Cognitive impairment is correlated with insulin resistance degree: the "PA-NICO-study".

Several epidemiological studies have shown that Diabetes Mellitus (DM) or Insulin Resistance (IR) increases the risk of dementia. Besides, some authors suggested that poor glucose control to be associated with worse cognitive function. We aimed to assess cognitive functions and IR-degree over time in diabetic. We also evaluated whether a greater magnitude of cognitive decline could be related with their IR degree. We enrolled 335 diabetic patients and 142 non-diabetic subjects; participants were subdivided into three groups in accordance with their IRdegree assessed by Homa-Index (HI): Normal-HI (non-diabetic NHI < 2,6), Moderate-HI (MHI > 2,6 < 10) and High-HI (HHI > 10). Metabolic status and a comprehensive neuropsycological test battery (MMSE, ADAS-Cog, ACDS-ADL) were assessed at baseline and every 12-months during the follow-up (6,8 years). At the end of the study, the average MMSE decreased significantly in patients of HHI group (P = .001) compared to baseline. MMSE scores were also reduced both in MHI group and in controls, but the difference between two groups was not significant. In HHI group, similar effects were observed for the ADAS-Cog score compared to baseline (P = 0.001); instead, when ACDS-ADL was evaluated, no differences was observed among the three groups. These results remained unchanged also after adjustment for confounding variables (i.e. APOε-status, sex, BMI, education level, heart diseases and HbA1c). We suggest that higher IR-degree is associated with greater cognitive decline in diabetic patients; so we hypothesize that IR degree, more than IR status itself, could be related to the severity of cognitive impairment.

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.

Possible implications of insulin resistance and glucose metabolism in Alzheimer's disease pathogenesis.

Type 2 diabetes mellitus (DM) appears to be a significant risk factor for Alzheimer disease (AD). Insulin and insulin-like growth factor-1 (IGF-1) also have intense effects in the central nervous system (CNS), regulating key processes such as neuronal survival and longevity, as well as learning and memory. Hyperglycaemia induces increased peripheral utilization of insulin, resulting in reduced insulin transport into the brain. Whereas the density of brain insulin receptor decreases during age, IGF-1 receptor increases, suggesting that specific insulin-mediated signals is involved in aging and possibly in cognitive decline. Molecular mechanisms that protect CNS neurons against ß-amyloid-derived-diffusible ligands (ADDL), responsible for synaptic deterioration underlying AD memory failure, have been identified. The protection mechanism does not involve simple competition between ADDLs and insulin, but rather it is signalling dependent down-regulation of ADDL-binding sites. Defective insulin signalling make neurons energy deficient and vulnerable to oxidizing or other metabolic insults and impairs synaptic plasticity. In fact, destruction of mitochondria, by oxidation of a dynamic-like transporter protein, may cause synapse loss in AD. Moreover, interaction between Aß and τ proteins could be cause of neuronal loss. Hyperinsulinaemia as well as complete lack of insulin result in increased τ phosphorylation, leading to an imbalance of insulin-regulated τ kinases and phosphatates. However, amyloid peptides accumulation is currently seen as a key step in the pathogenesis of AD. Inflammation interacts with processing and deposit of ß-amyloid. Chronic hyperinsulinemia may exacerbate inflammatory responses and increase markers of oxidative stress. In addition, insulin appears to act as 'neuromodulator', influencing release and reuptake of neurotransmitters, and improving learning and memory. Thus, experimental and clinical evidence show that insulin action influences cerebral functions. In this paper, we reviewed several mechanisms by which insulin may affect pathophysiology in AD.

Insulin resistance increases risk of carpal tunnel syndrome: a case-control study.

Carpal tunnel syndrome (CTS) is one of the most common upper limb compression neuropathies. In only 50% of cases it is possible to identify a cause. Our objective was to determine the role of glucose metabolism abnormalities in idiopathic CTS. We identified 117 patients with idiopathic moderate or severe CTS and 128 controls. In all we evaluated glucose and insulin levels at fasting and after 2-h oral glucose tolerance test (2h-OGTT). In addition we determined insulin resistance (IR). Following OGTT the prevalence of glucose metabolism abnormalities was significantly higher in the CTS group (p = 0.001). IR was documented in 80% of patients, of whom 45% had impaired glucose tolerance, 14% newly diagnosed diabetes mellitus, and 20% IR only. Waist circumference and body mass index were also significantly increased in the CTS group. In this study, we focused on evidence that pre-diabetes may represent a risk factor for CTS. We proposed to determine IR as a rule in all patients with idiopathic CTS.

Effects of safinamide on REM sleep behavior disorder in Parkinson disease: A randomized, longitudinal, cross-over pilot study.

BACKGROUND: Rapid Eye Movement sleep behavior disorder (RBD) is characterized by dream enactment and loss of muscle atonia during REM-sleep. RBD as a premotor feature occurred souvent in patients who develop Parkinson's disease. The glutamatergic, glycinergic, and GABA-ergic systems appear to play a crucial role in the pathogenesis of RBD. METHODS: The present exploratory longitudinal cross-over study aimed to observe the effect of safinamide on RBD symptoms. Thirty patients with PD and RBD were randomized into two groups (15 subjects each), those that received for a period of 3-months safinamide (50 mg/die) in addition (Group A + ) or in absence (Group B - ) to the usual antiparkinsonian therapy. Patients exploring the clinical and video-polysomnographic changes occurred during this pharmacological therapy. RESULTS: Twenty-two of 30 patients reported clear improvement in symptoms during safinamide treatment, and 16 were absolutely free from clinical RBD-symptoms at the end of the treatment. Eight patients reported slight improvement in RBD-symptoms. In 6/30 patients no substantial improvement was recorded about clinical RBD-symptoms had frightening dreams or from the bed after 1-week of treatment. In addition, after safinamide, the mean UPDRS-II and III scores decreased, while PDSS-2 score indicating an improvement in both motor symptoms and nocturnal sleep features. A significant reduction of sleep behavior disorder by questionnaire-Hong Kong-score (RBDQ-HS), mainly for two individual RBDQ-HK-items (dream related movements and failing out of bed) was registered. CONCLUSIONS: This pilot study indicated that safinamide is well tolerated and improves RBD-symptom in parkinsonian.

Complete oculomotor palsy caused by persistent trigeminal artery.

Primitive trigeminal artery (PTA) is the most frequent embryonic communication between the carotid and vertebro-basilar system. PTA is a pathophysiology phenomenon which has been implicated as a rare cause of cranial nerve dysfunction. We report the case of a 40-year-old woman who developed a complete oculomotor nerve palsy caused by a persistent ecstatic trigeminal artery. Brain MRI and MRA studies documented a neurovascular conflict between the oculomotor nerve and a PTA. To the best of our knowledge there is no report about complete third cranial nerve palsy NC due to a PTA. A role of this rare vascular condition is discussed.

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.

Role of impaired glucose metabolism in the postherpetic neuralgia.

BACKGROUND: Postherpetic neuralgia (PHN) is one of the most common and debilitating sequela of herpes zoster. The etiology of PHN is not completely understood. Several studies showed that diabetes mellitus may increase the risk of infectious diseases, including herpes zoster. Instead, the relationship between PHN and prediabetes has never been described. OBJECTIVE: To evaluate glucose metabolism abnormalities in patients with PHN. METHODS: We studied 87 consecutive patients with PHN and normal fasting glycemia and 108 pain-free controls. In both groups we evaluated glucose and insulin levels after a 2-hour oral glucose tolerance test and insulin resistance. In addition, in all patients we performed skin thoracic biopsy to exclude a small fiber neuropathy. RESULTS: After a 2-hour oral glucose tolerance test, the prevalence of glucose metabolism abnormalities was significantly higher in patients than in controls (P<0.001): impaired glucose tolerance was found in 36 (38%) patients and in 16 (15%) controls, whereas a newly diagnosed diabetes mellitus was found in 9 (9%) patients and in 6 (5%) controls. The insulin resistance showed no significant differences between patients and controls. CONCLUSIONS: Our study suggests that PHN may be a marker for impaired glucose tolerance. A glucose tolerance test should be considered in patients presenting with PHN.

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.

Opioid antagonist naltrexone for the treatment of pathological gambling in Parkinson disease.

UNLABELLED: Pathological gambling (PG) is a potential complication related to the treatment of Parkinson disease (PD) with dopamine agonists (DA). The cause of this disorder is unknown, but altered dopamine neurotransmission may be involved. OBJECTIVE: We evaluated the efficacy and tolerability of the opioid antagonist naltrexone in the treatment of PG in PD. METHODS: Our cases included 3 patients with PD who developed PG after DA treatment. RESULTS: Pathological gambling did not improve after reduction or discontinuation of DA. These patients responded poorly to serotonin reuptake inhibitors, whereas treatment with opioid antagonist naltrexone resulted in the remission of PG. Naltrexone treatment was well tolerated. In one patient, higher dose of naltrexone resulted in hepatic abnormalities, which resolved after dosage reduction. CONCLUSIONS: The opioid antagonist naltrexone could be an effective option for the treatment of PG in PD.

Motor cortex stimulation in Parkinson's disease.

Motor Cortex Stimulation (MCS) is less efficacious than Deep Brain Stimulation (DBS) in Parkinson's disease. However, it might be proposed to patients excluded from DBS or unresponsive to DBS. Ten patients with advanced PD underwent unilateral MCS contralaterally to the worst clinical side. A plate electrode was positioned over the motor cortex in the epidural space through single burr hole after identification of the area with neuronavigation and neurophysiological tests. Clinical assessment was performed by total UPDRS, UPDRS III total, UPDRS III-items 27-31, UPDRS IV, and UPDRS II before implantation in off-medication and on-medication states and after surgery at 1, 3, 6, 12, 18, 24, and 36 months in on-medication/on-stimulation and off-medication/on-stimulation states. We assessed changes of quality of life, throughout the Parkinson's disease quality of life scale (PDQoL-39), and the dose of anti-Parkinson's disease medications, throughout the Ldopa equivalent daily dose (LEDD). During off-medication state, we observed moderate and transitory reduction of total UPDRS and UPDRS total scores and significant and long-lasting improvement in UPDRS III items 27-31 score for axial symptoms. There was marked reduction of UPDRS IV score and LEDD. PDQL-39 improvement was also significant. No important complications and adverse events occurred.

Dementia is associated with insulin resistance in patients with Parkinson's disease.

BACKGROUND: Parkinson's disease is a neurodegenerative disorder involving the basal ganglia. Type-2 Diabetes Mellitus is an important risk factor for Alzheimer disease and vascular dementia. However, the association between Parkinson's disease and Diabetes Mellitus is controversial. OBJECTIVE: To investigate glucose metabolism abnormalities in 110 Parkinson's disease patients with and without dementia. SUBJECTS AND METHODS: We evaluated Insulin Resistance, glucose and insulin levels after a 2-h-oral-glucose-tolerance-test in 53 Parkinson's disease with dementia and 57 with Parkinson's disease without dementia, with normal fasting glucose. RESULTS: BMI, waist circumference, fasting glucose and insulin values, HbA1c, triglycerides, blood lipid profile, depression rating, educational levels, levodopa-dosage and antipsychotic use were similar in both groups. Disease duration and motor impairment were higher in patients with Parkinson's disease and dementia group. After 2-h-oral-glucose-tolerance-test, the prevalence of glucose metabolism abnormalities was significantly higher in group with Parkinson's disease and dementia group (p=0.03). The insulin resistance was present in 62% patients with Parkinson's disease with dementia, of whom 30% had also impaired glucose tolerance, 5,6% newly diagnosed Diabetes Mellitus and 26% only Insulin Resistance. These percentages were significantly higher in group with Parkinson's disease and dementia, also after adjustment for disease duration and motor disability. CONCLUSIONS: Our study suggests that PD patients with dementia are two times more likely to have insulin resistance than patients with PD.

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.

Acute hemifacial dystonia possibly induced by clebopride.

Dystonic reactions produce twisting and repetitive movements or abnormal posturing. Severe dystonic reactions have been shown to occur in concert with numerous medications. This report details the case of a patient who developed hemifacial dystonia as acute side reaction from administration of clebopride for dyspeptic prophylaxis. When the drug was immediately stopped, the dystonic posture disappeared completely within 2 weeks. The use of clebopride may be associated with not only a reversible or persistent parkinsonism syndrome but also hemifacial dystonia; therefore, attention must be drawn to this possible side effect.

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.

Glucose metabolism in the idiopathic blepharoptosis: utility of the Oral Glucose Tolerance Test (OGTT) and of the Insulin Resistance Index.

BACKGROUND: Diabetes mellitus (DM), neuromuscular, hereditary or immunological disorders are the most common identified causes of blepharoptosis. However, in about 15-25% they remained uncertain. OBJECTIVE: To determined the role of glucose metabolism abnormality in idiopathic blepharoptosis. METHODS: We identified 162 patients with unilateral idiopathic blepharoptosis and 128 control subjects. In all we evaluated a glucose and insulin levels at fasting and after 2 h-OGTT. In addition we determined insulin resistance (IR), by HOMA-index. RESULTS: Following a 2 h-OGTT the prevalence of undiagnosed glucose metabolism abnormality was significantly higher in blepharoptosis patients vs. control group (P<.001). The IR was documented in 129 patients (78%), of whom 55 (34%) had Impaired Glucose Tolerance (IGT), 36 (22%) newly diagnosed DM (NDDM) and 38 (30%) only IR. The Body Mass Index, blood pressure, serum lipids, triglycerides and smoking were not associated with an increased risk of developing ptosis. Conversely, waist circumference were significantly increased in blepharoptosis patients (P=.003). CONCLUSIONS: In this study we focused on emerging evidence that prediabetic status may represent a risk factor for developing blepharoptosis. We propose that 2 h-OGTT and mainly HOMA-index should be determined as a rule in all patients with idiopathic blepharoptosis.