberto Cantello

J. Clin. Med. 2023, 12(6), 2382; https://doi.org/10.3390/jcm12062382 - 20 Mar 2023

Viewed by 1100

Abstract

Introduction: This study aimed to assess the prognostic role of visual evoked potentials (VEPs) of the non-neuritic eye at the diagnosis of multiple sclerosis (MS). Patients and methods: We enrolled 181 MS patients (62% females, mean age at diagnosis: 38 years, standard deviation: 12) at the time of the first diagnostic work-up, including VEPs. We collected P100 latency and N75-P100 amplitude of non-neuritic eyes at diagnosis, and then we calculated the mean values in 127 patients with no history of optic neuritis (ON) or considered the unaffected eye in the remaining. At last follow-up (minimum: one year), disability was evaluated according to MS Severity Score or MSSS (median: 2.44, range: 0.18–9.63). Statistical analysis included Mann–Whitney descriptive analysis, Spearman correlation for independent samples, and linear regression for significant predictors of MSSS. Results: 38/181 patients had P100 latency >115 ms, and 63/181 showed N75-P100 amplitude < 5 microV in the unaffected eyes at MS diagnosis. At last follow-up, MSSS correlated with P100 latency (rho = 0.21, p = 0.004) and N75-P100 amplitude (rho = 0.19, p = 0.009) collected at diagnosis. P100 latency (not N75-P100 amplitude) resulted in a predictor for disability over time (MSSS) in the regression model (along with age at onset, MS course, and disease-modifying treatments). Conclusions: Our study showed a prognostic value of VEPs in clinically unaffected eyes at MS diagnosis to predict future disability, independently from a history of ON. Full article

(This article belongs to the Special Issue Predicting the Evolution of Neurological Diseases: The Role of Biomarkers in 2022 and Beyond)

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