The Contribution of Type 2 Diabetes to Parkinson's Disease Aetiology.

Type 2 diabetes (T2D) and Parkinson's disease (PD) are chronic disorders that have a significant health impact on a global scale. Epidemiological, preclinical, and clinical research underpins the assumption that insulin resistance and chronic inflammation contribute to the overlapping aetiologies of T2D and PD. This narrative review summarises the recent evidence on the contribution of T2D to the initiation and progression of PD brain pathology. It also briefly discusses the rationale and potential of alternative pharmacological interventions for PD treatment.

Detecting Early Cognitive Decline in Alzheimer's Disease with Brain Synaptic Structural and Functional Evaluation.

Early cognitive decline in patients with Alzheimer's (AD) is associated with quantifiable structural and functional connectivity changes in the brain. AD dysregulation of Aß and tau metabolism progressively disrupt normal synaptic function, leading to loss of synapses, decreased hippocampal synaptic density and early hippocampal atrophy. Advances in brain imaging techniques in living patients have enabled the transition from clinical signs and symptoms-based AD diagnosis to biomarkers-based diagnosis, with functional brain imaging techniques, quantitative EEG, and body fluids sampling. The hippocampus has a central role in semantic and episodic memory processing. This cognitive function is critically dependent on normal intrahippocampal connections and normal hippocampal functional connectivity with many cortical regions, including the perirhinal and the entorhinal cortex, parahippocampal cortex, association regions in the temporal and parietal lobes, and prefrontal cortex. Therefore, decreased hippocampal synaptic density is reflected in the altered functional connectivity of intrinsic brain networks (aka large-scale networks), including the parietal memory, default mode, and salience networks. This narrative review discusses recent critical issues related to detecting AD-associated early cognitive decline with brain synaptic structural and functional markers in high-risk or neuropsychologically diagnosed patients with subjective cognitive impairment or mild cognitive impairment.

Physical Exercise, a Potential Non-Pharmacological Intervention for Attenuating Neuroinflammation and Cognitive Decline in Alzheimer's Disease Patients.

This narrative review summarises the evidence for considering physical exercise (PE) as a non-pharmacological intervention for delaying cognitive decline in patients with Alzheimer's disease (AD) not only by improving cardiovascular fitness but also by attenuating neuroinflammation. Ageing is the most important risk factor for AD. A hallmark of the ageing process is a systemic low-grade chronic inflammation that also contributes to neuroinflammation. Neuroinflammation is associated with AD, Parkinson's disease, late-onset epilepsy, amyotrophic lateral sclerosis and anxiety disorders. Pharmacological treatment of AD is currently limited to mitigating the symptoms and attenuating progression of the disease. AD animal model studies and human studies on patients with a clinical diagnosis of different stages of AD have concluded that PE attenuates cognitive decline not only by improving cardiovascular fitness but possibly also by attenuating neuroinflammation. Therefore, low-grade chronic inflammation and neuroinflammation should be considered potential modifiable risk factors for AD that can be attenuated by PE. This opens the possibility for personalised attenuation of neuroinflammation that could also have important health benefits for patients with other inflammation associated brain disorders (i.e., Parkinson's disease, late-onset epilepsy, amyotrophic lateral sclerosis and anxiety disorders). In summary, life-long, regular, structured PE should be considered as a supplemental intervention for attenuating the progression of AD in human. Further studies in human are necessary to develop optimal, personalised protocols, adapted to the progression of AD and the individual's mental and physical limitations, to take full advantage of the beneficial effects of PE that include improved cardiovascular fitness, attenuated systemic inflammation and neuroinflammation, stimulated brain Aß peptides brain catabolism and brain clearance.

Nanotechnology Therapy for Alzheimer's Disease Memory Impairment Attenuation.

Currently, there is no cure for Alzheimer's disease (AD) in humans; treatment is symptomatic only. Aging of the population, together with an unhealthy diet and lifestyle, contribute to the steady, global increase of AD patients. This increase creates significant health, societal and economical challenges even for the most developed countries. AD progresses from an asymptomatic stage to a progressively worsening cognitive impairment. The AD cognitive impairment is underpinned by progressive memory impairment, an increasing inability to recall recent events, to execute recently planned actions, and to learn. These changes prevent the AD patient from leading an independent and fulfilling life. Nanotechnology (NT) enables a new, alternative pathway for development of AD treatment interventions. At present, the NT treatments for attenuation of AD memory impairment are at the animal model stage. Over the past four years, there has been a steady increase in publications of AD animal models with a wide variety of original NT treatment interventions, able to attenuate memory impairment. NT therapy development, in animal models of AD, is faced with the twin challenges of the nature of AD, a chronic impairment, unique to human, of the tau protein and A ß peptides that regulate several key physiological brain processes, and the incomplete understanding of AD's aetiology. This paper reviews the state-of-the-art in NT based treatments for AD memory impairment in animal models and discusses the future work for translation to the successful treatment of AD cognitive impairment in human.

Changes in local capillarity of pure and hybrid MyHC muscle fiber types after nerve injury in rat extensor digitorum longus muscle (EDL).

Recently, we evaluated capillary indices without discrimination by fiber type in rat extensor digitorum longus muscle (EDL) 4 weeks after nerve cut (NC), after double nerve crush (double NCR) and in two controls, from the start (CON-1) and the end (CON-2) of the experiment. In the present study, we determined the capillary indices related to specific myosin heavy chain (MyHC) fiber types. Fiber-type composition and local capillarity were assessed from a single, composite, multicolor image, where different MyHC-fiber types and capillaries were shown simultaneously. Applying local capillary indices [the number of capillaries around fiber (CAF) and the CAF scaled to fiber perimeter (CAF/FP)], to specific MyHC-fiber types, we found changes relevant to neuro-muscular studies. In the NC group, only type-2x fibers had a significantly lower CAF, and in the double NCR group, only type-2a fibers had a higher CAF in comparison with both controls. Both types of nerve injury elicited two responses: a coupled regulation of fiber size and capillarity in the oxidative, type 2a fibers and a capillarity independent regulation of fiber size in the glycolytic type-2b fibers. All subtypes of type-2 fibers had a better capillary supply (higher CAF/FP) in the NC and double NCR than in CON-2. The highest improvement was observed in type-2b fibers; this change was mirrored in an oxidative shift only in the double NCR group. Adopting fiber-type-specific capillary indices improves data analysis of rat EDL muscle samples.

Publisher Correction: An improved method of crafting a multi-electrode spiral cuff for the selective stimulation of peripheral nerves.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Peptides as Potential Therapeutics for Alzheimer's Disease.

Intracellular synthesis, folding, trafficking and degradation of proteins are controlled and integrated by proteostasis. The frequency of protein misfolding disorders in the human population, e.g., in Alzheimer's disease (AD), is increasing due to the aging population. AD treatment options are limited to symptomatic interventions that at best slow-down disease progression. The key biochemical change in AD is the excessive accumulation of per-se non-toxic and soluble amyloid peptides (Aß(1-37/44), in the intracellular and extracellular space, that alters proteostasis and triggers Aß modification (e.g., by reactive oxygen species (ROS)) into toxic intermediate, misfolded soluble Aß peptides, Aß dimers and Aß oligomers. The toxic intermediate Aß products aggregate into progressively less toxic and less soluble protofibrils, fibrils and senile plaques. This review focuses on peptides that inhibit toxic Aß oligomerization, Aß aggregation into fibrils, or stabilize Aß peptides in non-toxic oligomers, and discusses their potential for AD treatment.

An improved method of crafting a multi-electrode spiral cuff for the selective.

This article reviews an improved methodology and technology for crafting a multi-electrode spiral cuff for the selective activation of nerve fibres in particular superficial regions of a peripheral nerve. The analysis, structural and mechanical properties of the spot welds used for the interconnections between the stimulating electrodes and stainless-steel lead wires are presented. The cuff consisted of 33 platinum electrodes embedded within a self-curling 17-mm-long silicone spiral sheet with a nominal internal diameter of 2.5 mm. The weld was analyzed using scanning electron microscopy and nanohardness tests, while the interconnection was investigated using destructive load tests. The functionality of the cuff was tested in an isolated porcine vagus nerve. The results of the scanning electron microscopy show good alloying and none of the typical welding defects that occur between the wire and the platinum foil. The results of the destructive load tests show that the breaking loads were between 3.22 and 5 N. The results of the nanohardness testing show that the hardness of the weld was different for the particular sites on the weld sample. Finally, the results of the functional testing show that for different stimulation intensities both the compound action potential deflection and the shape are modulated.

Antioxidant Vitamins and Ageing.

The free radical theory of ageing (FRTA), presented by Denham Harman in 1950s, proposed that aerobic organisms age due to reactive oxygen species (ROS)/free radical induced damage that accumulates in cells over time. Since antioxidants can neutralize free radicals by electron donation, the most logical approach was to use them as supplements in order to prevent ageing. In this chapter, we will discuss the inability of antioxidant supplementation to improve health and longevity.Although many antioxidants are efficient free radical quenchers in vitro, their in vivo effects are less clear. Recent evidence from human trials implies that antioxidant supplements do not increase lifespan and can even increase the incidence of diseases. Synthetic antioxidants were unable to consistently prevent ROS-induced damage in vivo, possibly as dietary antioxidants may not act only as ROS scavengers. Antioxidants can have dichotomous roles on ROS production. They are easily oxidized and can act as oxidants to induce damage when present in large concentrations. In appropriate amounts, they can modulate cellular metabolism by induction of cell stress responses and/or activate cell damage repair and maintenance systems. Therefore, the antioxidants' beneficial role may be reversed/prevented by excessive amounts of antioxidant supplements. On the other hand, ROS are also involved in many important physiological processes in humans, such as induction of stress responses, pathogen defence, and systemic signalling. Thus, both "anti-oxidative or reductive stress" (the excess of antioxidants) as well as oxidative stress (the excess of ROS) can be damaging and contribute to the ageing processes.

Reduced risk of apoptosis: mechanisms of stress responses.

Apoptosis signaling pathways are integrated into a wider network of interconnected apoptotic and anti-apoptotic pathways that regulate a broad range of cell responses from cell death to growth, development and stress responses. An important trigger for anti- or pro-apoptotic cell responses are different forms of stress including hypoxia, energy deprivation, DNA damage or inflammation. Stress duration and intensity determine whether the cell's response will be improved cell survival, due to stress adaptation, or cell death by apoptosis, necrosis or autophagy. Although the interplay between enhanced stress tolerance and modulation of apoptosis triggering is not yet fully understood, there is a substantial body of experimental evidence demonstrating that apoptosis and anti-apoptosis signaling pathways can be manipulated to trigger or delay apoptosis in vitro or in vivo. Anti-apoptotic strategies cover a broad range of approaches. These interventions include mediators that prevent apoptosis (trophic factors and cytokines), apoptosis inhibition (caspase inhibition, stimulation of anti-apoptotic or inhibition of pro-apoptotic proteins and elimination of apoptotic stimulus), adaptive stress responses (induction of maintenance and repair, caspase inactivation) and cell-cell interactions (blocking engulfment and modified micro environment). There is a consensus that preclinical efficacy and safety evaluations of anti-apoptotic strategies should be performed with protocols that simulate as closely as possible the effects of aging, gender, risk factors, comorbidities and co-medications.

The Rationale for Insulin Therapy in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common form of dementia, with a prevalence that increases with age. By 2050, the worldwide number of patients with AD is projected to reach more than 140 million. The prominent signs of AD are progressive memory loss, accompanied by a gradual decline in cognitive function and premature death. AD is the clinical manifestation of altered proteostasis. The initiating step of altered proteostasis in most AD patients is not known. The progression of AD is accelerated by several chronic disorders, among which the contribution of diabetes to AD is well understood at the cell biology level. The pathological mechanisms of AD and diabetes interact and tend to reinforce each other, thus accelerating cognitive impairment. At present, only symptomatic interventions are available for treating AD. To optimise symptomatic treatment, a personalised therapy approach has been suggested. Intranasal insulin administration seems to open the possibility for a safe, and at least in the short term, effective symptomatic intervention that delays loss of cognition in AD patients. This review summarizes the interactions of AD and diabetes from the cell biology to the patient level and the clinical results of intranasal insulin treatment of cognitive decline in AD.

Evaluation of the Efficacy and Robustness of a Second Generation Implantable Stimulator in a Patient With Hemiplegia During 20 Years of Functional Electrical Stimulation of the Common Peroneal Nerve.

We evaluated the efficacy and robustness of a second generation implantable stimulator for correcting drop foot (DF) in a patient with left-sided hemiplegia over 20 years of functional electrical stimulation (FES) of the common peroneal nerve (CPN). Dorsal flexion and eversion of the affected foot was partially restored by FES of the superficial region of the CPN innervating mostly the tibialis anterior (TA) and partly peroneus longus (PL) and peroneus brevis (PB) muscles. The reasons for implant failure during the long-term follow-up assessment were analyzed and resolving procedures were identified. The stimulator had an average failure rate of once every three years, due to repetitive mechanical load on the lead wires of its internal and/or external unit, and had to be serviced once per year to replace the heel switch integrated into the shoe sole. FES-associated mechanical trauma to the CPN elicited a thickening of the connective tissue around the CPN and a slightly compromised conduction velocity of the CPN. FES of the CPN, with the second generation implantable stimulator, improved gait parameters of the affected leg during the 20 years period. Long-term, daily FES enables a functional and reliable recruitment of nerve fibers, thus providing a sufficient dorsal flexion and optimal eversion of the affected foot to sustain unassisted, almost normal gait. Therefore, the presented implant is suitable for very long-term FES of the CPN.

Changes in the Capillarity of the Rat Extensor Digitorum Longus Muscle 4 Weeks after Nerve Injury Studied by 2D Measurement Methods.

We have previously shown by 3D study that 2 weeks after nerve injury there was no change in the length of capillaries per muscle fibre length in rat extensor digitorum longus muscle (EDL). The primary goal of the present 2D study was to determine the capillarity of rat EDL 4 weeks after various modes of nerve injury. Additionally, we wished to calculate the same capillary/fibre parameters that were used in our 3D stereological study. EDL muscles derived from denervated (4 weeks after nerve injury), re-innervated (4 weeks after two successive nerve crushes) and age-matched controls from the beginning (CON-1) and the end (CON-2) of the experiment were analysed in two ways. Global indices of capillarity, such as capillary density (CD) and capillary/fibre (C/F) ratio, were determined by automatic analysis, local indices as the number (CAF) and the length of capillaries around individual muscle fibres (Lcap) in relation to muscle fibre size were estimated manually by tracing the muscle fibre outlines and the transversally and longitudinally cut segments of capillaries seen in 5-µm-thin muscle cross sections. Four weeks after both types of nerve injury, CD increased in comparison to the CON-2 group (p < 0.001) due to atrophied muscle fibres in denervated muscles and probably proliferation of capillaries in re-innervated ones. Higher C/F, CAF (both p < 0.001) and Lcap (p < 0.01) in re-innervated than denervated EDL confirmed this assumption. Calculated capillary/fibre parameters were comparable to our previous 3D study, which strengthens the practical value to the adapted 2D method used in this study.

Unfolded Protein Response and Macroautophagy in Alzheimer's, Parkinson's and Prion Diseases.

Proteostasis are integrated biological pathways within cells that control synthesis, folding, trafficking and degradation of proteins. The absence of cell division makes brain proteostasis susceptible to age-related changes and neurodegeneration. Two key processes involved in sustaining normal brain proteostasis are the unfolded protein response and autophagy. Alzheimer's disease (AD), Parkinson's disease (PD) and prion diseases (PrDs) have different clinical manifestations of neurodegeneration, however, all share an accumulation of misfolded pathological proteins associated with perturbations in unfolded protein response and macroautophagy. While both the unfolded protein response and macroautophagy play an important role in the prevention and attenuation of AD and PD progression, only macroautophagy seems to play an important role in the development of PrDs. Macroautophagy and unfolded protein response can be modulated by pharmacological interventions. However, further research is necessary to better understand the regulatory pathways of both processes in health and neurodegeneration to be able to develop new therapeutic interventions.

Redox control of protein degradation.

Intracellular proteolysis is critical to maintain timely degradation of altered proteins including oxidized proteins. This review attempts to summarize the most relevant findings about oxidant protein modification, as well as the impact of reactive oxygen species on the proteolytic systems that regulate cell response to an oxidant environment: the ubiquitin-proteasome system (UPS), autophagy and the unfolded protein response (UPR). In the presence of an oxidant environment, these systems are critical to ensure proteostasis and cell survival. An example of altered degradation of oxidized proteins in pathology is provided for neurodegenerative diseases. Future work will determine if protein oxidation is a valid target to combat proteinopathies.

Targeting stress responses for regenerative medicine.

Some internal and external stimuli elicit stress responses on the cellular level and at the level of the organism. When the stimulus is brief and its intensity mild to moderate, it triggers adaptation changes that improve the cell's or organism's survival. This adaptation is achieved through a variety of cellular mechanisms such as induction of repair mechanisms, improved removal of damaged macromolecules, upregulation of endogenous antioxidant defenses, and prevention of apoptosis triggering by moderate stressors. The key intracellular signaling pathways involved in stress adaptation are the mTORC1 and SIRT1. Manipulating these stress adaptation signaling pathways with a variety of agents, improves the cellular adaptation to stress, prolongs cell survival, and improves the transplantation outcome in animal models and in clinical trials. The challenge for the future is to fine-tune the numerous experimental techniques to suit the needs of transplantation and regenerative medicine.

Structural characterization of platinum foil for neural stimulating electrodes.

OBJECTIVE: The objective of this study was to investigate the structural properties of a cold-rolled platinum foil used to manufacture multi-electrode spiral nerve cuffs. METHODS: To attain this objective, 0.03-mm-thick cold-rolled platinum foil strips with 99.99 wt% purity were used. The resistivity measurements were made using a 4-point probe technique in which the strips were subjected to dynamic annealing in an argon atmosphere. The stored energy of platinum was recorded in an argon atmosphere using differential scanning calorimetry (DSC). Finally, the microstructure of the strips was investigated by optical microscopy. RESULTS: In the resistivity measurements, a small change is observed at ~280°C. This change could be explained as the partial recovery elicited by the decrease of dislocation density. Above 500°C, a significant decrease in resistivity was recorded, and the decrease reached a maximum at ~750°C. These results are consistent with the recrystallization trend detected in DSC, namely the DSC measurement detected very weak heat release during recrystallization, which was actually accumulated during the cold-working. This exothermal peak occurred in the temperature range 380-800°C.

Wavelet analysis increases sensitivity and specificity of spirography for ambulatory tremor discrimination.

The most frequently seen types of tremor are essential (ET) and parkinsonian tremor (PT) and in some patients clinical characteristics of these tremor types overlap. It is vital to distinguish between these two types of tremor in order to reach the right diagnosis and select the appropriate treatment. One of the widely used methods for tremor detection and discrimination, appropriate for a quick ambulatory assessment of the patient's tremor, is spirography. With spirography, the tremor can be observed through several parameters, for example, tremor spectrum and spiral image, which give useful information for its identification. Standard spirography parameters of ET and PT can overlap; therefore, these parameters are often not enough for identification of the observed tremor. To increase the specificity and sensitivity of spirography for PT, ET and normal, tremor free controls, we used the wavelet analysis with Morlet wavelet transform. To facilitate analysis, comparison, storage, and retrieval of spirography tremor records we also developed an integrated computer assisted spirography system that increases the convenience of outpatient tremor identification and follow-up. We conclude that wavelet analysis of spirography records increases the sensitivity and specificity of the method, thus, facilitating the distinction between ET and PT.

Simultaneous visualization of myosin heavy chain isoforms in single muscle sections.

We developed a staining protocol that enables simultaneous visualization of myosin heavy chain (MHC) pure and hybrid muscle fiber types in rat skeletal muscle. Up to eight different muscle fiber types can be visualized in a single section of the rat extensor digitorum longus muscle, which contains all four adult MHC isoforms and shows plasticity during the denervation-reinnervation process. Triple immunofluorescent staining of MHC-1, MHC-2a and MHC-2b with primary antibodies BA-D5 (isotype IgG2b), SC-71 (isotype IgG1) and BF-F3 (isotype IgM) and with three fluorophore-labeled isotype-specific secondary antibodies displays different muscle fiber types in a merged image of red, green and blue channels, each in its own color. Immunoperoxidase staining with primary antibody 6H1 directed against MHC-2x can be additionally applied on the same tissue section to facilitate the identification of muscle fibers containing MHC-2x. Triple staining can also be used in combination with other staining procedures to derive more information about the number of capillaries or the oxidative potential of muscle fiber types. Simultaneous visualization of multiple fiber types in a single merged image enables economical use of muscle samples and provides simple and rapid identification of all fiber types that are present in rat limb muscles.

Elicitation of neurological knowledge with argument-based machine learning.

OBJECTIVE: The paper describes the use of expert's knowledge in practice and the efficiency of a recently developed technique called argument-based machine learning (ABML) in the knowledge elicitation process. We are developing a neurological decision support system to help the neurologists differentiate between three types of tremors: Parkinsonian, essential, and mixed tremor (comorbidity). The system is intended to act as a second opinion for the neurologists, and most importantly to help them reduce the number of patients in the "gray area" that require a very costly further examination (DaTSCAN). We strive to elicit comprehensible and medically meaningful knowledge in such a way that it does not come at the cost of diagnostic accuracy. MATERIALS AND METHODS: To alleviate the difficult problem of knowledge elicitation from data and domain experts, we used ABML. ABML guides the expert to explain critical special cases which cannot be handled automatically by machine learning. This very efficiently reduces the expert's workload, and combines expert's knowledge with learning data. 122 patients were enrolled into the study. RESULTS: The classification accuracy of the final model was 91%. Equally important, the initial and the final models were also evaluated for their comprehensibility by the neurologists. All 13 rules of the final model were deemed as appropriate to be able to support its decisions with good explanations. CONCLUSION: The paper demonstrates ABML's advantage in combining machine learning and expert knowledge. The accuracy of the system is very high with respect to the current state-of-the-art in clinical practice, and the system's knowledge base is assessed to be very consistent from a medical point of view. This opens up the possibility to use the system also as a teaching tool.