Challenges in detecting disease modification in Parkinson's disease clinical trials.

Despite the wealth of encouraging data from numerous compounds that demonstrate "neuroprotection" in pre-clinical studies of Parkinson's disease, and despite numerous clinical trials, to date, no intervention has been demonstrated to able to modify the course of disease progression. While this "failure to translate" is likely due to numerous factors including our incomplete understanding of the pathogenic mechanisms underlying PD together with excessive reliance on data from the toxin-based animal models of PD, here we will discuss the "structural issues" pertaining to inadequate clinical trial design, selection of inappropriate endpoints and poor patient selection which are often not addressed following failed disease modification trials. Future directions to overcome these challenges such as reducing the heterogeneity of patient cohorts, identifying and utilising a pre-diagnostic population, embracing a personalised medicine approach and utilising novel trial designs may be required to ultimately fulfil the goal of conclusively demonstrating evidence of disease modification

Biomarker for tracking progression of Alzheimer's disease in clinical trials

Currently, there are no treatments available for mitigating the neurological effects of Alzheimer's disease. All clinical trials of disease-modifying treatments, which showed promise in animal models, have failed to show a significant treatment effect in human trials. The lack of a sensitive outcome measure and the focus on the dementia stage for investigating treatments are believed to be the primary reasons behind the failure of all clinical trials till date. The currently used outcome measure, the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), suffers from low sensitivity in tracking progression of cognitive impairment in clinical trials. A shift in the focus to the prodromal mild cognitive impairment (MCI) stage may help improve the efficiency of clinical trials. However, even lower sensitivity of the ADAS-Cog and an inability to specifically select progressive MCI patients limit the efficiency of clinical trials in the MCI stage. Cerebral atrophy measured on structural magnetic resonance (MR) imaging is highly promising for tracking disease progression in clinical trials. However, cerebral atrophy has not been yet approved as a valid biomarker due to the lack of an understanding behind its relationship with cognitive impairment. The focus of this dissertation spans across the two research areas of (i) developing automatic algorithms for analysis of patients' brain MR volumes, and (ii) improving the efficiency of clinical trials of disease-modifying treatments. This dissertation presents a novel knowledge-driven decision theory approach for automatic tissue segmentation of brain MR volumes, which shows better segmentation performance than the existing approaches. The remaining dissertation contributions focus at improving the efficiency of clinical trials of disease-modifying treatments. An improved scoring methodology is presented for the ADAS-Cog outcome measure, which measures cognitive impairment with better accuracy and significantly improves the sensitivity of the ADAS-Cog in the mild-to-moderate Alzheimer's disease stage. However, the ADAS-Cog continues to suffers from low sensitivity in the MCI stage due to inherent limitations of its items. For improving the efficiency of clinical trials in the MCI stage, a biomarker has been developed that combines the ADAS-Cog with cerebral atrophy for more accurate tracking of Alzheimer's progression and facilitating selection of MCI patients in clinical trials.Biomedical Engineerin

Can we learn lessons from the FDA's approval of aducanumab?

On 7 June 2021, aducanumab was granted accelerated approval for the treatment of Alzheimer disease (AD) by the FDA on the basis of amyloid-lowering effects considered reasonably likely to confer clinical benefit. This decision makes aducanumab the first new drug to be approved for the treatment of AD since 2003 and the first drug to ever be approved for modification of the course of AD. Many have questioned how scientific evidence, expert advice and the best interests of patients and families were considered in the approval decision. In this article, we argue that prior to approval, the FDA and Biogen’s shared interpretation of clinical trial data — that high-dose aducanumab was substantially clinically effective — avoided conventional scientific scrutiny, was prominently advanced by patient representative groups who had been major recipients of Biogen funds, and raised concerns that safeguards were insufficient to mitigate regulatory capture within the FDA. Here, we reflect on events leading to the FDA’s decision on 7 June 2021 and consider whether any lessons can be learned for the field

Improving longitudinal spinal cord atrophy measurements for clinical trials in multiple sclerosis by using the generalised boundary shift integral (GBSI)

Spinal cord atrophy is a common and clinically relevant feature of multiple sclerosis (MS), and can be used to monitor disease progression and as an outcome measure in clinical trials. Spinal cord atrophy is conventionally estimated with segmentation-based methods (e.g., cross-sectional spinal cord area (CSA)), where spinal cord change is calculated indirectly by numerical difference between timepoints. In this thesis, I validated the generalised boundary shift integral (GBSI), as the first registration-based method for longitudinal spinal cord atrophy measurement. The GBSI registers the baseline and follow-up spinal cord scans in a common half-way space, to directly determine atrophy on the cord edges. First, on a test dataset (9 MS patients and 9 controls), I have found that GBSI presented with lower random measurement error, than CSA, reflected by lower standard deviation, coefficient of variation and median absolute deviation. Then, on multi-centre, multi-manufacturer, and multi–field‐strength scans (282 MS patients and 82 controls), I confirmed that GBSI provided lower measurement variability in all MS subtypes and controls, than CSA, resulting into better separation between MS patients and controls, improved statistical power, and reduced sample size estimates. Finally, on a phase 2 clinical trial (220 primary-progressive MS patients), I demonstrated that spinal cord atrophy measurements on GBSI could be obtained from brain scans, considering their quality and association with corresponding spinal cord MRI-derived measurements. Not least, 1-year spinal cord atrophy measurements on GBSI, but not CSA, were associated with upper and lower limb motor function. In conclusion, spinal cord atrophy on the GBSI had higher measurement precision and stronger clinical correlates, than the segmentation method, and could be derived from high-quality brain acquisitions. Longitudinal spinal cord atrophy on GBSI could become a gold standard for clinical trials including spinal cord atrophy as an outcome measure, but should remain a secondary outcome measure, until further advancements increase the ease of acquisition and processing

Recent Saccadic Eye Movement Research Uncovers Patterns of Cognitive Dysfunction in Schizophrenia.

The frontal cortex and the subcortical areas of the brain play a major role in the control of thought and action. Eye movements are increasingly used in neuropsychological research to explore the executive and sensorimotor functions of such neural networks. This interface links the control of action, at the fundamental levels of neurophysiological and neurochemical processes, with the high-level cognitive operations that underlie visual orienting. Patients with schizophrenia have neurocognitive impairments that can be readily investigated with novel saccadic eye movement paradigms. Animal, human lesion, and neuroimaging studies have identified the cerebral centers that underlie saccadic eye movements. The areas of the prefrontal cortex include the dorsolateral prefrontal cortex, the frontal eye fields, the supplementary eye fields, and the anterior cingulate gyrus. Pathology of saccadic eye movements therefore provides information on the functional status of the underlying neural circuitry in brain disorders such as schizophrenia

Clinical review: Prevention and therapy of vasospasm in subarachnoid hemorrhage

Vasospasm is one of the leading causes of morbidity and mortality following aneurysmal subarachnoid hemorrhage (SAH). Radiographic vasospasm usually develops between 5 and 15 days after the initial hemorrhage, and is associated with clinically apparent delayed ischemic neurological deficits (DID) in one-third of patients. The pathophysiology of this reversible vasculopathy is not fully understood but appears to involve structural changes and biochemical alterations at the levels of the vascular endothelium and smooth muscle cells. Blood in the subarachnoid space is believed to trigger these changes. In addition, cerebral perfusion may be concurrently impaired by hypovolemia and impaired cerebral autoregulatory function. The combined effects of these processes can lead to reduction in cerebral blood flow so severe as to cause ischemia leading to infarction. Diagnosis is made by some combination of clinical, cerebral angiographic, and transcranial doppler ultrasonographic factors. Nimodipine, a calcium channel antagonist, is so far the only available therapy with proven benefit for reducing the impact of DID. Aggressive therapy combining hemodynamic augmentation, transluminal balloon angioplasty, and intra-arterial infusion of vasodilator drugs is, to varying degrees, usually implemented. A panoply of drugs, with different mechanisms of action, has been studied in SAH related vasospasm. Currently, the most promising are magnesium sulfate, 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, nitric oxide donors and endothelin-1 antagonists. This paper reviews established and emerging therapies for vasospasm

A specific role for serotonin in overcoming effort cost

Serotonin is implicated in many aspects of behavioral regulation. Theoretical attempts to unify the multiple roles assigned to serotonin proposed that it regulates the impact of costs, such as delay or punishment, on action selection. Here, we show that serotonin also regulates other types of action costs such as effort. We compared behavioral performance in 58 healthy humans treated during 8 weeks with either placebo or the selective serotonin reuptake inhibitor escitalopram. The task involved trading handgrip force production against monetary benefits. Participants in the escitalopram group produced more effort and thereby achieved a higher payoff. Crucially, our computational analysis showed that this effect was underpinned by a specific reduction of effort cost, and not by any change in the weight of monetary incentives. This specific computational effect sheds new light on the physiological role of serotonin in behavioral regulation and on the clinical effect of drugs for depression

Neuropathic pain in an elderly population of an urban area of iran with a special focus on carpal tunnel syndrome : epidemiological aspects, clinical characteristics, and non-surgical therapy

Background: People are getting older, and aging problems and disorders are increasing fast. Knowing the rates, causes, symptomatology, treatment, relief, and prognosis of associated disorders can help and facilitate the elderly, their families, primary health care providers, and health policymakers. Chronic pain in the elderly is a common complaint and its prevalence differs in society and depends on many factors, including type, severity, and localization but also comorbidities, socio-economic factors, and genetics. Pain is in two main categories, nociceptive and neuropathic. Nociceptive pain usually occurs after end-organ damage or derangement such as musculoskeletal problems, osteoarthritis, or trauma. Neuropathic pain arises from central or peripheral nervous system injuries. One of the most common types of peripheral neuropathic pain is hand pain caused by the carpal tunnel syndrome (CTS). Hand pain and CTS are common among the elderly, especially in women. The etiology usually remains uncertain until the late stages of the disorder, when intrinsic hand muscles become weak or atrophy, when it is too late to manage the CTS adequately. Thus, it is important to be aware of its clinical symptoms, signs, and provocation maneuvers, but also to have a noninvasive diagnostic tool when CTS is suspected. Also, it is important to have a solution for mild and moderate types of CTS to prevent surgery in older adults, especially in those with frailer constitutions. Objectives: We evaluated the prevalence of pain, with special focus on neuropathic pain and CTS, in a large population-based study in Tehran, the capital of Iran. We chose CTS as being the most common symptom of focal neuropathy and evaluated the median nerve by noninvasive, high-resolution ultrasonography. We investigated and diagnosed CTS and determined its severity. Following the results of our diagnostic study, we performed interventional treatment studies on patients diagnosed with CTS. To find the optimum steroid dose site, we examined three different doses of steroid in a mixture injected in the tunnel near the affected nerve medianus with an adhesion removal technique called hydro dissection. Finally, we compared different methods of injection in our last study to examine a hypothesis about nonsurgical flexor retinaculum release. Methods and material: More than 5,000 patients were investigated randomly by a multistage cluster sample. Participants were then interviewed using a sociodemographic checklist, a standard pain questionnaire, and general health through GHQ-28. In the 2nd study, demographics were noted along with the clinical presentation of CTS, and the median nerve anatomy was assessed by ultrasound and electrodiagnostic tests. The median nerve cross-sectional area (CSA) at the tunnel inlet and four different areas over the median nerve were measured and analyzed. In the 3rd paper with an intervention, we designed a prospective three group, randomized, double-blind trial to evaluate 40, 80, and 0 mg triamcinolone in a mixture of 3 mL containing 1 cc of lidocaine 2%. Outcome measures included the Boston Carpal Tunnel Questionnaire, VAS (visual analog scale), median nerve conduction criteria, and the ultrasound median CSA. All data were recorded at the baseline, 14 days, 1 month, and 6 months after the injection. In the 4th study, the design was similar to the 3rd one, though we had only two groups and the injecting mixture was 40 mg of triamcinolone and 1 cc of lidocaine 2%. The location of the injection was different with one group injected in the flexor retinaculum and the other near the nerve. All data were recorded as in the 3rd study but only at baseline, and 6 weeks after injection. Results: We found a 13.7% prevalence of chronic neuropathic pain and 30% of chronic nociceptive pain, overall chronic of 31.7% and overall acute of 39.1% which, in combination, add up to 70.8%. The major comorbidities were osteoporosis, diabetes, disability, and stroke. In the 2nd study with 203 CTS and 103 control subjects, CSA at the tunnel inlet with a threshold of 8.5 mm2 had a sensitivity and specificity of 96.9% and 93.6% respectively. In the 3rd study with 161 patients, we did not find any statistically significant differences between groups, i.e., all groups with a steroid dose had similar results. In the last study with 50 eligible subjects randomized into two groups, there was a significant improvement in Boston scores (p-value 0.023), VAS (p-value 0.026), and ultrasonographic measure (p-value 0.004), in favor of intra-flexor retinaculum steroid injection compared to near the nerve. Conclusions: Neuropathic pain prevalence is relatively high; 13.7% among Iranian elderly people, and the overall pain is very high around 70 %. It should be addressed by health policymakers, primary care physicians, and caregivers. High-resolution ultrasonography is a noninvasive diagnostic tool with about 95% sensitivity and specificity in detecting CTS in the elderly and should be introduced as a screening tool by primary physicians engaged in elderly care. The use of plain lidocaine was beneficial in managing CTS in elderly patients, and we did not find any superiority for the steroids. Finally, in case of no contraindication for steroids, we prefer the intra-flexor retinaculum injection. Larger studies should be performed in future studies in this field to confirm our results