The Network Structure of Cognitive Impairment: From Subjective Cognitive Decline to Alzheimer's Disease.

It was proposed that a reorganization of the relationships between cognitive functions occurs in dementia, a vision that surpasses the idea of a mere decline of specific domains. The complexity of cognitive structure, as assessed by neuropsychological tests, can be captured by exploratory graph analysis (EGA). EGA was applied to the neuropsychological assessment of people (humans) with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and Alzheimer's disease (AD; total N = 638). Both sexes were included. In AD, memory scores detach from the other cognitive functions, and memory subdomains reduce their reciprocal relation. SCD showed a pattern of segregated neuropsychological domains, and MCI showed a noisy and less stable pattern. Results suggest that AD drives a reorganization of cognitive functions toward a less-fractionated architecture compared with preclinical conditions. Cognitive functions show a reorganization that goes beyond the performance decline. Results also have clinical implications in test interpretations and usage.

Irisin Levels in Cerebrospinal Fluid Correlate with Biomarkers and Clinical Dementia Scores in Alzheimer Disease.

OBJECTIVE: Irisin, released by muscles during exercise, was recently identified as a neuroprotective factor in mouse models of Alzheimer disease (AD). In a cohort of AD patients, we studied cerebrospinal fluid (CSF) and plasma irisin levels, sex interactions, and correlations with disease biomarkers. METHODS: Correlations between CSF and plasma irisin levels and AD biomarkers (amyloid ß 1-42, hyperphosphorylated tau, and total tau [t-tau]) and Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) were analyzed in a cohort of patients with Alzheimer dementia (n = 82), mild cognitive impairment (n = 44), and subjective memory complaint (n = 20) biologically characterized according to the recent amyloid/tau/neurodegeneration classification. RESULTS: CSF irisin was reduced in Alzheimer dementia patients (p < 0.0001), with lower levels in female patients. Moreover, CSF irisin correlated positively with Aß42 in both female (r = 0.379, p < 0.001) and male (r = 0.262, p < 0.05) patients, and negatively with CDR-SOB (r = -0.234, p < 0.05) only in female patients. A negative trend was also observed between CSF irisin and t-tau levels in all patients (r = -0.144, p = 0.082) and in the female subgroup (r = -0.189, p = 0.084). INTERPRETATION: The results highlight the relationship between irisin and biomarkers of AD pathology, especially in females. Our findings also offer perspectives toward the use of irisin as a marker of the AD continuum. ANN NEUROL 2024;96:61-73.

Cognitive and Neuropathophysiological Outcomes of Gamma-tACS in Dementia: A Systematic Review.

Despite the numerous pharmacological interventions targeting dementia, no disease-modifying therapy is available, and the prognosis remains unfavorable. A promising perspective involves tackling high-frequency gamma-band (> 30 Hz) oscillations involved in hippocampal-mediated memory processes, which are impaired from the early stages of typical Alzheimer's Disease (AD). Particularly, the positive effects of gamma-band entrainment on mouse models of AD have prompted researchers to translate such findings into humans using transcranial alternating current stimulation (tACS), a methodology that allows the entrainment of endogenous cortical oscillations in a frequency-specific manner. This systematic review examines the state-of-the-art on the use of gamma-tACS in Mild Cognitive Impairment (MCI) and dementia patients to shed light on its feasibility, therapeutic impact, and clinical effectiveness. A systematic search from two databases yielded 499 records resulting in 10 included studies and a total of 273 patients. The results were arranged in single-session and multi-session protocols. Most of the studies demonstrated cognitive improvement following gamma-tACS, and some studies showed promising effects of gamma-tACS on neuropathological markers, suggesting the feasibility of gamma-tACS in these patients anyhow far from the strong evidence available for mouse models. Nonetheless, the small number of studies and their wide variability in terms of aims, parameters, and measures, make it difficult to draw firm conclusions. We discuss results and methodological limitations of the studies, proposing possible solutions and future avenues to improve research on the effects of gamma-tACS on dementia.

Motor Neuron Disease Population-Based Registry in Egypt: Where Do We Stand?

BACKGROUND: There is a growing body of evidence indicating that the worldwide distribution of amyotrophic lateral sclerosis (ALS) is far from uniform. This is evident through variations in the epidemiology, genetics, and phenotypical characteristics of ALS and other motor neuron diseases (MND) across different regions. However, comprehensive ALS epidemiological studies are still lacking in many parts of the world, especially in Africa. Therefore, we propose the establishment of a population-based register for ALS/MND in Egypt, an important part of Africa with a population of more than 100 millions of people. SUMMARY: Given Egypt's distinctive social and demographic characteristics, it is highly recommended to employ specific, recently developed epidemiological techniques for assessing the prevalence and incidence of these diseases within the country. By utilizing these methods, we can gather invaluable data that will contribute to a deeper understanding of ALS and enable us to effectively address its impact on the population of Egypt. KEY MESSAGES: Our goal with this pioneering ALS/MND population-based register in Egypt is to define the burden of ALS in this part of Africa and to increase the chances for this consanguineous population to get access to modern individualized genetic therapies. Additionally, we aspire to uncover potential environmental factors and gene-environment interactions that contribute to the development of ALS. This knowledge of MND individual and group risk in Egypt will not only open doors for interventions but also provide opportunities for future research and discovery.

Temporal gamma tACS and auditory stimulation affect verbal memory in healthy adults.

Research suggests a potential of gamma oscillation entrainment for enhancing memory in Alzheimer's disease and healthy subjects. Gamma entrainment can be accomplished with oscillatory electrical, but also sensory stimulation. However, comparative studies between sensory stimulation and transcranial alternating current stimulation (tACS) effects on memory processes are lacking. This study examined the effects of rhythmic gamma auditory stimulation (rAS) and temporal gamma-tACS on verbal long-term memory (LTM) and working memory (WM) in 74 healthy individuals. Participants were assigned to two groups according to the stimulation techniques (rAS or tACS). Memory was assessed in three experimental blocks, in which each participant was administered with control, 40, and 60 Hz stimulation in counterbalanced order. All interventions were well-tolerated, and participants reported mostly comparable side effects between real stimulation (40 and 60 Hz) and the control condition. LTM immediate and delayed recall remained unaffected by stimulations, while immediate recall intrusions decreased during 60 Hz stimulation. Notably, 40 Hz interventions improved WM compared to control stimulations. These results highlight the potential of 60 and 40 Hz temporal cortex stimulation for reducing immediate LTM recall intrusions and improving WM performance, respectively, probably due to the entrainment of specific gamma oscillations in the auditory cortex. The results also shed light on the comparative effects of these neuromodulation tools on memory functions, and their potential applications for cognitive enhancement and in clinical trials.

Consequences of age and education correction of cognitive screening tests - A simulation study of the MoCA test in Italy.

BACKGROUND: Cognitive screening tools are widely used in clinical practice to screen for age-related cognitive impairment and dementia. These tools' test scores are known to be influenced by age and education, leading to routine correction of raw scores for these factors. Despite these corrections being common practice, there is evidence suggesting that corrected scores may perform worse in terms of discrimination than raw scores. OBJECTIVE: To address the ongoing debate in the field of dementia research, we assessed the impact of the corrections on discrimination, specificity, and sensitivity of the Montreal Cognitive Assessment test in Italy, both for the overall population and across age and education strata. METHODOLOGY: We created a realistic model of the resident population in Italy in terms of age, education, cognitive impairment and test scores, and performed a simulation study. RESULTS: We confirmed that the discrimination performance was higher for raw scores than for corrected scores in discriminating patients with cognitive impairment from individuals without (areas under the curve of 0.947 and 0.923 respectively). With thresholds determined on the overall population, raw scores showed higher sensitivities for higher-risk age-education groups and higher specificities for lower-risk groups. Conversely, corrected scores showed uniform sensitivity and specificity across demographic strata, and thus better performance for certain age-education groups. CONCLUSION: Raw and corrected scores show different performances due to the underlying causal relationships between the variables. Each approach has advantages and disadvantages, the optimal choice between raw and corrected scores depends on the aims and preferences of practitioners and policymakers.

Real-life management of patients with mild cognitive impairment: an Italian survey.

BACKGROUND: Mild cognitive impairment (MCI) is a syndrome with heterogeneous underlying causes and different rates of disease progression, whose clinical heterogeneity leads to a wide variation in diagnostic and therapeutic approaches in clinical practice. The lack of uniform practical recommendations on diagnostic workup and treatment for MCI patients hinders optimal management of these patients, worsening their prognosis. Standardized guidelines for the investigation and follow-up of MCI are therefore urgently required. AIM: Aim of our study was to assess the diagnostic and therapeutic approach to MCI patients in the setting of Italian Memory Clinics. METHODS: A survey was delivered to a sample of Italian neurologists through two different phases: a first exploratory phase recording general information about the usual clinical management of patients with MCI, and a subsequent operative phase assessing the practical diagnostic and therapeutic decisions taken in a real life setting to manage subjects with MCI. RESULTS: A total of 121 neurologists participated to the first phase of the survey and 203 patients were enrolled in the second phase. Information gathered in the first phase of the survey highlighted a non-uniform use of diagnostic criteria and procedures for MCI, as well as a very heterogeneous therapeutic strategy among Italian neurologists. In the second phase, recorded data on diagnostic and therapeutic approach confirmed the large variability observed in the first phase of the survey. CONCLUSIONS: The results of our study reflect a suboptimal management of MCI patients in Italy and highlight the need of standardized diagnostic and therapeutic approaches for this condition.

Nerve conduction study on the split-hand plus index in Amyotrophic lateral sclerosis: correlations with lower motor neuron impairment.

INTRODUCTION: In the arms of patients with Amyotrophic lateral sclerosis (ALS) two peculiar patterns of dissociated muscular atrophy have been described: the split-hand sign (with predominant atrophy of the lateral aspect of the hand, compared to hypothenar eminence) and the split-hand-plus sign (SHPS), a predominant abductor pollicis brevis (ABP) atrophy with sparing of flexor pollicis longus (FPL). AIMS: In this case-control study, we evaluated the diagnostic utility of a neurophysiological indicator of SHPS and assessed its association with clinical features. METHODS: We prospectively studied 59 incident ALS patients, 61 patients with ALS-mimic disorders (OND) and 61 non-neurological controls (NNCs). ABP and FPL compound muscle action potentials (CMAP) amplitudes were obtained by supramaximal stimulation of median nerve at elbow. Split-hand plus index (SHPI) was calculated according to the formula: APB-CMAP/FPL-CMAP. RESULTS: SHPI was significantly lower in ALS compared to OND patients and NNCs (p < 0.0001). SHPI value < 1 was observed in 2% of NNCs and 9% of OND patients and demonstrated an accuracy of 71% in differentiating ALS from OND and an accuracy of 74% in differentiating ALS from NNC. SHPI was associated with higher LMN score, and higher disease severity as quantified by the ALSFRS-r. CONCLUSION: Our results indicate that SHPI is a reliable indicator to distinguish ALS patients from ONDs and NNCs. SHPI was significantly associated to the degree of lower motor neuron impairment but showed no association with upper motoneuron impairment.

Reperfusion strategies in stroke with medium-to-distal vessel occlusion: a prospective observational study.

INTRODUCTION: Medium vessel occlusion (MeVO) accounts for 30% of acute ischemic stroke cases. The risk/benefit profile of endovascular thrombectomy (EVT) and intravenous thrombolysis (IVT) or the combination of the two (bridging therapy (BT)) is still unclear in MeVO. Here, we compare reperfusion strategies in MeVO for clinical and radiological outcomes. METHODS: This prospective single center study enrolled consecutive patients with AIS due to primary MeVO undergoing IVT, EVT, or BT at a comprehensive stroke center. Primary outcome was good functional status, defined as modified Rankin Scale (mRS) 0-2 at 3-month follow-up. Additional outcomes included mortality, successful recanalization, defined as mTICI ≥ 2b, stroke severity at discharge, and symptomatic intracerebral hemorrhage (sICH) according to SITS-MOST criteria. Logistic regression was modeled to define independent predictors of the primary outcome. RESULTS: Overall, 180 consecutive people were enrolled (IVT = 59, EVT = 38, BT = 83), mean age 75. BT emerged as independent predictor of primary outcome (OR = 2.76, 95% CI = 1.08-7.07) together with age (OR = 0.94, 95% CI = 0.9-0.97) and baseline NIHSS (OR = 0.88, 95% CI = 0.81-0.95). BT associated with a 20% relative increase in successful recanalization compared to EVT (74.4 vs 56.4%, p = 0.049). Rates of sICH (1.1%) and procedural complications (vasospasm 4.1%, SAH in 1.7%) were very low, with no difference across groups. DISCUSSION: BT may carry a higher chance of good functional outcome compared to EVT/IVT only in people with AIS due to MeVO, with marginally higher rates of successful recanalization. Randomized trials are needed to define optimal treatment tailoring for MeVO.

Sarcopenia in subjects with Alzheimer's disease: prevalence and comparison of agreement between EGWSOP1, EGWSOP2, and FNIH criteria.

BACKGROUND: Sarcopenia is an age-related clinical syndrome characterized by the progressive loss of muscle mass and muscle strength. It appears to be closely linked to dementia, particularly Alzheimer's disease (AD); however, its prevalence among AD patients remains unclear. In this study, we assessed differences in sarcopenia prevalence between non-demented individuals and AD patients. Moreover, we assessed sex-specific differences in sarcopenia prevalence and explored the diagnostic value of the Muscle Quality Index (MQI) for diagnosing sarcopenia among AD patients. METHOD: Cross-sectional study including 145 patients with probable AD and 51 older adults with normal cognition. Sarcopenia was diagnosed according to the criteria of the European Working Group on Sarcopenia in Older People (EWGSOP1 and EWGSOP2) and of the Foundation for the National Institutes of Health (FNIH). The MQI was computed as the ratio of handgrip strength to skeletal muscle mass. RESULTS: No significant difference in sarcopenia prevalence was observed between AD patients and controls. Prevalence ranged from 3.4 to 23.4% in AD patients and from 2 to 11.8% in controls, depending on diagnostic criteria. Prevalence was higher using EWGSOP1 and decreased using EWGSOP2 and FNIH. Prevalence was higher in males than in females with AD. The MQI was lower in AD patients than in controls (95%CI: - 0.23, - 0.05, p < 0.001), but displayed poor diagnostic accuracy in identifying sarcopenia cases. CONCLUSIONS: AD patients and controls show comparable sarcopenia prevalence. Sarcopenia prevalence is higher in males than females among AD patients and higher when using EWGSOP1 compared to FNIH and EWGSOP2 criteria.

Sleep and circadian rhythm disruptions in behavioral variant frontotemporal dementia.

INTRODUCTION: Sleep and rest-activity rhythm alterations are common in neurodegenerative diseases. However, their characterization in patients with behavioral variant frontotemporal dementia (bvFTD) has proven elusive. We investigated rest-activity rhythm alterations, sleep disturbances, and their neural correlates in bvFTD. METHODS: Twenty-seven bvFTD patients and 25 healthy controls completed sleep questionnaires and underwent 7 days of actigraphy while concurrently maintaining a sleep diary. Cortical complexity and thickness were calculated from T1-weighted magnetic resonance (MR) images. RESULTS: Compared to controls, bvFTD patients showed longer time in bed (95% confidence interval [CI]: 79.31, 321.83) and total sleep time (95% CI: 24.38, 321.88), lower sleep efficiency (95% CI: -12.58, -95.54), and rest-activity rhythm alterations in the morning and early afternoon. Increased sleep duration was associated with reduced cortical thickness in frontal regions. DISCUSSION: Patients with bvFTD showed longer sleep duration, lower sleep quality, and rest-activity rhythm alterations. Actigraphy could serve as a cost-effective and accessible tool for ecologically monitoring changes in sleep duration in bvFTD patients. HIGHLIGHTS: We assessed sleep and circadian rhythms in behavioral variant frontotemporal dementia (bvFTD) using actigraphy. Patients with bvFTD show increased sleep duration and reduced sleep quality. Patients with bvFTD show rest-activity alterations in the morning and early afternoon. Sleep duration is associated with reduced cortical thickness in frontal regions. These alterations may represent an early sign of neurodegeneration.

Genotype-phenotype correlation in the spectrum of frontotemporal dementia-parkinsonian syndromes and advanced diagnostic approaches.

The term frontotemporal dementia (FTD) refers to a group of progressive neurodegenerative disorders characterized mainly by atrophy of the frontal and anterior temporal lobes. Based on clinical presentation, three main clinical syndromes have traditionally been described: behavioral variant frontotemporal dementia (bvFTD), non-fluent/agrammatic primary progressive aphasia (nfPPA), and semantic variant PPA (svPPA). However, over the last 20 years, it has been recognized that cognitive phenotypes often overlap with motor phenotypes, either motor neuron diseases or parkinsonian signs and/or syndromes like progressive supranuclear palsy (PSP) and cortico-basal syndrome (CBS). Furthermore, FTD-related genes are characterized by genetic pleiotropy and can cause, even in the same family, pure motor phenotypes, findings that underlie the clinical continuum of the spectrum, which has pure cognitive and pure motor phenotypes as the extremes. The genotype-phenotype correlation of the spectrum, FTD-motor neuron disease, has been well defined and extensively investigated, while the continuum, FTD-parkinsonism, lacks a comprehensive review. In this narrative review, we describe the current knowledge about the genotype-phenotype correlation of the spectrum, FTD-parkinsonism, focusing on the phenotypes that are less frequent than bvFTD, namely nfPPA, svPPA, PSP, CBS, and cognitive-motor overlapping phenotypes (i.e. PPA + PSP). From a pathological point of view, they are characterized mainly by the presence of phosphorylated-tau inclusions, either 4 R or 3 R. The genetic correlate of the spectrum can be heterogeneous, although some variants seem to lead preferentially to specific clinical syndromes. Furthermore, we critically review the contribution of genome-wide association studies (GWAS) and next-generation sequencing (NGS) in disentangling the complex heritability of the FTD-parkinsonism spectrum and in defining the genotype-phenotype correlation of the entire clinical scenario, owing to the ability of these techniques to test multiple genes, and so to allow detailed investigations of the overlapping phenotypes. Finally, we conclude with the importance of a detailed genetic characterization and we offer to patients and families the chance to be included in future randomized clinical trials focused on autosomal dominant forms of FTLD.

Neurofilament light predicts worse nonmotor symptoms and depression in Parkinson's disease.

BACKGROUND: The identification of biomarkers that reflect worse progression of nonmotor symptoms (NMS) in Parkinson's disease (PD) is currently an unmet need. The main aim of this study was to investigate whether cerebrospinal fluid (CSF) and serum neurofilament light (NfL), measured at baseline or longitudinally, can be used to predict the progression of NMS in patients with PD. METHODS: Baseline and longitudinal NfL levels were measured in the CSF and serum in 392 PD patients and 184 healthy controls from the Parkinson's Progression Marker Initiative. NMS were assessed using several scales, including, but not restricted to, the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part I, the Geriatric Depression Scale (GDS) and the State-Trait Anxiety Inventory (STAI). The relationship between baseline and longitudinal NfL levels with changes in NMS was assessed using linear mixed effects models (LME) in PD patients. In addition, we compared CSF and serum NfL levels between groups and assessed the relationship between NfL biomarkers with baseline NMS. Finally, to assess the specificity of our findings we ran the previous LME models using other biomarkers such as CSF amyloid-ß1-42, total tau, phosphorylated tau181 and total α-synuclein and we also ran the models in healthy controls. RESULTS: Baseline levels and longitudinal changes in serum and CSF NfL predicted worse longitudinal MDS-UPDRS-I and depression scores over time in PD (p < 0.01). This relationship remained significant only for CSF NfL when controlling for motor and cognitive status. Furthermore, longitudinal changes in serum and CSF NfL were associated with worse anxiety over time in PD patients (p < 0.05). In contrast to CSF NfL, serum NfL levels were slightly higher at baseline (p = 0.043) and showed significant longitudinal increases (p < 0.001) in PD patients compared to controls. There were no significant correlations between NfL levels (CSF or serum) with other NMS scales, baseline NMS variables, other biomarkers or in healthy controls. CONCLUSIONS: Our findings indicate that both serum and CSF NfL are associated with worse longitudinal NMS burden, particularly in relation to the progression of depression and anxiety. Serum NfL showed stronger associations with NMS suggesting it could potentially be used as a non-invasive marker of NMS progression for PD.

Should Cognitive Screening Tests Be Corrected for Age and Education? Insights From a Causal Perspective.

Cognitive screening tests such as the Mini-Mental State Examination are widely used in clinical routine to predict cognitive impairment. The raw test scores are often corrected for age and education, although documented poorer discrimination performance of corrected scores has challenged this practice. Nonetheless, test correction persists, perhaps due to the seemingly counterintuitive nature of the underlying problem. We used a causal framework to inform the long-standing debate from a more intuitive angle. We illustrate and quantify the consequences of applying the age-education correction of cognitive tests on discrimination performance. In an effort to bridge theory and practical implementation, we computed differences in discrimination performance under plausible causal scenarios using Open Access Series of Imaging Studies (OASIS)-1 data. We show that when age and education are causal risk factors for cognitive impairment and independently also affect the test score, correcting test scores for age and education removes meaningful information, thereby diminishing discrimination performance.

Effect of RNS60 in amyotrophic lateral sclerosis: a phase II multicentre, randomized, double-blind, placebo-controlled trial.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options. RNS60 is an immunomodulatory and neuroprotective investigational product that has shown efficacy in animal models of ALS and other neurodegenerative diseases. Its administration has been safe and well tolerated in ALS subjects in previous early phase trials. METHODS: This was a phase II, multicentre, randomized, double-blind, placebo-controlled, parallel-group trial. Participants diagnosed with definite, probable or probable laboratory-supported ALS were assigned to receive RNS60 or placebo administered for 24 weeks intravenously (375 ml) once a week and via nebulization (4 ml/day) on non-infusion days, followed by an additional 24 weeks off-treatment. The primary objective was to measure the effects of RNS60 treatment on selected biomarkers of inflammation and neurodegeneration in peripheral blood. Secondary objectives were to measure the effect of RNS60 on functional impairment (ALS Functional Rating Scale-Revised), a measure of self-sufficiency, respiratory function (forced vital capacity, FVC), quality of life (ALS Assessment Questionnaire-40, ALSAQ-40) and survival. Tolerability and safety were assessed. RESULTS: Seventy-four participants were assigned to RNS60 and 73 to placebo. Assessed biomarkers did not differ between arms. The mean rate of decline in FVC and the eating and drinking domain of ALSAQ-40 was slower in the RNS60 arm (FVC, difference 0.41 per week, standard error 0.16, p = 0.0101; ALSAQ-40, difference -0.19 per week, standard error 0.10, p = 0.0319). Adverse events were similar in the two arms. In a post hoc analysis, neurofilament light chain increased over time in bulbar onset placebo participants whilst remaining stable in those treated with RNS60. CONCLUSIONS: The positive effects of RNS60 on selected measures of respiratory and bulbar function warrant further investigation.

Phosphorylated TDP-43 aggregates in peripheral motor nerves of patients with amyotrophic lateral sclerosis.

Phosphorylated TDP-43 (pTDP-43) aggregates in the cytoplasm of motor neurons and neuroglia in the brain are one of the pathological hallmarks of amyotrophic lateral sclerosis. Although the axons exceed the total volume of motor neuron soma by several orders of magnitude, systematic studies investigating the presence and distribution of pTDP-43 aggregates within motor nerves are still lacking. The aim of this study is to define the TDP-43/pTDP-43 pathology in diagnostic motor nerve biopsies performed on a large cohort of patients presenting with a lower motor neuron syndrome and to assess whether this might be a discriminating tissue biomarker for amyotrophic lateral sclerosis and non-amyotrophic lateral sclerosis cases. We retrospectively evaluated 102 lower motor neuron syndrome patients referred to our centre for a diagnostic motor nerve biopsy. Histopathological criteria of motor neuron disease and motor neuropathy were applied by two independent evaluators, who were blind to clinical data. TDP-43 and pTDP-43 were evaluated by immunohistochemistry, and results compared to final clinical diagnosis. We detected significant differences between amyotrophic lateral sclerosis and non-amyotrophic lateral sclerosis cases in pTDP-43 expression in myelinated fibres: axonal accumulation was detected in 98.2% of patients with amyotrophic lateral sclerosis versus 30.4% of non-amyotrophic lateral sclerosis samples (P < 0.0001), while concomitant positive staining in Schwan cell cytoplasm was found in 70.2% of patients with amyotrophic lateral sclerosis versus 17.4% of patients who did not have amyotrophic lateral sclerosis (P < 0.001). Importantly, we were also able to detect pTDP-43 aggregates in amyotrophic lateral sclerosis cases displaying normal features at standard histopathological analysis. Our findings demonstrated that a specific pTDP-43 signature is present in the peripheral nervous system of patients with amyotrophic lateral sclerosis, and could be exploited as a specific, accessible tissue biomarker. The detection of pTDP-43 aggregates within motor nerves of living patients with amyotrophic lateral sclerosis, occurring before axonal degeneration, suggests that this is an early event that may contribute to amyotrophic lateral sclerosis pathogenesis.

Role of plasma phosphorylated neurofilament heavy chain (pNfH) in amyotrophic lateral sclerosis.

The phosphorylated neurofilament heavy chain (pNfH) is a promising biomarker in amyotrophic lateral sclerosis (ALS). We examined plasma pNfH concentrations in order to corroborate its role as a diagnostic and prognostic biomarker in ALS. Incident ALS cases enrolled in a population-based registry were retrospectively selected and matched by sex and age with a cohort of healthy volunteers. Plasma pNfH levels were measured by an ELISA kit and correlated with clinical parameters. Discrimination ability of pNfH was tested using receiving operating characteristic (ROC) curves. Kaplan-Meier (KM) analysis and Cox proportional hazard models were used for survival analysis. Plasma pNfH was significantly higher in patients compared to controls. An optimal cut-off of 39.74 pg/ml discriminated cases from controls with an elevated sensitivity and specificity. Bulbar-onset cases had higher plasma pNfH compared to spinal onset (p = 0.0033). Furthermore, plasma pNfH positively correlated with disease progression rate (r = 0.19, p = 0.031). Baseline plasma pNfH did not influence survival in our cohort. Our findings confirmed the potential utility of plasma pNfH as a diagnostic biomarker in ALS. However, further studies with longitudinal data are needed to corroborate its prognostic value.

The challenge of amyotrophic lateral sclerosis descriptive epidemiology: to estimate low incidence rates across complex phenotypes in different geographic areas.

PURPOSE OF REVIEW: Amyotrophic lateral sclerosis (ALS) is a rare progressive neurodegenerative disease of motor neurons with a fatal outcome. The rareness of the disease and the rapidly fatal course are the main challenges for the ALS epidemiological research. The understanding of ALS has clearly advanced in the recent years both in the genetics and in the leading pathways of disease determinants. Epidemiological research has played a primary role in these discoveries. RECENT FINDINGS: Epidemiological studies have shown a variation of incidence, mortality and prevalence of ALS between geographical areas and different populations, supporting the notion that genetic factors, linked to populations' ancestries, along with environmental and lifestyle factors, play a significant role in the occurrence of the disease. The burden of motor neuron diseases is increasing and currently more relevant in high-income countries but increasing at the highest rate in low and middle-income countries. The ALS phenotype is not restricted to motor functions. C9orf72 repeat expansion seems to present a recognizable phenotype characterized by earlier disease onset, the presence of cognitive and behavioural impairment. SUMMARY: Population-based disease registries have played a major role in developing new knowledge on ALS, in characterizing genotype-phenotype correlations, in discovering new genetic modifiers and finally in planning research and health services, considering the high cost of motor neuron disease care. Epidemiological research based on multicentre international collaboration is essential to provide new data on ALS, especially in some regions of the world with poor data.

Decipher non-canonical SPAST splicing mutations with the help of functional assays in patients affected by spastic paraplegia 4 (SPG4).

Flowchart showing the molecular approach used to decipher the non-canonical splicing mutations.

Descriptive Epidemiology of Neurodegenerative Diseases: What Are the Critical Questions?

The field of neurodegenerative diseases is a major challenge faced by public health and is still in need of robust preventive measures and disease-modifying treatments. Population-based studies can offer the framework in the context of primary and secondary prevention of neurodegenerative diseases. The epidemiology of neurodegenerative disorders in the last decades has focused on descriptive studies mainly based on the use of clinical criteria. However, clinical definition is basically insufficient both to well-characterize different phenotypes and to make an early diagnosis. Descriptive epidemiology needs a new framework to update the area of neurodegenerative research, based on the advancement of both clinical and biological diagnostic criteria and the urgency for an early diagnosis of the disease. In here, we address the present and future of population-based studies in neurodegenerative disorders and discuss the shift of paradigms in the diagnosis of disease and disease definition. We further debate the changes in biomarker implementation models and type of biomarkers used in population-based studies. Descriptive epidemiology of neurodegenerative disorders is rapidly evolving. These implementations will improve the future design and outcome of population-based studies and policy-making in public health intervention.