A Linear Predictor Based on FTIR Spectral Biomarkers Improves Disease Diagnosis Classification: An Application to Multiple Sclerosis.

Multiple sclerosis (MS) is a neurodegenerative disease of the central nervous system that can lead to long-term disability. The diagnosis of MS is not simple and requires many instrumental and clinical tests. Sampling easily collected biofluids using spectroscopic approaches is becoming of increasing interest in the medical field to integrate and improve diagnostic procedures. Here we present a statistical approach where we combine a number of spectral biomarkers derived from the ATR-FTIR spectra of blood plasma samples of healthy control subjects and MS patients, to obtain a linear predictor useful for discriminating between the two groups of individuals. This predictor provides a simple tool in which the contribution of different molecular components is summarized and, as a result, the sensitivity (80%) and specificity (93%) of the identification are significantly improved compared to those obtained with typical classification algorithms. The strategy proposed can be very helpful when applied to the diagnosis of diseases whose presence is reflected in a minimal way in the analyzed biofluids (blood and its derivatives), as it is for MS as well as for other neurological disorders.

ATR-FTIR spectroscopy of plasma supported by multivariate analysis discriminates multiple sclerosis disease.

Multiple sclerosis (MS) is one of the most common neurodegenerative diseases showing various symptoms both of physical and cognitive type. In this work, we used attenuated total reflection Fourier transformed infrared (ATR-FTIR) spectroscopy to analyze plasma samples for discriminating MS patients from healthy control individuals, and identifying potential spectral biomarkers helping the diagnosis through a quick non-invasive blood test. The cohort of the study consists of 85 subjects, including 45 MS patients and 40 healthy controls. The differences in the spectral features both in the fingerprint region (1800-900 cm-1) and in the high region (3050-2800 cm-1) of the infrared spectra were highlighted also with the support of different chemometric methods, to capture the most significant wavenumbers for the differentiation. The results show an increase in the lipid/protein ratio in MS patients, indicating changes in the level (metabolism) of these molecular components in the plasma. Moreover, the multivariate tools provided a promising rate of success in the diagnosis, with 78% sensitivity and 83% specificity obtained through the random forest model in the fingerprint region. The MS diagnostic tools based on biomarkers identification on blood (and blood component, like plasma or serum) are very challenging and the specificity and sensitivity values obtained in this work are very encouraging. Overall, the results obtained suggest that ATR-FTIR spectroscopy on plasma samples, requiring minimal or no manipulation, coupled with statistical multivariate approaches, is a promising analytical tool to support MS diagnosis through the identification of spectral biomarkers.

Ischemic Stroke and Provoked Seizure as a Manifestation of Brugmansia suaveolens (Angel's Trumpet) Acute Intoxication: A Detailed Clinical, Electroencephalogram, and Magnetic Resonance Imaging Description and 5-Month Follow-up.

METHODS: We present a detailed clinical, laboratory, electroencephalogram/magnetic resonance imaging description and a 4-month follow-up of a case of stroke and provoked seizures as manifestation of angel's trumpet intoxication. RESULTS/DISCUSSION: A 76-year-old woman presented with stuporous state evolving in 48 hours in bilateral mydriasis, vomiting, global aphasia, confusion, and stereotyped movement. An interictal electroencephalogram, performed 72 hours later, showed frequent generalized epileptiform discharges, and a brain magnetic resonance imaging revealed 2 small subcortical lesions in the right frontal lobe on diffusion weighted imaging sequences. When completely recovered, she could tell that she had mistaken angel's trumpet flowers for pumpkin flowers, so she had eaten them. CONCLUSIONS: Angel's trumpet intoxication is a neurological emergency that deserves attention of both the media in matter of plant poisoning and the scientific forums because of the high lethal potential to better choose the diagnostic and therapeutic process.

Thermal Liquid Biopsy (TLB) of Blood Plasma as a Potential Tool to Help in the Early Diagnosis of Multiple Sclerosis.

BACKGROUND: Multiple sclerosis (MS) is frequently characterized by a variety of clinical signs, often exhibiting little specificity. The diagnosis requires a combination of medical observations and instrumental tests, and any support for its objective assessment is helpful. OBJECTIVE: Herein, we describe the application of thermal liquid biopsy (TLB) of blood plasma samples, a methodology for predicting the occurrence of MS with a noninvasive, quick blood test. METHODS: TLB allows one to define an index (TLB score), which provides information about overall real-time alterations in plasma proteome that may be indicative of MS. RESULTS: This pilot study, based on 85 subjects (45 MS patients and 40 controls), showed good performance indexes (sensitivity and specificity both around 70%). The diagnostic methods better discriminate between early stage and low-burden MS patients, and it is not influenced by gender, age, or assumption of therapeutic drugs. TLB is more accurate for patients having low disability level (≤ 3.0, measured by the expanded disability status scale, EDSS) and a relapsing-remitting diagnosis. CONCLUSION: Our results suggest that TLB can be applied to MS, especially in an initial phase of the disease when diagnosis is difficult and yet more important (in such cases, accuracy of prediction is close to 80%), as well as in personalized patient periodic monitoring. The next step will be determining its utility in differentiating between MS and other disorders, in particular in inflammatory diseases.

The Role of Topiramate in the Management of Cocaine Addiction: a Possible Therapeutic Option.

Topiramate (TPM) is an antiepileptic drug able to play a role in both neurological and psychiatric disorders. TPM facilitates gamma-aminobutyric acid (GABA) transmission and inhibits glutamatergic transmission (i.e. AMPA/kainate receptors). Several studies reported that the modulation of GABAergic and glutamatergic synaptic transmission may reduce cocaine reinforcement. Therefore, TPM could be used in the management of cocaine dependence.

Gambling disorder during dopamine replacement treatment in Parkinson's disease: a comprehensive review.

Gambling Disorder (GD) is characterized by "the failure to resist gambling impulses despite severe personal, family or occupational consequences". In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-V), GD replaces the DSM-IV diagnosis of Pathological Gambling (PG). GD estimated prevalence ranges between 0.4% and 3.4% within the adult population and it seems to be more common in patients with Parkinson's disease (PD). In this population, GD recently has become more widely recognized as a possible complication of dopamine agonist (DA) therapy. This association has aroused great interest for the dramatic impact GD has on patients' quality of life. Management of PG in patients with PD could be demanding. It is based on patient and caregiver education, modification of dopamine replacement therapy, and in some cases psychoactive drug administration. In this review article, the authors provide an overview of GD pathogenesis during DA therapy as well as a summary of available treatment options.

Cerebral stroke injury: the role of cytokines and brain inflammation.

Stroke represents the most frequent cause of permanent disability in adults worldwide. Cerebral ischemia triggers the pathological pathways of the ischemic cascade and causes irreversible neuronal injury in the ischemic core within minutes of the onset. Elements of the immune system are involved in all stages of ischemic cascade from acute intravascular events triggered by the interruption of blood supply, to the parenchymal processes leading to brain damage and to the ensuing tissue repair. In this review, we will provide a brief overview of current understanding of the role of cytokines and brain inflammation during acute ischemic stroke.

Insulin resistance possible risk factor for cognitive impairment in fibromialgic patients.

To evaluate glucose metabolism and/or insulin resistance (IR) in 96 patients with Fibromyalgia (FM), associated or not to cognitive impairment. We investigated glucose metabolism in 96 FM patients. Enrolled patients were divided into two groups: 48 patients with memory deficit (group A) and 48 without memory deficit (control group). We evaluated glucose and insulin levels after a 2 h-Oral-Glucose-Tolerance-Test (2 h-OGTT) and insulin resistance (IR) by the homeostasis model assessment formula (HOMA). Body Mass Index (BMI), waist-to-hip-ratio (WHR), anxiety level, fasting plasma insulin and Non-Steroidal Anti-Inflammatory agents use were higher in patients with FM with memory impairment; while age, sex, waist circumference, education level, fasting plasma glucose, glycate hemoglobin, triglycerides, blood lipid profile, C- Reactivity-Protein (CRP), blood pressure and smoking habits were similar in both groups. Following OGTT the prevalence of glucose metabolism abnormalities was significantly higher in group A. IR was present in 79% patients, of whom 23% had also impaired glucose tolerance, 4% newly diagnosed diabetes mellitus and 52% IR only. Obesity and overweight prevailed in group A. IR, but not BMI or WHR was associated to an increased risk of memory impairment (OR = 2,6; 95% CI: 1,22-3,7). The results of this study suggest that IR may represent a risk factor for memory impairment in fibromialgic patients.

MR imaging and cognitive correlates of relapsing-remitting multiple sclerosis patients with cerebellar symptoms.

Multiple sclerosis (MS) is a demyelinating disease affecting the central nervous system, frequently associated with cognitive impairments. Damages of the cerebellum are very common features of patients with MS, although the impact of this clinical factor is generally neglected. Recent evidence from our group demonstrated that MS patients with cerebellar damages are characterized by selective cognitive dysfunctions related to attention and language abilities. Here, we aimed at investigating the presence of neuroanatomical abnormalities in relapsing-remitting MS patients with (RR-MSc) and without (RR-MSnc) cerebellar signs. Twelve RR-MSc patients, 14 demographically, clinically, and radiologically, matched RR-MSnc patients and 20 controls were investigated. All patients underwent neuropsychological assessment. After refilling of FLAIR lesions on the 3D T1-weighted images, VBM was performed using SPM8 and DARTEL. A correlation analysis was performed between VBM results and neuropsychological variables characterizing RR-MSc patients. Despite a similar clinical status, RR-MSc patients were characterized by more severe cognitive damages in attention and language domains with respect to RR-MSnc and controls. With respect to controls, RR-MSnc patients were characterized by a specific atrophy of the bilateral thalami that became more widespread (including motor cortex) in the RR-MSc group (FWE < 0.05). However, consistent with their well-defined neuropsychological deficits, RR-MSc group showed atrophies in the prefrontal and temporal cortical areas when directly compared with RR-MSnc group. Our results demonstrated that RR-MS patients having cerebellar signs were characterized by a distinct neuroanatomical profile, mainly involving cortical regions underpinning executive functions and verbal fluency.

Computer-assisted cognitive rehabilitation of attention deficits for multiple sclerosis: a randomized trial with fMRI correlates.

BACKGROUND: Although a growing body of evidence has highlighted the role of cognitive rehabilitation (CR) in the management of cognitive dysfunctions in multiple sclerosis (MS), there is still no evidence for a validated therapeutic approach. OBJECTIVE: We propose a new therapeutic strategy characterized by a computer-based intensive attention training program in MS patients with predominant attention deficits. We aim to investigate the effectiveness of our rehabilitation procedure, tailored for those with impaired abilities, using functional magnetic resonance imaging (fMRI). METHODS: Using a double-blind randomized controlled study, we enrolled 12 MS patients, who underwent a CR program (experimental group), and 11 age-gender-matched MS patients, who underwent a placebo intervention (control group). fMRI was recorded during the execution of a cognitive task broadly used for assessing attention abilities in MS patients (paced visual serial addition test). RESULTS: Significant effects were detected both at a phenotypic and at an intermediate phenotypic level. After CR, the experimental group, in comparison with the control group, showed a specific enhanced performance in attention abilities as assessed by the Stroop task with an effect size of 0.88, which was associated with increased activity in the posterior cerebellar lobule and in the superior parietal lobule. CONCLUSIONS: Our study demonstrates that intensive CR tailored for those with impaired abilities affects neural plasticity and improves some aspects of cognitive deficits in MS patients. The reported neurophysiological and behavioral effects corroborate the benefits of our therapeutic approach, which might have a reliable application in the clinical management of cognitive deficits in MS.

The Effect of Lipoic Acid Therapy on Cognitive Functioning in Patients with Alzheimer's Disease.

Diabetes mellitus (DM) is an important risk factor for Alzheimer's disease (AD). Most diabetic patients have insulin resistance (IR) that is associated with compensatory hyperinsulinemia, one of the mechanisms suggested for increased AD risk in patients with DM. Alpha-lipoic acid (ALA) is a disulfide molecule with antioxidant properties that has positive effects on glucose metabolism and IR. This study evaluated the effect of ALA treatment (600 mg/day) on cognitive performances in AD patients with and without DM. One hundred and twenty-six patients with AD were divided into two groups, according to DM presence (group A) or absence (group B). Cognitive functions were assessed by MMSE, Alzheimer's Disease Assessment Scale-cognitive (ADAS-Cog), Clinician's Interview-Based Impression of Severity (CIBIC), Clinical Dementia Rating (CDR), and Alzheimer's Disease Functional and Change Scale (ADFACS). IR was assessed by HOMA index. At the end of the study, MMSE scores showed a significant improvement in 43% patients of group A (26 subjects) and 23% of group B (15 subjects), compared to baseline (P = .001). Also ADAS-Cog, CIBIC, and ADFACS scores showed a significant improvement in group A versus group B. IR was higher in group A. Our study suggests that ALA therapy could be effective in slowing cognitive decline in patients with AD and IR.

Blink reflex recovery cycle in patients with essential tremor associated with resting tremor.

OBJECTIVE: An increased R2 recovery component of the blink reflex (R2-BRrc) has been commonly observed in Parkinson disease, cranio-cervical dystonia, and dystonic tremor, while the BRrc was reported normal in patients with essential tremor (ET). We studied BRrc in patients with ET associated with resting tremor (rET) in comparison with patients with ET. METHODS: This was a cross-sectional study investigating R2-BRrc at interstimulus intervals (ISI) of 100, 150, 200, 300, 400, 500, and 750 msec in 14 patients with rET, 14 patients with ET, and 16 healthy controls. To compare individual patients, we calculated an R2 recovery index in each subject as the mean of R2 area ratio values at ISIs of 150, 200, 300, 400, and 500 msec. All patients and controls underwent DAT-SPECT. RESULTS: Patients with rET differed from those with ET for the presence of resting tremor associated in several cases (36%) with a subtle arm dystonia. DAT-SPECT was normal in all patients and controls. All patients with rET (with and without dystonia) had an increased R2-BRrc while all patients with ET had a normal BRrc comparable to that of control subjects. The R2 recovery index was abnormal in all patients with rET but in none of the patients with ET. CONCLUSIONS: Patients with rET showed increased R2-BRrc, suggesting that this form of tremor may be a dystonic tremor rather than a subtype of ET. BRrc helps to correctly diagnose DAT-negative patients with resting tremor also in the absence of overt dystonic posturing.

Cerebellar-parietal dysfunctions in multiple sclerosis patients with cerebellar signs.

Consistent findings have shown that the cerebellum is critically implicated in a broad range of cognitive processes including executive functions. Of note, cerebellar symptoms and a number of cognitive deficits have been widely reported in patients with multiple sclerosis (MS). This study investigated for the first time the role of cerebellar symptoms in modulating the neural networks associated with a cognitive task broadly used in MS patients (Paced Visual Serial Addition Test (PVSAT)). Twelve relapsing-remitting (RR) MS patients with prevalent cerebellar signs and symptoms (RR-MSc), 15 RR-MS patients without cerebellar manifestation (RR-MSnc) and 16 matched-healthy controls were examined during functional magnetic resonance imaging (fMRI). We tested whether the RR-MSc patients displayed abnormal activations within "cognitive" cerebellar regions and other areas typically engaged in working memory and tightly connected with the cerebellum. Despite similar behavioral performances during fMRI, RR-MSc patients displayed, relatively to both RR-MSnc patients and controls, significantly greater responses in the left cerebellar Crus I/Lobule VI. RR-MSc patients also displayed reduced functional connectivity between the left cerebellar Crus I and the right superior parietal lobule (FWE<.05). These results demonstrated that the presence of the cerebellar signs drastically impacts on the neurofunctional networks underlying working memory in MS. The altered communication between the cerebellum and a cortical area implicated in short-term buffering and storage of relevant information, offer new insights into the pathophysiological mechanisms of cognition in MS.

Tacrolimus-induced polyneuropathy after heart transplantation.

Tacrolimus has been often described to induce neuropathy in liver-, pancreas-, and renal-transplanted patients. Here, we report the first case of a 56-year-old woman who developed a progressive symmetric demyelinating sensorimotor polyneuropathy in the distal muscles of the lower limbs after therapy with tacrolimus because of heart transplantation. This condition suddenly reverted after the tacrolimus was stopped.

Effects of insulinic therapy on cognitive impairment in patients with Alzheimer disease and diabetes mellitus type-2.

BACKGROUND: Type-2 Diabetes Mellitus (DM-2) is an important risk factor for Alzheimer disease (AD) and vascular dementia (VD). The role of insulinic therapy on cognitive decline is controversial. OBJECTIVE: To evaluate cognitive impairment in patients with AD and DM-2 treated with either oral antidiabetic drugs or combination of insulin with other diabetes medications. METHODS: 104 patients with mild-to-moderate AD and DM-2 were divided into two groups, according to antidiabetic pharmacotherapy: group A, patients treated with oral antidiabetic drugs and group B, patients treated with insulin combined with other oral antidiabetic medications. Cognitive functions were assessed by the Mini Mental State Examination (MMSE) and the Clinician's Global Impression (CGI), with a follow-up of 12 months. RESULTS: At the end of the study, the MMSE scores showed a significant worsening in 56.5% patients of group A and in 23.2% patients of group B, compared to baseline MMSE scores (P=.001). Also CGI-C scores showed a significant worsening for all domains after 12 months in group A vs group B (P=.001). The two groups were matched for body mass index, serum lipids, triglycerides, Apo epsilon4 allele and smoke habit. Conversely, ischemic heart disease and hypertension were significantly higher in group B (P=.002). After adjustment for this risk variables, our results remained significant (P=.001). CONCLUSIONS: Our study suggests that insulinic therapy could be effective in slowing cognitive decline in patients with AD.

Role of the Oral Glucose Tolerance Test (OGTT) in the idiopathic restless legs syndrome.

BACKGROUND: Restless legs syndrome (RLS) is a sensorimotor disorder characterised by a distressing urge to move the legs. Several clinical conditions have been associated with RLS, such as iron deficiency, uraemia, pregnancy, polyneuropathy and Diabetes Mellitus (DM). However the causes remain unknown in about 70-80% of cases. OBJECTIVE: To evaluate the role of glucose metabolism abnormalities in idiopathic RLS. METHODS: We enrolled 132 consecutive patients with idiopathic RLS associated with normal fasting glycaemia and 128 control subjects. We evaluated glucose and insulin levels after a 2-h oral glucose tolerance test (2h-OGTT) in patients and control subjects. In addition we determined Insulin Resistance (IR) by Homa-Index. RESULTS: After 2h-OGTT, the prevalence of glucose metabolism abnormalities was significantly higher in patients with RLS than in controls (P=.002). Impaired Glucose Tolerance (IGT) was found in 54 (41%) patients and in 23 (18%) controls, while a new-diagnosed DM (NDDM) was found in 25 (19%) patients and in 8 (6%) controls. The IR showed no significant differences between patients and controls. CONCLUSIONS: Our study suggests that IGT (prediabetes) is frequently associated with idiopathic RLS. We propose to perform a 2h-OGTT in idiopathic RLS patients with normal fasting glycaemia.