Diabetes mellitus contributes to higher cerebrospinal fluid tau levels selectively in Alzheimer's disease patients with the APOE4 genotype.

BACKGROUND AND PURPOSE: Diabetes mellitus (DM) is considered a risk factor for Alzheimer's disease (AD) and shares some pathological pathways, such as activation of amyloid cascade and tau phosphorylation. The aim of the present study was to investigate to what extent DM could impact on neurodegeneration within the AD continuum, using ß amyloid (A: Aß1-42 ) and phosphorylated tau (T: p-tau) biomarkers to discriminate patients by Alzheimer's pathological change (A+/T-) and AD (A+/T+), according to the National Institute on Aging and Alzheimer's Association classification. In addition, we aimed to evaluate whether APOE genotype interacts with tau protein and glucose metabolism dysfunction to affect the pathological process. METHODS: For this retrospective observational study, 1350 patients were recruited. The patients underwent a complete clinical investigation, neuropsychological assessment, lumbar puncture for cerebrospinal fluid (CSF) biomarkers analysis and APOE genotyping. RESULTS: A total of 607 patients fulfilled the clinical criteria of mild cognitive impairment or early dementia. In A+T- patients (n = 350), DM did not influence CSF biomarker levels, while among A+T+ patients (n = 257) those with DM showed increased total tau (t-tau) levels compared to non-DM patients (DM: 919.4 ± 444 vs. non-DM: 773.1 ± 348.2; p = 0.04), but similar p-tau (p = 0.72) and Aß1-42  levels (p = 0.83). Furthermore, multivariable regression analyses showed a significant association between DM and t-tau CSF levels, adjusting for age and sex, in APOE E4+ carriers (coefficient 222.83, 95% confidence interval 47.49-398.1; p = 0.01), but not in APOE E4- (p = 0.53). CONCLUSIONS: The present study shows a clear dependency of CSF t-tau levels on DM for APOE E4+ AD patients, suggesting important differences between APOE E4-related and non-related disease, with key implications for AD pathophysiology and treatment.

Clinical Outcomes of Switching to Insulin Glargine 300 U/ml from Other Basal Insulins in People with Type 2 Diabetes in Italy: A Real-World Study.

INTRODUCTION: Primary aim was to provide real-world evidence of the outcomes after the switch to glargine 300 U/ml (Gla-300) from other basal insulins (first or second generation) in Italy. METHODS: Multicenter, observational, retrospective study based on electronic medical records. RESULTS: Overall, 953 T2DM insulin ± OAD treated people switched to Gla-300 or Gla-100 from January 2015 to July 2018. Three clinically relevant cohorts were identified: patients switching to Gla-300 from first-generation basal insulin (cohort 1), patients switching to Gla-300 from degludec-100 (Deg-100) (cohort 2), and those switching to Gla-100 from any basal insulin (cohort 3). The three cohorts differed in terms of age, diabetes duration, and metabolic control. HbA1c changes after 6 months from the switch were - 0.27% (95% CI - 0.38; - 0.16), - 0.06% (95% CI - 0.31; 0.19), and - 0.30% (95% CI - 0.51; - 0.09) in the three cohorts, respectively. FPG significantly decreased in cohort 1 (- 14.07 mg/dl, 95% CI - 20.25; - 7.89), while body weight significantly decreased in cohort 2 (- 1.47 kg, 95% CI - 2.55; - 0.39). Doses of insulin marginally changed during the follow-up (+ 0.89 U in basal insulin daily dose in cohort 1 and + 2.07 U in short-acting insulin daily dose in cohort 2). CONCLUSIONS: Switching to Gla-300 from first-generation basal insulin in the real world is associated with improvements in metabolic control despite a suboptimal titration of both basal and short-acting insulins. Inertia in insulin titration documented in the Gla-100 cohort is also observed with the second-generation basal insulin. The switch to Gla-300 from Deg-100 was associated with a decrease in body weight of - 1.47 kg despite a slight increase in short-acting insulin daily doses of about + 2 U.

Observational clinical and nerve conduction study on effects of a nutraceutical combination on painful diabetic distal symmetric sensory-motor neuropathy in patients with diabetes type 1 and type 2.

BACKGROUND: Painful distal symmetric polyneuropathy (pDSPN) is one of the most common and invalidating complications of diabetes mellitus, both of type 1 and type 2. Mechanisms responsible for the occurrence of the pDSPN are multifactorial and involve metabolic pathways regulating inflammation, microvessel circulation, axonal degeneration and so on. Several therapeutic approaches have been proposed to treat pain and each of them showed positive effects associated to drug-related side effects. METHODS: Twenty-five consecutive patients with diagnosis of diabetes mellitus and pDSPN and tried to manage pain with a dietary supplement composed of a mixture of natural extracts (ß-caryophyllene, myrrh, carnosic acid) and PEA. This is a nutraceutical with potential multiple effects on metabolic, pain and vascular compartments, a profile considered useful in pDSPN. Patients were enrolled and polyneuropathy evaluated by means of nerve conduction study. Pain was assessed using VAS score scale and MNSI. Each patient was evaluated at T0 (time of enrollment) and at T1 (after 16 weeks of treatment). RESULTS: Supplement administration was well tolerated and induced unexpectedly significant amelioration of polyneuropathy with increase amplitude and reduction of pain. No side effects were reported. CONCLUSIONS: This fixed combination could well be considered as a potential nutraceutical option to manage pDSPN in diabetic patients.

Insulin and the Future Treatment of Alzheimer's Disease.

Alzheimer's disease is a neurodegenerative disorder leading to dementia. Scientific efforts in the last decade focused mainly on understanding pathophysiology of disease and possible pharmacological approach to alleviate cognitive decline symptoms. Amyloid cascade hypothesis though criticized, remains the leading hypothesis to understand pathogenic mechanisms of cognitive decline. Intriguingly, changes of metabolic activity of cortical neurons are associated with reduced or absent sensitivity to insulin in Alzheimer's disease brain. Insulin is a multipotent hormone regulating, not only glucose levels, but also cell survival and synaptic plasticity mechanisms of neurons. Replacement of insulin might represent a new strategic approach to counteract neurodegeneration. Here we review most of the available data regarding relationship between Alzheimer's disease and insulin and propose new direction to deepen our understanding about insulin involvement in the pathogenesis of Alzheimer's dementia.

Homotaurine induces measurable changes of short latency afferent inhibition in a group of mild cognitive impairment individuals.

Current treatment options for patients with Alzheimer's disease (AD) are limited at providing symptomatic relief, with no effects on the underlying pathophysiology. Recently, advances in the understanding of the AD pathogenesis highlighted the role of ABeta (Aß) oligomers particularly interfering with mechanisms of cortical plasticity such as long-term potentiation (LTP) and long-term depression (LTD). These findings led to the development of potential anti-amyloid therapies, and among them homotaurine, a glycosaminoglycan mimetic designed to interfere with the actions of Aß early in the cascade of amyloidogenic events, and by its γ-aminobutyric acid type (GABA) A receptor affinity. Recently, we showed that AD patients have impaired LTP-like cortical plasticity, as measured by standard theta burst stimulation protocols applied over the primary motor cortex (M1). Furthermore, AD patients have a weakened short latency afferent inhibition (SLAI), a neurophysiological measure of central cholinergic transmission, which changes reflect the cholinergic dysfunction occurring in the pathology. Here, we aimed at investigating whether homotaurine administration could modulate in vivo measured mechanisms of synaptic plasticity, namely LTP and LTD, and also SLAI in a group of mild cognitive impaired patients. We observed that homotaurine administration did not induce relevant changes of both LTP and LTD recordings, while induced changes of SLAI in our group of patients. We suggest that homotaurine effects are dependent on changes of cortical GABA transmission suggesting a potential role for this compound in ameliorating the cholinergic transmission by modulating the inhibitory cortical activity.

Ageing as a Trait de Union between diabetes and dementia for frailty.

A frail patient is one who carries a sum of poly-pathologies, whose co-existence may shorten his life expectation. Diabetes mellitus type 2 and metabolic syndrome play a substantial role in it, but dementia has increasingly risen in importance. Interestingly, the insulin pathway was suggested to be responsible for the metabolic cascade that leads to amyloid-beta deposit and pathology. Nevertheless, a clear relationship between them was just experimentally, rather than clinically demonstrated. In this work the authors suggest a possible link between insulin, diabetes and Alzheimer's disease, whose co-existence could be responsible for physical and cognitive decline but not for frailty. We suggest that these factors could be responsible for frailty only if senescence-associated.

Apathy as marker of frail status.

Frailty is a complex and dynamic condition associated with aging. This condition is characterised by the difficult adaptation of an old subject to new challenges occurring during life. Frailty is supposed to be due to the progressive decrease of physiological reserves and multiorgan and multisystem change. It coincides with a reduced or absent resilience. In general comorbidities like hypertension, heart disease, inflammation and infectious diseases are potential risk factors for and psychophysical decline. The aim of this work is to highlight the importance of impaired cognition as factor predisposing to frailty. The authors are convinced and suggest that the presence of neurobehavioral disturbance like apathy associated to impaired executive function could be the major predisposing factor for frailty and unsuccessful aging. Unfortunately available literature largely underestimates the presence of these factors. Thus to better identify markers of frailty, a good neuropsychological assessment and the evaluation of behavioural disturbances are suggested.

Gait impairment in neurological disorders: a new technological approach.

Gait recovery is considered one of the main objectives of rehabilitation interventions in neurological disabilities, as restricted movement can significantly reduce an individual's ability to take part in normal activities of daily living. Locomotor training has been shown to improve gait rehabilitation. Studies have recently been published on the use of robots and other devices in patients with gait disabilities, particularly in the rehabilitation of the lower limbs. However, analysis of the recent literature reveals a relative paucity of strong methodological studies. The evidence that is available, while strong, is not yet sufficient to allow definite conclusions to be drawn regarding the efficacy of these devices. From these considerations, it is clear that validated and standardized methods need to be adopted for each of the different systems available. This would help to clarify the indications for and correct use of robotic devices in the different neurological disorders.

Kyphoplasty: a new opportunity for rehabilitation of neurologic disabilities.

Using percutaneous kyphoplasty, we treated a patient with a diagnosis of Guillain-Barré syndrome who complained of an unremitting pain in the spine, refractory to the conventional medical therapy, elicited by pressure over the spinous process, and in absence of neurologic deficits. The method provided swift midline back pain relief associated with an evident augmentation in the stability and in the vertebral body's height. The injection of polymethylmethacrylate was effective and safe, no cement leakages were observed, and no complications such as pulmonary embolism, toxicity, or infection were observed. Due to the rapid pain relief, a rehabilitation program was promptly undertaken with a good improvement of the disability score (FIM scale score). Kyphoplasty is a new method for treatment of vertebral collapses consequent to osteoporosis, aggressive hemangiomas, myelomas, and metastases, and it may aid in rehabilitation of the underlying systemic neurologic disorder if the pain is interfering with those therapies.