Cerebrospinal Fluid TAR DNA-Binding Protein 43 Combined with Tau Proteins as a Candidate Biomarker for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Spectrum Disorders.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are nowadays recognized as spectrum disorders with a molecular link, the TAR DNA-binding protein 43 (TDP-43), rendering it a surrogate biomarker for these disorders. METHODS: We measured cerebrospinal fluid (CSF) levels of TDP-43, beta-amyloid peptide with 42 amino acids (Aß42), total tau protein (τT), and tau protein phosphorylated at threonine 181 (τP-181) in 32 patients with ALS, 51 patients with FTD, and 17 healthy controls. Double-sandwich commercial enzyme-linked immunosorbent assays were used for measurements. RESULTS: Both ALS and FTD patients presented with higher TDP-43 and τT levels compared to the control group. The combination of biomarkers in the form of the TDP-43 × τT / τP-181 formula achieved the best discrimination between ALS or FTD and controls, with sensitivities and specificities >0.8. CONCLUSION: Combined analysis of TDP-43, τT, and τP-181 in CSF may be useful for the antemortem diagnosis of ALS and FTD.

Frontotemporal Dysfunction in Amyotrophic Lateral Sclerosis: A Discriminant Function Analysis.

BACKGROUND: There is growing evidence for extramotor dysfunction (EMd) in amyotrophic lateral sclerosis (ALS), with a reported prevalence of up to 52%. OBJECTIVE: In the present study, we explore the clinical utility of a brief neuropsychological battery for the investigation of cognitive, behavioral, and language deficits in patients with ALS. METHODS: Thirty-four consecutive ALS patients aged 44-89 years were tested with a brief neuropsychological battery, including executive, behavioral, and language measures. Patients were initially classified as EMd or non-EMd based on their scores on the frontal assessment battery (FAB). RESULTS: Between-group comparisons revealed significant differences in all measures (p < 0.01). Discriminant analysis resulted in a single canonical function, with all tests serving as significant predictors. This function agreed with the FAB in 13 of 17 patients screened as EMd and identified extramotor deficits in 2 additional patients. Overall sensitivity and specificity estimates against FAB were 88.2%. CONCLUSIONS: We stress the importance of discriminant function analysis in clinical neuropsychological assessment and argue that the proposed neuropsychological battery may be of clinical value, especially when the option of extensive and comprehensive neuropsychological testing is limited. The psychometric validity of an ALS-frontotemporal dementia diagnosis using neuropsychological tests is also discussed.

Investigating the economic burden of ALS in Greece: a cost-of-illness approach.

The present study aims to investigate the economic burden of ALS per patient in Greece. A sample of 33 patients who were monitored in Aeginition University Hospital in Athens, a reference centre for ALS in Greece, was used for the calculations. According to the findings of this study the total annual cost per ALS patient in Greece was €7450. The direct cost was estimated at €4305 (or 57.8% of the total cost), while the indirect cost was €3145 (or 42.2% of the total cost). Medications, professional home help and cost due to work absenteeism were the leading components of total cost. In general, the aforementioned amount is considered substantial, albeit lower than the corresponding amount of other countries.

LRP4 antibodies in serum and CSF from amyotrophic lateral sclerosis patients.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) and myasthenia gravis (MG) are caused, respectively, by motor neuron degeneration and neuromuscular junction (NMJ) dysfunction. The membrane protein LRP4 is crucial in the development and function of motor neurons and NMJs and LRP4 autoantibodies have been recently detected in some MG patients. Because of the critical role in motor neuron function we searched for LRP4 antibodies in ALS patients. METHODS: We developed a cell-based assay and a radioimmunoassay and with these we studied the sera from 104 ALS patients. RESULTS: LRP4 autoantibodies were detected in sera from 24/104 (23.4%) ALS patients from Greece (12/51) and Italy (12/53), but only in 5/138 (3.6%) sera from patients with other neurological diseases and 0/40 sera from healthy controls. The presence of LRP4 autoantibodies in five of six tested patients was persistent for at least 10 months. Cerebrospinal fluid samples from six of seven tested LRP4 antibody-seropositive ALS patients were also positive. No autoantibodies to other MG autoantigens (AChR and MuSK) were detected in ALS patients. No differences in clinical pattern were seen between ALS patients with or without LRP4 antibodies. CONCLUSIONS: We infer that LRP4 autoantibodies are involved in patients with neurological manifestations affecting LRP4-containing tissues and are found more frequently in ALS patients than MG patients. LRP4 antibodies may have a direct pathogenic activity in ALS by participating in the denervation process.

Double seronegative myasthenia gravis with anti-LRP 4 antibodies.

About 10% of patients with generalized myasthenia gravis do not have detectable antibodies to acetylcholine receptor or muscle specific kinase (double seronegative myasthenia). The presence of anti-low density lipoprotein receptor-related protein 4 antibodies (LRP4 Abs) has recently been reported in variable proportion of double seronegative cases. We report the presenting characteristics of two double seronegative myasthenic patients from Greece with anti-LRP4 antibodies shortly after disease onset. The first patient, a 52-year-old male, presented with a one month history of isolated neck extensor weakness; the second patient is a 52-year-old female with three months history of ocular-bulbar-cervical myasthenic weakness. Both patients presented with mild severity and responded promptly and adequately to pyridostigmine. In the female patient thymic residual tissue was detected on CT of the mediastinum. She underwent thymectomy, and histological examination revealed follicular hyperplasia. This is the first clinical report of the presenting features of newly diagnosed myasthenia with anti-LRP4 antibodies. The clinical and therapeutic implications of the anti-LRP4 antibody positivity remain to be clarified.

Humoral immune activation in amyotrophic lateral sclerosis patients.

There is evidence that immunological factors may involved in the pathogenetic mechanisms of amyotrophic lateral sclerosis (ALS). Few studies to date have explored the status of the humoral immune response in patients with ALS. We examined the presence of humoral immune activation in ALS patients, serum immunoglobulins (IgG, IgA and IgM) levels were measured in 36 patients with ALS and 35 normal controls. Serum IgG, IgM and IgA levels were not significantly different in our ALS patients compared with the control group (P=ns). No correlations of serum IgG, IgM and IgA concentrations with duration, severity of the disease or the clinical form of onset (bulbar or spinal) were found in our ALS patients. Our results do not suggest a humoral immune activation in ALS patients. This does not exclude that immunological mechanisms may be involved in ALS pathogenesis.

Volume matters: the influence of different botulinum toxin-A dilutions for sialorrhea in amyotrophic lateral sclerosis.

INTRODUCTION: We aimed to determine the effect of different botulinum toxin-A (BTX-A) dilutions on the treatment efficacy and side effects for amyotrophic lateral sclerosis (ALS) related sialorrhea. METHODS: Ten patients were enrolled in the study. BTX-A dilution for Group A was 100 U in 1 ml of saline, whereas the dilution for Group B was 100 U in 2 ml of saline. Both groups received 20 U of BTX-A in each parotid gland, and assessments were made by means of the Drooling Impact Scale, items 1 and 3 of the ALS functional rating scale, and visual analog scales for drooling and swallowing function. RESULTS: Although both groups exhibited a similar improvement in drooling, Group B had a mild but significant deterioration in bulbar function that was not evident in Group A. CONCLUSIONS: These results suggest that BTX-A has a safer profile when reconstituted with 1 ml instead of 2 ml of saline.

Proinflammatory cytokines in serum and cerebrospinal fluid of CIDP patients.

INTRODUCTION: Little is known about the role of cytokines in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Interleukin (IL)-12 and IL-15 are the major growth and differentiation factors for Th-1 cells and IL-17 is a marker of Th-17 cell expansion and activation, a high proinflammatory new subset of T cells that induce severe autoimmunity. PATIENTS AND METHODS: We measured by enzyme-like immunosorbent assay serum and cerebrospinal fluid (CSF) levels of IL-15, IL-12, and IL-17 in 24 patients with CIDP and 12 patients with other non-inflammatory neurological disorders and serum levels in 16 healthy subjects. RESULTS: We found a positive association of CSF IL-12 (P = 0·012) with CIDP presence (P<0·001). CONCLUSIONS: Our findings suggest that IL-12 may be involved as potential marker of immune activation in CIDP. The increase in its levels in CSF may be a marker of initiation of Th-1 cell-mediated immunity.

Monosymptomatic clinically isolated syndrome with sudden sensorineural hearing loss: case report and critical review of the literature.

INTRODUCTION: Isolated cranial nerve involvement is rare in patients with multiple sclerosis (10.4%) and extremely rare is an eighth nerve palsy, especially in the context of a clinically isolated syndrome (<1%). CASE REPORT: A 34-year-old male presented with a history of left-sided tinnitus and sudden sensorineural hearing loss (SSNHL). Magnetic resonance imaging of the brain revealed >9, nonenhancing periventricular and corpus callosum lesions. Brainstem auditory evoked potentials were abnormal, ipsilateral to the affected ear, consistent with the presumed underlying demyelinating pathology. Visual evoked potentials showed bilateral prolonged P100 latencies. Oligoclonal bands were not detected in the cerebrospinal fluid, but IgG index was marginally elevated. After administration of corticosteroids, the patient recovered auditory function over a several month period. CONCLUSIONS: This report describes a case of SSNHL in the context of magnetic resonance imaging of the brain and electrophysiological findings consistent with a demyelinating etiology. SSNHL is a rare and possibly underrecognized manifestation of clinically isolated syndrome.

AchR-positive myasthenia gravis with MRI evidence of early muscle atrophy.

Muscle atrophy, when it occurs in myasthenia gravis (MG), is usually associated with long-standing disease or with chronic corticosteroid treatment. Early muscle atrophy in a steroid-naive patient has been reported previously only in muscle-specific tyrosine kinase (MuSK)-MG. We report a 63-year-old male patient with acetylcholine receptor (AchR)-positive MG with a short duration of disease, no steroid treatment and MRI evidence of muscle atrophy.

The impact of comorbidity and other clinical and sociodemographic factors on health-related quality of life in Greek patients with Parkinson's disease.

OBJECTIVES: This study was designed to evaluate the impact of other common self-reported comorbid disorders (hypertension, dyslipidemia, ischemic heart disease, diabetes mellitus, minor stroke, arthritis, low back pain or osteoporosis and depression) on health-related Quality of Life (HRQoL) of Parkinson's disease (PD) patients and to explore the association of their HRQoL with various sociodemographic and clinical factors. METHODS: Data about age, gender, education, occupation, income, marital and residential status, social relations, disease duration, functional status, treatment and concomitant diseases were collected of 139 Greek patients (68 men and 71 women) with PD. Patients were consecutively recruited from the outpatient clinic of the first Neurology Department of Athens National University at Aeginition Hospital. Disease severity was assessed using the unified Parkinson's disease rating scale including Hoehn and Yahr and Schwab and England (S&E) scales. HRQoL was measured by the specific Parkinson's disease questionnaire (PDQ-39). A multivariate multiple regression model with normal errors was used for the statistical analysis. RESULTS: The main determinants of HRQoL were low degree of independence measured by the S&E scale (F = 35.942, p < 0.001), social isolation (F = 20.508, p < 0.001), disease duration (F = 14.983, p < 0.001), sleep (F = 6.507, p = 0.013) and gastrointestinal disturbances (F = 4.643, p = 0.035) and the presence of depression (F = 6.022, p = 0.017). CONCLUSION: Among the other chronic comorbidities only depression was associated with a poor HRQoL in PD patients. Functional dependence and social isolation contributed most to worse HRQoL. Our findings suggest that adequate social support and management of depression, sleep and gastrointestinal disturbances could reduce the distress and improve HRQoL in patients with PD.

Prevalence of major depression in ALS: comparison of a semi-structured interview and four self-report measures.

This study aimed to compare prevalence estimates of current major depression obtained with a semi-structured interview and four frequently used self-report depression severity measures in a sample of amyotrophic lateral sclerosis (ALS) patients. Thirty-seven ALS patients (56.8% males) aged 37-80 years (mean 62.0 ± 10.7) without respiratory insufficiency or dementia were studied during hospitalization or on a follow-up visit. SCID-IV interview as well as self-report Hospital Anxiety and Depression Scale (HADS), ALS Depression Inventory (ADI), Center for Epidemiological Studies-Depression scale (CES-D) and Beck Depression Inventory (BDI-I) were administered. Kappa coefficients of diagnostic agreement between various instruments were calculated. Results showed that 37.8% of patients had a lifetime diagnosis of depression and in 13.5% depression followed ALS onset. Percentages of patients 'diagnosed' with current major depression were: 21.6% (SCID-IV), 16.7% (HADS-D ≥ 11), 16.2% (ADI ≥ 29), 25% (CES-D ≥ 24) and 24.3% (BDI-I ≥ 16). High kappa values were recorded between CES-D, BDI-I and SCID-IV as well as between HADS-D and ADI. CES-D, BDI-I and SCID-IV gave the highest prevalence estimates of current major depression in ALS patients and were in poor agreement with estimates based on HADS and ADI; it is suggested that this is possibly because the former give a far greater emphasis on physical symptoms of depression than the latter.

MRI evidence of early muscle atrophy in MuSK positive myasthenia gravis.

Muscle atrophy, particularly of facial and bulbar muscles, seems to be a relatively common long-term consequence of musclespecific tyrosine kinase-myasthenia gravis (MuSK-MG), perhaps reflecting the chronic state of disease or long-term therapy with corticosteroids. We performed magnetic resonance imaging (MRI) to assess muscle wasting in the facial and bulbar muscles in two female MuSK-MG patients, with short duration of symptoms prior to diagnosis and prior to commencement of steroid therapy. The study revealed marked atrophy of temporalis, masseters, and lingual muscles with fatty replacement. MRI evidence of early muscle atrophy in MuSK-MG may indicate that MuSK antibodies per se may predispose to muscle atrophy.