Objective assessment of bradykinesia in Parkinson’s disease using evolutionary algorithms: clinical validation

Background: There is an urgent need for developing objective, effective and convenient measurements to help clinicians accurately identify bradykinesia. The purpose of this study is to evaluate the accuracy of an objective approach assessing bradykinesia in finger tapping (FT) that uses evolutionary algorithms (EAs) and explore whether it can be used to identify early stage Parkinson’s disease (PD). Methods: One hundred and seven PD, 41 essential tremor (ET) patients and 49 normal controls (NC) were recruited. Participants performed a standard FT task with two electromagnetic tracking sensors attached to the thumb and index finger. Readings from the sensors were transmitted to a tablet computer and subsequently analyzed by using EAs. The output from the device (referred to as "PD-Monitor") scaled from − 1 to +1 (where higher scores indicate greater severity of bradykinesia). Meanwhile, the bradykinesia was rated clinically using the Movement Disorder Society- Sponsored Revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) FT item. Results: With an increasing MDS-UPDRS FT score, the PD-Monitor score from the same hand side increased correspondingly. PD-Monitor score correlated well with MDS-UPDRS FT score (right side: r = 0.819, P = 0.000; left side: r = 0.783, P = 0.000). Moreover, PD-Monitor scores in 97 PD patients with MDS-UPDRS FT bradykinesia and each PD subgroup (FT bradykinesia scored from 1 to 3) were all higher than that in NC. Receiver operating characteristic (ROC) curves revealed that PD-Monitor FT scores could detect different severity of bradykinesia with high accuracy (≥89.7%) in the right dominant hand. Furthermore, PD-Monitor scores could discriminate early stage PD from NC, with area under the ROC curve greater than or equal to 0.899. Additionally, ET without bradykinesia could be differentiated from PD by PD-Monitor scores. A positive correlation of PD-Monitor scores with modified Hoehn and Yahr stage was found in the left hand sides. Conclusions: Our study demonstrated that a simple to use device employing classifiers derived from EAs could not only be used to accurately measure different severity of bradykinesia in PD, but also had the potential to differentiate early stage PD from normality

Recent publications from the Alzheimer's Disease Neuroimaging Initiative: Reviewing progress toward improved AD clinical trials

INTRODUCTION: The Alzheimer's Disease Neuroimaging Initiative (ADNI) has continued development and standardization of methodologies for biomarkers and has provided an increased depth and breadth of data available to qualified researchers. This review summarizes the over 400 publications using ADNI data during 2014 and 2015. METHODS: We used standard searches to find publications using ADNI data. RESULTS: (1) Structural and functional changes, including subtle changes to hippocampal shape and texture, atrophy in areas outside of hippocampus, and disruption to functional networks, are detectable in presymptomatic subjects before hippocampal atrophy; (2) In subjects with abnormal β-amyloid deposition (Aβ+), biomarkers become abnormal in the order predicted by the amyloid cascade hypothesis; (3) Cognitive decline is more closely linked to tau than Aβ deposition; (4) Cerebrovascular risk factors may interact with Aβ to increase white-matter (WM) abnormalities which may accelerate Alzheimer's disease (AD) progression in conjunction with tau abnormalities; (5) Different patterns of atrophy are associated with impairment of memory and executive function and may underlie psychiatric symptoms; (6) Structural, functional, and metabolic network connectivities are disrupted as AD progresses. Models of prion-like spreading of Aβ pathology along WM tracts predict known patterns of cortical Aβ deposition and declines in glucose metabolism; (7) New AD risk and protective gene loci have been identified using biologically informed approaches; (8) Cognitively normal and mild cognitive impairment (MCI) subjects are heterogeneous and include groups typified not only by "classic" AD pathology but also by normal biomarkers, accelerated decline, and suspected non-Alzheimer's pathology; (9) Selection of subjects at risk of imminent decline on the basis of one or more pathologies improves the power of clinical trials; (10) Sensitivity of cognitive outcome measures to early changes in cognition has been improved and surrogate outcome measures using longitudinal structural magnetic resonance imaging may further reduce clinical trial cost and duration; (11) Advances in machine learning techniques such as neural networks have improved diagnostic and prognostic accuracy especially in challenges involving MCI subjects; and (12) Network connectivity measures and genetic variants show promise in multimodal classification and some classifiers using single modalities are rivaling multimodal classifiers. DISCUSSION: Taken together, these studies fundamentally deepen our understanding of AD progression and its underlying genetic basis, which in turn informs and improves clinical trial desig

Unexpected partial correction of metabolic and behavioral phenotypes of Alzheimer’s APP/PSEN1 mice by gene targeting of diabetes/Alzheimer’s-related Sorcs1

INTRODUCTION: Insulin resistance and type 2 diabetes mellitus (T2D) are associated with increased risk for cognitive impairment, Alzheimer’s disease (AD) and vascular dementia. SORCS1 encodes a protein-sorting molecule genetically linked to both T2D and AD. The association of SORCS1 with both AD and T2D is sexually dimorphic in humans, with both disease associations showing more robust effects in females. Based on published evidence that manipulation of the mouse genome combining multiple genes related to cerebral amyloidosis, to T2D, or both, might provide novel mouse models with exacerbated amyloid and/or diabetes phenotypes, we assessed memory, glucose homeostasis, and brain biochemistry and pathology in male and female wild-type, Sorcs1 -/-, APP/PSEN1, and Sorcs1 -/- X APP/PSEN1 mice. RESULTS: Male mice with either the APP/PSEN1 or Sorcs1 -/- genotype displayed earlier onset and persistent impairment in both learning behavior and glucose homeostasis. Unlike prior examples in the literature, the behavioral and metabolic abnormalities in male mice were not significantly exacerbated when the two disease model mice (Sorcs1 -/- models T2D; APP/PSEN1 models AD) were crossed. However, female Sorcs1 -/- X APP/PSEN1 mice exhibited worse metabolic dysfunction than Sorcs1 -/- knockout mice and worse memory than wild-type mice. The deletion of Sorcs1 from APP/PSEN1 mutant mice led to no obvious changes in brain levels of total or oligomeric amyloid-beta (Aβ) peptide. CONCLUSIONS: In general, unexpectedly, there was a trend for gene targeting of Sorcs1-/- to partially mitigate, not exacerbate, the metabolic and amyloid pathologies. These results indicate that crossing AD model mice and T2D model mice may not always cause exacerbation of both the amyloidosis phenotype and the metabolic phenotype and highlight the unexpected pitfalls of creating mixed models of disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40478-016-0282-y) contains supplementary material, which is available to authorized users