Antti Tolonen

Standardized Handwriting to Assess Bradykinesia, Micrographia and Tremor in Parkinson's Disease

Objective To assess whether standardized handwriting can provide quantitative measures to distinguish patients diagnosed with Parkinsons disease from age- and gender-matched healthy control participants. Design Exploratory study. Pen tip trajectories were recorded during circle, spiral and line drawing and repeated character ‘elelelel’ and sentence writing, performed by Parkinson patients and healthy control participants. Parkinson patients were tested after overnight withdrawal of anti-Parkinsonian medication. Setting University Medical Center Groningen, tertiary care, the Netherlands. Participants Patients with Parkinsons disease (n = 10; mean age 69.0 years; 6 male) and healthy controls (n = 10; mean age 68.1 years; 6 male). Interventions Not applicable. Main Outcome Measures Movement time and velocity to detect bradykinesia and the size of writing to detect micrographia. A rest recording to investigate the presence of a rest-tremor, by frequency analysis. Results Mean disease duration in the Parkinson group was 4.4 years and the patients were in modified Hoehn-Yahr stages 1–2.5. In general, Parkinson patients were slower than healthy control participants. Median time per repetition, median velocity and median acceleration of the sentence task and median velocity of the elel task differed significantly between Parkinson patients and healthy control participants (all p<0.0014). Parkinson patients also wrote smaller than healthy control participants and the width of the ‘e’ in the elel task was significantly smaller in Parkinson patients compared to healthy control participants (p<0.0014). A rest-tremor was detected in the three patients who were clinically assessed as having rest-tremor. Conclusions This study shows that standardized handwriting can provide objective measures for bradykinesia, tremor and micrographia to distinguish Parkinson patients from healthy control participants.

Differential diagnosis of neurodegenerative diseases using structural MRI data.

Different neurodegenerative diseases can cause memory disorders and other cognitive impairments. The early detection and the stratification of patients according to the underlying disease are essential for an efficient approach to this healthcare challenge. This emphasizes the importance of differential diagnostics. Most studies compare patients and controls, or Alzheimers disease with one other type of dementia. Such a bilateral comparison does not resemble clinical practice, where a clinician is faced with a number of different possible types of dementia. Here we studied which features in structural magnetic resonance imaging (MRI) scans could best distinguish four types of dementia, Alzheimers disease, frontotemporal dementia, vascular dementia, and dementia with Lewy bodies, and control subjects. We extracted an extensive set of features quantifying volumetric and morphometric characteristics from T1 images, and vascular characteristics from FLAIR images. Classification was performed using a multi-class classifier based on Disease State Index methodology. The classifier provided continuous probability indices for each disease to support clinical decision making. A dataset of 504 individuals was used for evaluation. The cross-validated classification accuracy was 70.6% and balanced accuracy was 69.1% for the five disease groups using only automatically determined MRI features. Vascular dementia patients could be detected with high sensitivity (96%) using features from FLAIR images. Controls (sensitivity 82%) and Alzheimers disease patients (sensitivity 74%) could be accurately classified using T1-based features, whereas the most difficult group was the dementia with Lewy bodies (sensitivity 32%). These results were notable better than the classification accuracies obtained with visual MRI ratings (accuracy 44.6%, balanced accuracy 51.6%). Different quantification methods provided complementary information, and consequently, the best results were obtained by utilizing several quantification methods. The results prove that automatic quantification methods and computerized decision support methods are feasible for clinical practice and provide comprehensive information that may help clinicians in the diagnosis making.

Five-class differential diagnostics of neurodegenerative diseases using random undersampling boosting

Differentiating between different types of neurodegenerative diseases is not only crucial in clinical practice when treatment decisions have to be made, but also has a significant potential for the enrichment of clinical trials. The purpose of this study is to develop a classification framework for distinguishing the four most common neurodegenerative diseases, including Alzheimers disease, frontotemporal lobe degeneration, Dementia with Lewy bodies and vascular dementia, as well as patients with subjective memory complaints. Different biomarkers including features from images (volume features, region-wise grading features) and non-imaging features (CSF measures) were extracted for each subject. In clinical practice, the prevalence of different dementia types is imbalanced, posing challenges for learning an effective classification model. Therefore, we propose the use of the RUSBoost algorithm in order to train classifiers and to handle the class imbalance training problem. Furthermore, a multi-class feature selection method based on sparsity is integrated into the proposed framework to improve the classification performance. It also provides a way for investigating the importance of different features and regions. Using a dataset of 500 subjects, the proposed framework achieved a high accuracy of 75.2% with a balanced accuracy of 69.3% for the five-class classification using ten-fold cross validation, which is significantly better than the results using support vector machine or random forest, demonstrating the feasibility of the proposed framework to support clinical decision making.

Graphical Tasks to Measure Upper Limb Function in Patients With Parkinson's Disease: Validity and Response to Dopaminergic Medication.

The most widely used method to assess motor functioning in Parkinsons disease (PD) patients is the unified Parkinsons disease rating scale-III (UPDRS-III). The UPDRS-III has limited ability to detect subtle changes in motor symptoms. Alternatively, graphical tasks can be used to provide objective measures of upper limb motor dysfunction. This study investigated the validity of such graphical tasks to assess upper limb function in PD patients and their ability to detect subtle changes in performance. Fourteen PD patients performed graphical tasks before and after taking dopaminergic medication. Graphical tasks included figure tracing, writing, and a modified Fitts’ task. The Purdue pegboard test was performed to validate these graphical tasks. Movement time (MT), writing size, and the presence of tremor were assessed. MT on the graphical tasks correlated significantly with performance on the Purdue pegboard test (Spearmans ρ > 0.65; p < 0.05). MT decreased significantly after the intake of dopaminergic medication. Tremor power decreased after taking dopaminergic medication in most PD patients who suffered from tremor. Writing size did not correlate with performance on the Purdue pegboard test, nor did it change after taking medication. Our set of graphical tasks is valid to assess upper limb function in PD patients. MT proved to be the most useful measure for this purpose. The response on dopaminergic medication was optimally reflected by an improved MT on the graphical tasks in combination with a decreased tremor power, whereas writing size did not respond to dopaminergic treatment.

Data-Driven Differential Diagnosis of Dementia Using Multiclass Disease State Index Classifier

Clinical decision support systems (CDSSs) hold potential for the differential diagnosis of neurodegenerative diseases. We developed a novel CDSS, the PredictND tool, designed for differential diagnosis of different types of dementia. It combines information obtained from multiple diagnostic tests such as neuropsychological tests, MRI and cerebrospinal fluid samples. Here we evaluated how the classifier used in it performs in differentiating between controls with subjective cognitive decline, dementia due to Alzheimer’s disease, vascular dementia, frontotemporal lobar degeneration and dementia with Lewy bodies. We used the multiclass Disease State Index classifier, which is the classifier used by the PredictND tool, to differentiate between controls and patients with the four different types of dementia. The multiclass Disease State Index classifier is an extension of a previously developed two-class Disease State Index classifier. As the two-class Disease State Index classifier, the multiclass Disease State Index classifier also offers a visualization of its decision making process, which makes it especially suitable for medical decision support where interpretability of the results is highly important. A subset of the Amsterdam Dementia cohort, consisting of 504 patients (age 65 ± 8 years, 44% females) with data from neuropsychological tests, cerebrospinal fluid samples and both automatic and visual MRI quantifications, was used for the evaluation. The Disease State Index classifier was highly accurate in separating the five classes from each other (balanced accuracy 82.3%). Accuracy was highest for vascular dementia and lowest for dementia with Lewy bodies. For the 50% of patients for which the classifier was most confident on the classification the balanced accuracy was 93.6%. Data-driven CDSSs can be of aid in differential diagnosis in clinical practice. The decision support system tested in this study was highly accurate in separating the different dementias and controls from each other. In addition to the predicted class, it also provides a confidence measure for the classification.

Quantitative EEG Parameters for Prediction of Outcome in Severe Traumatic Brain Injury: Development Study

Monitoring of quantitative EEG (QEEG) parameters in the intensive care unit (ICU) can aid in the treatment of traumatic brain injury (TBI) patients by complementing visual EEG review done by an expert. We performed an explorative study investigating the prognostic value of 59 QEEG parameters in predicting the outcome of patients with severe TBI. Continuous EEG recordings were done on 28 patients with severe TBI in the ICU of Turku University Hospital. We computed a set of QEEG parameters for each patient, and correlated these to patient outcome, measured by dichotomized Glasgow Outcome Scale (GOS) at a follow-up visit between 6 and 12 months, using area under receiver operating characteristic curve (AUC) as a nonlinear correlation measure. For 17 of the 59 QEEG parameters (28.8%), the AUC differed significantly from 0.5, most of these parameters measured EEG power or variability. The best QEEG parameters for outcome prediction were alpha power (AUC = 0.87, P < .01) and variability of the relative fast theta power (AUC = 0.84, P < .01). The results of this study indicate that QEEG parameters provide useful information for predicting outcome in severe TBI. Novel QEEG parameters with potential in outcome prediction were found, the prognostic value of these parameters should be confirmed in later studies. The results also provide further evidence of the usefulness of parameters studied in preexisting studies.

Distinguishing Parkinson's disease from other syndromes causing tremor using automatic analysis of writing and drawing tasks

An easily performed and objective test of patients fine motor skills would be valuable in the diagnosis of Parkinsons disease (PD). In this study we present a set of automatic methods for quantifying the motor symptoms of PD and show that these automatically extracted features can be used to distinguish PD from other movement disorders causing tremor, namely essential tremor (ET), functional tremor (FT) and enhanced physiological tremor (EPT). The classification accuracies (mean of sensitivity and specificity) for separating PD from the other tremor syndromes were 82.0 % for ET, 69.8 % for FT and 72.2 % for EPT.

Standardized handwriting provides quantitative measures to assess bradykinesia, tremor and micrographia in Parkinson's disease

Objective: The socio-demographic, epidemiologic, clinical features and genetic causes of Parkinson’s disease patients attending the Neurology out-patients clinic of the Korle Bu Teaching and Comboni hospitals are reviewed. Background: Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disease thought to be rare in Africa. A colloborative project with the Parkinson’s Institute in Milan, Italy is ongoing in Ghana. Methods: Consecutive patients clinically diagnosed with Parkinson’s disease over the last year who were enrolled in the ‘‘Parkinson’s disease in Africa collaboration project’’ were recruited. A detailed personal, family and social history was taken followed by a neurological examination, complete Unified Parkinson’s Disease Rating Scale (UPDRS) assessment (part I to part IV), Hoehn and Yahr staging and initiation of treatment with Levodopa. Patients are reviewed at 3, 6 and 12 months. Brain imaging with a head CT scan is done were feasible. A saliva sample was collected after informed consent for analysis of the LRRK2-G2019S mutation amongst others. Results: 35 subjects with parkinsonism have been identified so far: Mean age at onset 65.7610.5 years; disease duration 7.4563.1 years; Hoehn and Yahr stage 2. Mean daily levodopa dosage 5201187mg. The LRRK2 exon 41 screening did not reveal the presence of any G2019S mutation in the Parkinson’s disease patients studied so far. Recruitment of more patients, follow up at 6 months and 12 months as well as completion of UPDRS data are the main thrust of the study now Conclusions: A good response to Levedopa is seen and further genetic analysis is required

Automatic MRI Quantifying Methods in Behavioral-Variant Frontotemporal Dementia Diagnosis

Aims: We assessed the value of automated MRI quantification methods in the differential diagnosis of behavioral-variant frontotemporal dementia (bvFTD) from Alzheimer disease (AD), Lewy body dementia (LBD), and subjective memory complaints (SMC). We also examined the role of the C9ORF72-related genetic status in the differentiation sensitivity. Methods: The MRI scans of 50 patients with bvFTD (17 C9ORF72 expansion carriers) were analyzed using 6 quantification methods as follows: voxel-based morphometry (VBM), tensor-based morphometry, volumetry (VOL), manifold learning, grading, and white-matter hyperintensities. Each patient was then individually compared to an independent reference group in order to attain diagnostic suggestions. Results: Only VBM and VOL showed utility in correctly identifying bvFTD from our set of data. The overall classification sensitivity of bvFTD with VOL + VBM achieved a total sensitivity of 60%. Using VOL + VBM, 32% were misclassified as having LBD. There was a trend of higher values for classification sensitivity of the C9ORF72 expansion carriers than noncarriers. Conclusion: VOL, VBM, and their combination are effective in differential diagnostics between bvFTD and AD or SMC. However, MRI atrophy profiles for bvFTD and LBD are too similar for a reliable differentiation with the quantification methods tested in this study.

DIFFERENT COMBINATIONS OF DIAGNOSTIC TESTS DISCRIMINATE SPECIFIC SUBTYPES OF DEMENTIA

TDP-43), ii) covarying with CSF biomarkers (Ab42, total tau, ptau) and iii) covarying with episodic memory scores (FCSRT, Landscape Test and CERAD Constructional Praxis recall). Results:Amyloid/Tau pathology affected mainly posterior HC while anterior left HC was more atrophied in TDP-43pathies. We also observed a significant correlation between posterior hippocampal atrophy and AD CSF biomarkers levels. In addition, visual memory scores correlated with posterior HC atrophy, whereas verbal memory correlated with both anterior and posterior hippocampal atrophy. Conclusions:These findings fit well with the hypothesis that HC is involved in two different cortical systems that harbor different cognitive functions, which could have distinct vulnerability to different proteinopathies. Taken together, these data suggest that there is a potential differentiation along the hippocampal longitudinal axis based on the underlying pathology, which could be used as a potential biomarker to identify the underlying pathology in different neurodegenerative diseases.