Automatically computed rating scales from MRI for patients with cognitive disorders.

OBJECTIVES: The aims of this study were to examine whether visual MRI rating scales used in diagnostics of cognitive disorders can be estimated computationally and to compare the visual rating scales with their computed counterparts in differential diagnostics. METHODS: A set of volumetry and voxel-based morphometry imaging biomarkers was extracted from T1-weighted and FLAIR images. A regression model was developed for estimating visual rating scale values from a combination of imaging biomarkers. We studied three visual rating scales: medial temporal lobe atrophy (MTA), global cortical atrophy (GCA), and white matter hyperintensities (WMHs) measured by the Fazekas scale. Images and visual ratings from the Amsterdam Dementia Cohort (ADC) (N = 513) were used to develop the models and cross-validate them. The PredictND (N = 672) and ADNI (N = 752) cohorts were used for independent validation to test generalizability. RESULTS: The correlation coefficients between visual and computed rating scale values were 0.83/0.78 (MTA-left), 0.83/0.79 (MTA-right), 0.64/0.64 (GCA), and 0.76/0.75 (Fazekas) in ADC/PredictND cohorts. When performance in differential diagnostics was studied for the main types of dementia, the highest balanced accuracy, 0.75-0.86, was observed for separating different dementias from cognitively normal subjects using computed GCA. The lowest accuracy of about 0.5 for all the visual and computed scales was observed for the differentiation between Alzheimer's disease and frontotemporal lobar degeneration. Computed scales produced higher balanced accuracies than visual scales for MTA and GCA (statistically significant). CONCLUSIONS: MTA, GCA, and WMHs can be reliably estimated automatically helping to provide consistent imaging biomarkers for diagnosing cognitive disorders, even among less experienced readers. KEY POINTS: • Visual rating scales used in diagnostics of cognitive disorders can be estimated computationally from MRI images with intraclass correlations ranging from 0.64 (GCA) to 0.84 (MTA). • Computed scales provided high diagnostic accuracy with single-subject data (area under the receiver operating curve range, 0.84-0.94).

Quantitative Measurements of Motor Function in Alzheimer's Disease, Frontotemporal Dementia, and Dementia with Lewy Bodies: A Proof-of-Concept Study.

BACKGROUND: This study examines the efficacy of using quantitative measurements of motor dysfunction, compared to clinical ratings, in Alzheimer's disease (AD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB). METHODS: In this cross-sectional study, 49 patients with a diagnosis of AD (n = 17), FTD (n = 19), or DLB (n = 13) were included and underwent cognitive testing, clinical motor evaluation, and quantitative motor tests: pronation/supination hand tapping, grasping and lifting, and finger and foot tapping. RESULTS: Our results revealed significantly higher Q-Motor values in pronation/supination and in grip lift force assessment in AD, FTD, and DLB compared to healthy controls (HC). Q-Motor values detected significant differences between AD and HC, while clinical ratings did not. CONCLUSION: Our results suggest that quantitative measurements provide more objective and sensitive measurements of motor dysfunction in dementia.

Comparison of the clinical impact of 2-[18F]FDG-PET and cerebrospinal fluid biomarkers in patients suspected of Alzheimer's disease.

BACKGROUND: The two biomarkers 2-[18F]FDG-PET and cerebrospinal fluid biomarkers are both recommended to support the diagnosis of Alzheimer's disease. However, there is a lack of knowledge for the comparison of the two biomarkers in a routine clinical setting. OBJECTIVE: The aim was to compare the clinical impact of 2-[18F]FDG-PET and cerebrospinal fluid biomarkers on diagnosis, prognosis, and patient management in patients suspected of Alzheimer's disease. METHODS: Eighty-one patients clinically suspected of Alzheimer's disease were retrospectively included from the Copenhagen Memory Clinic. As part of the clinical work-up all patients had a standard diagnostic program examination including MRI and ancillary investigations with 2-[18F]FDG-PET and cerebrospinal fluid biomarkers. An incremental study design was used to evaluate the clinical impact of the biomarkers. First, the diagnostic evaluation was based on the standard diagnostic program, then the diagnostic evaluation was revised after addition of either cerebrospinal fluid biomarkers or 2-[18F]FDG-PET. At each diagnostic evaluation, two blinded dementia specialists made a consensus decision on diagnosis, prediction of disease course, and change in patient management. Confidence in the decision was measured on a visual analogue scale (0-100). After 6 months, the diagnostic evaluation was performed with addition of the other biomarker. A clinical follow-up after 12 months was used as reference for diagnosis and disease course. RESULTS: The two biomarkers had a similar clinical value across all diagnosis when added individually to the standard diagnostic program. However, for the correctly diagnosed patient with Alzheimer's disease cerebrospinal fluid biomarkers had a significantly higher impact on diagnostic confidence (mean scores±SD: 88±11 vs. 82±11, p = 0.046) and a significant reduction in the need for ancillary investigations (23 vs. 18 patients, p = 0.049) compared to 2-[18F]FDG-PET. CONCLUSION: The two biomarkers had similar clinical impact on diagnosis, but cerebrospinal fluid biomarkers had a more significant value in corroborating the diagnosis of Alzheimer's disease compared to 2-[18F]FDG-PET.

Comparing a Single Clinician Versus a Multidisciplinary Consensus Conference Approach for Dementia Diagnostics.

BACKGROUND: Evidence-based recommendations on the optimal evaluation approach for dementia diagnostics are limited. This impedes a harmonized workup across clinics and nations. OBJECTIVE: To evaluate the diagnostic performance of a multidisciplinary consensus conference compared to a single clinician approach. METHODS: In this prospective study, we enrolled 457 patients with suspected cognitive decline, from two European memory clinics. A diagnostic evaluation was performed at baseline independently in two ways: 1) by a single clinician and 2) at a multidisciplinary consensus conference. A syndrome diagnosis and an etiological diagnosis was made. The confidence in the diagnosis was recorded using a visual analogue scale. An expert panel re-evaluation diagnosis served as reference for the baseline syndrome diagnosis and a 12-24-month follow-up diagnosis for the etiological diagnosis. RESULTS: 439 patients completed the study. We observed 12.5%discrepancy (k = 0.81) comparing the baseline syndrome diagnoses of the single clinician to the consensus conference, and 22.3%discrepancy (k = 0.68) for the baseline etiological diagnosis. The accuracy of the baseline etiological diagnosis was significantly higher at the consensus conference and was driven mainly by increased accuracy in the MCI group. Confidence in the etiological diagnosis at baseline was significantly higher at the consensus conference (p < 0.005), especially for the frontotemporal dementia diagnosis. CONCLUSION: The multidisciplinary consensus conference performed better on diagnostic accuracy of disease etiology and increased clinicians' confidence. This highlights the importance of a multidisciplinary diagnostic evaluation approach for dementia diagnostics, especially when evaluating patients in the MCI stage.

Evaluating 2-[18F]FDG-PET in differential diagnosis of dementia using a data-driven decision model.

2-[18F]fluoro-2-deoxy-d-glucose positron emission tomography (2-[18F]FDG-PET) has an emerging supportive role in dementia diagnostic as distinctive metabolic patterns are specific for Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). Previous studies have demonstrated that a data-driven decision model based on the disease state index (DSI) classifier supports clinicians in the differential diagnosis of dementia by using different combinations of diagnostic tests and biomarkers. Until now, this model has not included 2-[18F]FDG-PET data. The objective of the study was to evaluate 2-[18F]FDG-PET biomarkers combined with commonly used diagnostic tests in the differential diagnosis of dementia using the DSI classifier. We included data from 259 subjects diagnosed with AD, DLB, FTD, vascular dementia (VaD), and subjective cognitive decline from two independent study cohorts. We also evaluated three 2-[18F]FDG-PET biomarkers (anterior vs. posterior index (API-PET), occipital vs. temporal index, and cingulate island sign) to improve the classification accuracy for both FTD and DLB. We found that the addition of 2-[18F]FDG-PET biomarkers to cognitive tests, CSF and MRI biomarkers considerably improved the classification accuracy for all pairwise comparisons of DLB (balanced accuracies: DLB vs. AD from 64% to 77%; DLB vs. FTD from 71% to 92%; and DLB vs. VaD from 71% to 84%). The two 2-[18F]FDG-PET biomarkers, API-PET and occipital vs. temporal index, improved the accuracy for FTD and DLB, especially as compared to AD. Moreover, different combinations of diagnostic tests were valuable to differentiate specific subtypes of dementia. In conclusion, this study demonstrated that the addition of 2-[18F]FDG-PET to commonly used diagnostic tests provided complementary information that may help clinicians in diagnosing patients, particularly for differentiating between patients with FTD, DLB, and AD.

cCOG: A web-based cognitive test tool for detecting neurodegenerative disorders.

INTRODUCTION: Web-based cognitive tests have potential for standardized screening in neurodegenerative disorders. We examined accuracy and consistency of cCOG, a computerized cognitive tool, in detecting mild cognitive impairment (MCI) and dementia. METHODS: Clinical data of 306 cognitively normal, 120 mild cognitive impairment (MCI), and 69 dementia subjects from three European cohorts were analyzed. Global cognitive score was defined from standard neuropsychological tests and compared to the corresponding estimated score from the cCOG tool containing seven subtasks. The consistency of cCOG was assessed comparing measurements administered in clinical settings and in the home environment. RESULTS: cCOG produced accuracies (receiver operating characteristic-area under the curve [ROC-AUC]) between 0.71 and 0.84 in detecting MCI and 0.86 and 0.94 in detecting dementia when administered at the clinic and at home. The accuracy was comparable to the results of standard neuropsychological tests (AUC 0.69-0.77 MCI/0.91-0.92 dementia). DISCUSSION: cCOG provides a promising tool for detecting MCI and dementia with potential for a cost-effective approach including home-based cognitive assessments.

Gait Disturbances are Associated with Increased Cognitive Impairment and Cerebrospinal Fluid Tau Levels in a Memory Clinic Cohort.

BACKGROUND: Gait analysis with accelerometers is a relatively inexpensive and easy to use method to potentially support clinical diagnoses of Alzheimer's disease and other dementias. It is not clear, however, which gait features are most informative and how these measures relate to Alzheimer's disease pathology. OBJECTIVE: In this study, we tested if calculated features of gait 1) differ between cognitively normal subjects (CN), mild cognitive impairment (MCI) patients, and dementia patients, 2) are correlated with cerebrospinal fluid (CSF) biomarkers related to Alzheimer's disease, and 3) predict cognitive decline. METHODS: Gait was measured using tri-axial accelerometers attached to the fifth lumbar vertebra (L5) in 58 CN, 58 MCI, and 26 dementia participants, while performing a walk and dual task. Ten gait features were calculated from the vertical L5 accelerations, following principal component analysis clustered in four domains, namely pace, rhythm, time variability, and length variability. Cognitive decline over time was measured using MMSE, and CSF biomarkers were available in a sub-group. RESULTS: Linear mixed models showed that dementia patients had lower pace scores than MCI patients and CN subjects (p < 0.05). In addition, we found associations between the rhythm domain and CSF-tau, especially in the dual task. Gait was not associated with CSF Aß42 levels and cognitive decline over time as measured with the MMSE. CONCLUSION: These findings suggest that gait - particularly measures related to pace and rhythm - are altered in dementia and have a direct link with measures of neurodegeneration.

Detecting frontotemporal dementia syndromes using MRI biomarkers.

BACKGROUND: Diagnosing frontotemporal dementia may be challenging. New methods for analysis of regional brain atrophy patterns on magnetic resonance imaging (MRI) could add to the diagnostic assessment. Therefore, we aimed to develop automated imaging biomarkers for differentiating frontotemporal dementia subtypes from other diagnostic groups, and from one another. METHODS: In this retrospective multicenter cohort study, we included 1213 patients (age 67 ±â€¯9, 48% females) from two memory clinic cohorts: 116 frontotemporal dementia, 341 Alzheimer's disease, 66 Dementia with Lewy bodies, 40 vascular dementia, 104 other dementias, 229 mild cognitive impairment, and 317 subjective cognitive decline. Three MRI atrophy biomarkers were derived from the normalized volumes of automatically segmented cortical regions: 1) the anterior vs. posterior index, 2) the asymmetry index, and 3) the temporal pole left index. We used the following performance metrics: area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. To account for the low prevalence of frontotemporal dementia we pursued a high specificity of 95%. Cross-validation was used in assessing the performance. The generalizability was assessed in an independent cohort (n = 200). RESULTS: The anterior vs. posterior index performed with an AUC of 83% for differentiation of frontotemporal dementia from all other diagnostic groups (Sensitivity = 59%, Specificity = 95%, positive likelihood ratio = 11.8, negative likelihood ratio = 0.4). The asymmetry index showed highest performance for separation of primary progressive aphasia and behavioral variant frontotemporal dementia (AUC = 85%, Sensitivity = 79%, Specificity = 92%, positive likelihood ratio = 9.9, negative likelihood ratio = 0.2), whereas the temporal pole left index was specific for detection of semantic variant primary progressive aphasia (AUC = 85%, Sensitivity = 82%, Specificity = 80%, positive likelihood ratio = 4.1, negative likelihood ratio = 0.2). The validation cohort provided corresponding results for the anterior vs. posterior index and temporal pole left index. CONCLUSION: This study presents three quantitative MRI biomarkers, which could provide additional information to the diagnostic assessment and assist clinicians in diagnosing frontotemporal dementia.

Impact of a clinical decision support tool on prediction of progression in early-stage dementia: a prospective validation study.

BACKGROUND: In clinical practice, it is often difficult to predict which patients with cognitive complaints or impairment will progress or remain stable. We assessed the impact of using a clinical decision support system, the PredictND tool, to predict progression in patients with subjective cognitive decline (SCD) and mild cognitive impairment (MCI) in memory clinics. METHODS: In this prospective multicenter study, we included 429 patients with SCD (n = 230) and MCI (n = 199) (female 54%, age 67 ± 9, MMSE 28 ± 2) and followed them for at least 12 months. Based on all available patient baseline data (demographics, cognitive tests, cerebrospinal fluid biomarkers, and MRI), the PredictND tool provides a comprehensive overview of the data and a classification defining the likelihood of progression. At baseline, a clinician defined an expected follow-up diagnosis and estimated the level of confidence in their prediction using a visual analogue scale (VAS, 0-100%), first without and subsequently with the PredictND tool. As outcome measure, we defined clinical progression as progression from SCD to MCI or dementia, and from MCI to dementia. Correspondence between the expected and the actual clinical progression at follow-up defined the prognostic accuracy. RESULTS: After a mean follow-up time of 1.7 ± 0.4 years, 21 (9%) SCD and 63 (32%) MCI had progressed. When using the PredictND tool, the overall prognostic accuracy was unaffected (0.4%, 95%CI - 3.0%; + 3.9%; p = 0.79). However, restricting the analysis to patients with more certain classifications (n = 203), we found an increase of 3% in the accuracy (95%CI - 0.6%; + 6.5%; p = 0.11). Furthermore, for this subgroup, the tool alone showed a statistically significant increase in the prognostic accuracy compared to the evaluation without tool (6.4%, 95%CI 2.1%; 10.7%; p = 0.004). Specifically, the negative predictive value was high. Moreover, confidence in the prediction increased significantly (∆VAS = 4%, p < .0001). CONCLUSIONS: Adding the PredictND tool to the clinical evaluation increased clinicians' confidence. Furthermore, the results indicate that the tool has the potential to improve prediction of progression for patients with more certain classifications.

Impact of a Clinical Decision Support Tool on Dementia Diagnostics in Memory Clinics: The PredictND Validation Study.

BACKGROUND: Determining the underlying etiology of dementia can be challenging. Computer- based Clinical Decision Support Systems (CDSS) have the potential to provide an objective comparison of data and assist clinicians. OBJECTIVES: To assess the diagnostic impact of a CDSS, the PredictND tool, for differential diagnosis of dementia in memory clinics. METHODS: In this prospective multicenter study, we recruited 779 patients with either subjective cognitive decline (n=252), mild cognitive impairment (n=219) or any type of dementia (n=274) and followed them for minimum 12 months. Based on all available patient baseline data (demographics, neuropsychological tests, cerebrospinal fluid biomarkers, and MRI visual and computed ratings), the PredictND tool provides a comprehensive overview and analysis of the data with a likelihood index for five diagnostic groups; Alzheimer´s disease, vascular dementia, dementia with Lewy bodies, frontotemporal dementia and subjective cognitive decline. At baseline, a clinician defined an etiological diagnosis and confidence in the diagnosis, first without and subsequently with the PredictND tool. The follow-up diagnosis was used as the reference diagnosis. RESULTS: In total, 747 patients completed the follow-up visits (53% female, 69±10 years). The etiological diagnosis changed in 13% of all cases when using the PredictND tool, but the diagnostic accuracy did not change significantly. Confidence in the diagnosis, measured by a visual analogue scale (VAS, 0-100%) increased (ΔVAS=3.0%, p<0.0001), especially in correctly changed diagnoses (ΔVAS=7.2%, p=0.0011). CONCLUSION: Adding the PredictND tool to the diagnostic evaluation affected the diagnosis and increased clinicians' confidence in the diagnosis indicating that CDSSs could aid clinicians in the differential diagnosis of dementia.

Evaluating combinations of diagnostic tests to discriminate different dementia types.

INTRODUCTION: We studied, using a data-driven approach, how different combinations of diagnostic tests contribute to the differential diagnosis of dementia. METHODS: In this multicenter study, we included 356 patients with Alzheimer's disease, 87 frontotemporal dementia, 61 dementia with Lewy bodies, 38 vascular dementia, and 302 controls. We used a classifier to assess accuracy for individual performance and combinations of cognitive tests, cerebrospinal fluid biomarkers, and automated magnetic resonance imaging features for pairwise differentiation between dementia types. RESULTS: Cognitive tests had good performance in separating any type of dementia from controls. Cerebrospinal fluid optimally contributed to identifying Alzheimer's disease, whereas magnetic resonance imaging features aided in separating vascular dementia, dementia with Lewy bodies, and frontotemporal dementia. Combining diagnostic tests increased the accuracy, with balanced accuracies ranging from 78% to 97%. DISCUSSION: Different diagnostic tests have their distinct roles in differential diagnostics of dementias. Our results indicate that combining different diagnostic tests may increase the accuracy further.

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.

Familial hemiplegic migraine type 1 associated with parkinsonism: a case report.

Familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) are allelic disorders caused by mutations in the CACNA1A gene on chromosome 19p13. It is well described that FHM1 can present with cerebellar signs, but parkinsonism has not previously been reported in FHM1 or EA2 even though parkinsonism has been described in SCA6. We report a 63-year-old woman with FHM1 caused by an R583Q mutation in the CACNA1A gene, clinically presenting with migraine and permanent cerebellar ataxia. Since the age of 60 years, the patient also developed parkinsonism with rigidity, bradykinesia and a resting tremor. An MRI showed a normal substantia nigra, but a bilateral loss of substance in the basal ganglia, which is in contrast to the typically normal MRI in idiopathic Parkinson's disease. Dopamine transporter (DAT) imaging with single-photon emission computed tomography demonstrated a decreased DAT-binding potential in the putamen. We wish to draw attention to FHM1 associated with parkinsonism; however, whether the reported case is a consequence of FHM1 being allelic to SCA6, unknown modifiers to the specific R583Q CACNA1A mutation or idiopathic Parkinson's disease remains unanswered.

[Acute vertigo of neurological origin]. / Akut svimmelhed hos den neurologiske patient.

Acute vertigo of neurological origin may be caused by haemorrhages and tumours in the posterior fossa and, most frequently, by ischaemic infarction in the vertebrobasilar circulation. Urgent diagnosis is necessary to avoid further ischaemic episodes, herniation due to cerebellar oedema and/or fatal brainstem infarction. The history should focus on accompanying neurological symptoms. However, vertigo with cerebellar lesions may be monosymptomatic and then bedside evaluation of oculomotor function is the key to correct diagnosis. This paper discusses the pathophysiology, symptomatology and clinical evaluation of acute vertigo of neurological origin.