Trials Of Disease-modifying Therapies Research Articles

12. Use of pre-trial cognitive trajectory to accelerate primary prevention trials of disease-modifying therapies in AD

12. Use of pre-trial cognitive trajectory to accelerate primary prevention trials of disease-modifying therapies in AD

006 Clinical advances in our understanding and classification of the dementias

: The last few years have seen important developments in our understanding of the dementias. These include advances in genetics, pathology, imaging and biomarkers. In 2009 two large genome-wide association...

Clinical trials of disease-modifying therapies for neurodegenerative diseases: the challenges and the future

Neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease represent a crucial and exponentially increasing challenge to health care systems throughout the world. There is an urgent need for effective treatments that will both delay their onset and slow their inexorable progression. Many obstacles stand in the way of realizing these goals. It is expected that future advances will have a major impact on how and when the diagnosis will be made. It is hoped that these will eventually make it possible to initiate effective disease-modifying therapies long before the neurodegenerative process becomes established and symptomatic.

CSF phospho-tau correlates with behavioural decline and brain insoluble phospho-tau levels in a rat model of tauopathy

The aim of the present study was to identify the relationship between progressive neurobehavioural decline and phospho-tau levels (p-tau(181)) in the cerebrospinal fluid (CSF) and the brain in transgenic rats expressing human truncated tau protein. Behavioural analyses, as quantified using the NeuroScale scoring method, revealed that the transgenic rats fell into two main groups based on the baseline behavioural functioning: (1) mild neurobehavioural impairment (MNI, score 3.3-26) and (2) severe neurobehavioural impairment (SNI, score 36-44). SNI transgenic rats showed a significant increase in brain sarkosyl insoluble p-tau(181) when compared to their MNI counterparts. In order to determine whether CSF phospho-tau reflects the behavioural decline and increase in sarkosyl insoluble tau in the brain, p-tau(181) was measured in the CSF in a longitudinal study. The study showed a significant increase in CSF p-tau(181) during the progression of the disease from MNI to SNI. Moreover, increased levels of p-tau(181) in CSF correlated with an increase in the sarkosyl insoluble p-tau(181) levels in the brain. The increase in the CSF level of p-tau(181) during progressive behavioural decline suggests that it may represent a useful surrogate biomarker for preclinical drug development and a potential surrogate endpoint for clinical trials of disease-modifying therapy for Alzheimer's disease and related human tauopathies.

Measuring disease progression in frontotemporal lobar degeneration

There is currently much interest in biomarkers of disease activity in frontotemporal lobar degeneration (FTLD). We assessed MRI and behavioral measures of progression in a longitudinal FTLD cohort. Thirty-two patients with FTLD (11 behavioral variant frontotemporal dementia [bvFTD], 11 semantic dementia [SemD], 10 progressive nonfluent aphasia [PNFA]) and 24 age-matched healthy controls were assessed using volumetric brain MRI and standard behavioral measures (Mini-Mental State Examination, Frontal Assessment Battery, Clinical Dementia Rating Scale, Neuropsychiatric Inventory with Caregiver Distress scale) at baseline and 1 year later. A semi-automated image registration protocol was used to calculate annualized rates of brain atrophy (brain boundary shift integral [BBSI]) and ventricular expansion (ventricular boundary shift integral [VBSI]). Associations between these rates and changes in behavioral indices were investigated. Rates of whole brain atrophy were greater in the entire FTLD cohort and in each subgroup compared with controls (all p < or = 0.004). Rates of ventricular expansion were greater in the entire cohort (p < 0.001) and the SemD (p = 0.002) and PNFA (p = 0.05) subgroups compared with controls. Changes in Mini-Mental State Examination, Frontal Assessment Battery, and Clinical Dementia Rating Scale scores were associated with MRI measures of progression, though not uniformly across FTLD subgroups. Both BBSI and VBSI yielded feasible sample size estimates for detecting meaningful treatment effects in SemD and PNFA language subgroups. Sample sizes were substantially larger using MRI biomarkers for the bvFTD subgroup, and using behavioral biomarkers in general. Semi-automated MRI atrophy measures are potentially useful objective biomarkers of progression in frontotemporal lobar degeneration (FTLD); however, careful stratification of FTLD subtypes will be important in future clinical trials of disease-modifying therapies.

IC-P2-130: Profiles of longitudinal brain atrophy in semantic dementia

Semantic dementia (SD) is a sporadic neurodegenerative disorder characterized clinically by progressive erosion of semantic processing in verbal and nonverbal domains and pathologically by the presence of ubiquitin-positive, TDP-43 positive neuronal inclusions. Brain imaging typically shows asymmetrical antero-inferior temporal lobe atrophy more severe on the left. Within the spectrum of the frontotemporal lobar degenerations (FTLD), the uniform and specific clinico-pathological signature of SD makes it the leading candidate FTLD subtype for trials of disease-modifying therapy. The aims of this study were to characterise in detail the pattern of global and regional longitudinal brain atrophy in SD and to identify imaging biomarkers of SD that could underpin therapeutic trials. In a cohort of 21 patients with SD (including 8 with pathological confirmation) we performed whole brain and region of interest analyses on volumetric brain MRI scans at two time-points. Mean whole brain atrophy rate measured using the boundary shift integral (BSI) was 2.5% per year (0.4% per year in controls) with ventricular enlargement at 6.2ml per year (0.6ml per year in controls). In regional analyses, all patients had a smaller left temporal lobe at baseline (left mean 31.9ml, right mean 49.2ml), however the mean rate of atrophy was significantly greater in the right temporal lobe (right 3.9ml per year, left 2.8ml per year). Similarly, whereas the left hippocampus was smaller at baseline (left mean 1.92ml, right mean 2.41ml) mean atrophy rate was significantly greater in the right hippocampus (right 0.17ml per year, left 0.10 ml per year). These findings suggest that as SD evolves, atrophy is initially more prominent on the left but then the rate of loss in the right temporal lobe overtakes the left, consistent with the later development of symptoms attributable to right temporal lobe dysfunction in SD. Our findings show that MRI measures of temporal lobe volume loss would provide a feasible and sensitive index of disease progression in SD: whereas whole-brain and hippocampal volume measures have been advanced as candidate biomarkers in other degenerative dementias, in SD temporal lobe volumetry would require fewer patients to detect the same level of effect.

IC-P2-117: Comparing voxel-based morphometry (VBM) to region of interest (ROI) measures while assessing hippocampal atrophy in patients with mild cognitive impairment

atrophy rates with 90% power. Results: The FTLD cohort exhibited significantly greater whole-brain atrophy rates than controls using both manual segmentation (p 0.029) and the automated BSI (p 0.001). The BBSI and VBSI techniques significantly reduced variability of results compared with manual segmentation and were used as the primary outcome for the following analyses. Pairwise comparisons of all three FTLD subgroups with controls demonstrated significantly higher whole-brain atrophy rates (bvFTLD, p 0.040; SD, p 0.001; and PNFA, p 0.023). Ventricular expansion rates were also significantly greater than controls for the whole FTLD cohort (p 0.001) and for the SD (p 0.001) and PNFA (p 0.001) subgroups, but not bvFTLD (p 0.226), potentially due to the pathogenetic heterogeneity of bvFTLD patients. In future multi-centre clinical trials, using the BBSI would require 221 FTLD patients (with similar numbers per subgroup) to detect a 30% reduction in atrophy rate with 90% power. Conclusions: Whole-brain and ventricular BSI measurements show promise as biomarkers of disease progression in FTLD and could be utilised as outcome measures of treatment effects in future clinical trials of disease-modifying therapies.

Diagnostic Potential of Saccadometry in Progressive Supranuclear Palsy

Progressive supranuclear palsy (PSP), an atypical parkinsonian syndrome characterized by extrapyramidal features, imbalance, supranuclear gaze paresis and dementia, can be difficult to diagnose, especially in the early stages. From the clinician's point of view, the main difficulty with this disorder is the inability to provide an accurate diagnosis, at least for the initial stages of the disease, where symptoms are often confused with other parkinsonian disorders. This inability complicates the recruitment of patients with early-stage parkinsonism to trials of disease-modifying therapy. To determine whether quantitative, objective examination of saccadic latency distributions can help to distinguish PSP patients from other groups of parkinsonian patients. We used a newly developed portable saccadometer to compare saccadic latency distributions of a group of PSP patients with two other groups in whom the initial differential diagnosis included PSP: one of these groups had Parkinson's disease and the other had developed a range of parkinsonian conditions (multiple system atrophy, dementia with Lewy bodies and corticobasal degeneration). The use of a combination of saccadic parameters provided a greater discriminative power than the use of only one parameter, such as median latency. Statistical analysis and parameterization of the distributions robustly distinguished the three groups. This approach appears to have considerable diagnostic potential in allowing a more accurate diagnosis of PSP, and may help particularly to eliminate misdiagnosis with other parkinsonian conditions.

Chili peppers, nerve regeneration, and clinical trial design

Distal sensory neuropathies (SN) are common and affect work, sleep, activities of daily living, and quality of life.1 Despite the frequency of SN it is difficult to determine its causes. SN is the most common neurologic complication of HIV infection.2 Glucose dysregulation may cause SN, but the majority of cases are idiopathic.3 Clinical trials of disease-modifying therapies for SN have been largely negative and there are currently no Food and Drug Administration–approved therapies for reversal or slowing of SN progression. One challenge for testing therapeutic approaches is the limited ability of currently available primary outcome measures such as clinical impairment scales and nerve conduction studies to document functional changes in small caliber sensory nerve fibers that are involved early in SN.4 A consequence is that subjects with relatively advanced SN are the focus of clinical trials. Furthermore, as the common forms of SN progress slowly, conventional outcome measures require lengthy studies (on the order of years) to demonstrate efficacy for slowing of progression.5 There is thus a need for easily applied and reproducible surrogate …

Évaluation et sclérose en plaques

We conducted a review of existing assessment tools that can be useful to physical medicine and rehabilitation professionals involved in the management of patients with multiple sclerosis (MS). Most generic tools traditionally used in neurorehabilitation, such as gait tests, the functional independence measure, or the SF-36, can be applied to MS, but few have been tested on large patient samples. Disease-specific scales often seem more pertinent and sensitive to change, and their qualities and limitations are better known through clinical trials of disease-modifying therapies.

Neuroimaging Biomarkers for Clinical Trials of Disease-Modifying Therapies in Alzheimer's Disease

The pathophysiologic process leading to neurodegeneration in Alzheimer's disease (AD) is thought to begin long before clinical symptoms develop. Existing therapeutics for AD improve symptoms, but increasing efforts are being directed toward the development of therapies to impede the pathologic progression of the disease. Although these medications must ultimately demonstrate efficacy in slowing clinical decline, there is a critical need for biomarkers that will indicate whether a candidate disease-modifying therapeutic agent is actually altering the underlying degenerative process. A number of in vivo neuroimaging techniques, which can reliably and noninvasively assess aspects of neuroanatomy, chemistry, physiology, and pathology, hold promise as biomarkers. These neuroimaging measures appear to relate closely to neuropathological and clinical data, such as rate of cognitive decline and risk of future decline. As this work has matured, it has become clear that neuroimaging measures may serve a variety of potential roles in clinical trials of candidate neurotherapeutic agents for AD, depending in part on the question of interest and phase of drug development. In this article, we review data related to the range of neuroimaging biomarkers of Alzheimer's disease and consider potential applications of these techniques to clinical trials, particularly with respect to the monitoring of disease progression in trials of disease-modifying therapies.

Neuroimaging biomarkers for clinical trials of disease-modifying therapies in Alzheimer’s disease

Neuroimaging biomarkers for clinical trials of disease-modifying therapies in Alzheimer’s disease