What is the meaning of PASAT rejection in multiple sclerosis?

BACKGROUND: Paced Auditory Serial Addition Test (PASAT) is one of the most used neuropsychological tests in multiple sclerosis (MS), specially for screening. However, the applicability of the test is limited because of the rejection of the test completion in a proportion of patients. We aimed to investigate the clinical, neuropsychological, and MRI findings associated to PASAT rejection. METHODS: Cross-sectional and observational study. A total of 343 patients with MS underwent neuropsychological testing and structural MRI. RESULTS: One hundred and twenty-one (35.3%) of patients declined the administration of the test. Among those patients that declined the administration, rejection occurred before the onset of test in 35.5%, during or after the practice in 43%, and during the test administration in 21.5%. Rejection of the test was associated to a worse performance in all cognitive tests administered, but not to depression or baseline fatigue scales. In regression analysis, education, cognitive impairment, EDSS, and white matter lesion load were independently associated to rejection of the test. CONCLUSIONS: Paced Auditory Serial Addition Test rejection is associated with a higher probability of cognitive impairment in MS. This suggests that patients that reject the administration of PASAT should be further examined with a neuropsychological battery to evaluate the possibility of cognitive dysfunction.

Structural MRI correlates of PASAT performance in multiple sclerosis.

BACKGROUND: The Paced Auditory Serial Addition Test (PASAT) is a useful cognitive test in patients with multiple sclerosis (MS), assessing sustained attention and information processing speed. However, the neural underpinnings of performance in the test are controversial. We aimed to study the neural basis of PASAT performance by using structural magnetic resonance imaging (MRI) in a series of 242 patients with MS. METHODS: PASAT (3-s) was administered together with a comprehensive neuropsychological battery. Global brain volumes and total T2-weighted lesion volumes were estimated. Voxel-based morphometry and lesion symptom mapping analyses were performed. RESULTS: Mean PASAT score was 42.98 ± 10.44; results indicated impairment in 75 cases (31.0%). PASAT score was correlated with several clusters involving the following regions: bilateral precuneus and posterior cingulate, bilateral caudate and putamen, and bilateral cerebellum. Voxel-based lesion symptom mapping showed no significant clusters. Region of interest-based analysis restricted to white matter regions revealed a correlation with the left cingulum, corpus callosum, bilateral corticospinal tracts, and right arcuate fasciculus. Correlations between PASAT scores and global volumes were weak. CONCLUSION: PASAT score was associated with regional volumes of the posterior cingulate/precuneus and several subcortical structures, specifically the caudate, putamen, and cerebellum. This emphasises the role of both cortical and subcortical structures in cognitive functioning and information processing speed in patients with MS.

Different apathy clinical profile and neural correlates in behavioral variant frontotemporal dementia and Alzheimer's disease.

OBJECTIVES: Apathy is one of the most common and disabling syndromes of dementia. Clinical apathy expression and neuroanatomical basis of apathy seem to differ between behavioral variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD), although evidence is scarce and poorly understood. Our main purposes were to compare the clinical apathy profile from patients with bvFTD and AD and analyze the relationship between apathy and brain metabolism measured using positron emission tomography imaging with 18 F fluorodeoxyglucose (FDG-PET). METHODS: Forty-two bvFTD, 42 AD, and 30 healthy volunteers without cognitive or behavioral complaints were included. Apathy was defined using Robert's 2009 diagnostic criteria, and specific apathy characteristics were assessed with the Lille Apathy Rating Scale. All participants underwent FDG-PET brain scan to provide data for voxel-based morphometric analysis. RESULTS: Multivariate analysis showed that subjects affected by bvFTD displayed greater impairment of emotional apathy and self-awareness in comparison with AD sample. Additionally, FDG-PET imaging analyses revealed that apathy was associated with different neuroanatomical substrates in each dementia group: left lateral prefrontal, medial frontal/anterior cingulate, lateral orbitofrontal and anterior insular cortices in bvFTD, and right anterior cingulate in AD. CONCLUSIONS: These results support that apathy is a complex syndrome, with different clinical expressions across different pathological conditions. Those differences in qualitative aspects of apathy seem to be associated with differences in the damage sites, as shown by our FDG-PET imaging analysis. Our findings provide a better knowledge about pathophysiology of apathy in dementia, which could have practical implications for therapeutic management. Copyright © 2017 John Wiley & Sons, Ltd.

Conversion between Addenbrooke's Cognitive Examination III and Mini-Mental State Examination.

ABSTRACTBackground:We aim to provide a conversion between Addenbrooke's Cognitive Examination III (ACE-III) and Mini-Mental State Examination (MMSE) scores, to predict the MMSE result based on ACE-III, thus avoiding the need for both tests, and improving their comparability. METHODS: Equipercentile equating method was used to elaborate a conversion table using a group of 400 participants comprising healthy controls and Alzheimer's disease (AD) patients. Then, reliability was assessed in a group of 100 healthy controls and patients with AD, 52 with primary progressive aphasia and 22 with behavioral variant frontotemporal dementia. RESULTS: The conversion table between ACE-III and MMSE denoted a high reliability, with intra-class correlation coefficients of 0.940, 0.922, and 0.902 in the groups of healthy controls and AD, behavioral variant frontotemporal dementia, and primary progressive aphasia, respectively. CONCLUSION: Our conversion table between ACE-III and MMSE suggests that MMSE may be estimated based on the ACE-III score, which could be useful for clinical and research purposes.

Neural Basis of Cognitive Assessment in Alzheimer Disease, Amnestic Mild Cognitive Impairment, and Subjective Memory Complaints.

INTRODUCTION: Interpreting cognitive tests is often challenging. The same test frequently examines multiple cognitive functions, and the functional and anatomical basis underlying test performance is unknown in many cases. This study analyses the correlation of different neuropsychological test results with brain metabolism in a series of patients evaluated for suspected Alzheimer disease. METHODS: 20 healthy controls and 80 patients consulting for memory loss were included, in which cognitive study and 18F-fluorodeoxyglucose PET were performed. Patients were categorized according to Reisberg's Global Deterioration Scale. Voxel-based analysis was used to determine correlations between brain metabolism and performance on the following tests: Free and Cued Selective Reminding Test (FCSRT), Boston Naming Test (BNT), Trail Making Test, Rey-Osterrieth Complex Figure test, Visual Object and Space Perception Battery (VOSP), and Tower of London (ToL) test. RESULTS: Mean age in the patient group was 73.9 ± 10.6 years, and 47 patients were women (58.7%). FCSRT findings were positively correlated with metabolism in the medial and anterior temporal region bilaterally, the left precuneus, and posterior cingulate. BNT results were correlated with metabolism in the middle temporal, superior, fusiform, and frontal medial gyri bilaterally. VOSP results were related to the occipital and parietotemporal regions bilaterally. ToL scores were correlated to metabolism in the right temporoparietal and frontal regions. CONCLUSIONS: These results suggest that different areas of the brain are involved in the processes required to complete different cognitive tests. Ascertaining the functional basis underlying these tests may prove helpful for understanding and interpreting them.

Comparative Diagnostic Accuracy of the ACE-III, MIS, MMSE, MoCA, and RUDAS for Screening of Alzheimer Disease.

BACKGROUND: Our aim was to evaluate and compare the diagnostic properties of 5 screening tests for the diagnosis of mild Alzheimer disease (AD). METHODS: We conducted a prospective and cross-sectional study of 92 patients with mild AD and of 68 healthy controls from our Department of Neurology. The diagnostic properties of the following tests were compared: Mini-Mental State Examination (MMSE), Addenbrooke's Cognitive Examination III (ACE-III), Memory Impairment Screen (MIS), Montreal Cognitive Assessment (MoCA), and Rowland Universal Dementia Assessment Scale (RUDAS). RESULTS: All tests yielded high diagnostic accuracy, with the ACE-III achieving the best diagnostic properties. The area under the curve was 0.897 for the ACE-III, 0.889 for the RUDAS, 0.874 for the MMSE, 0.866 for the MIS, and 0.856 for the MoCA. The Mini-ACE score from the ACE-III showed the highest diagnostic capacity (area under the curve 0.939). Memory scores of the ACE-III and of the RUDAS showed a better diagnostic accuracy than those of the MMSE and of the MoCA. All tests, especially the ACE-III, conveyed a higher diagnostic accuracy in patients with full primary education than in the less educated group. Implementing normative data improved the diagnostic accuracy of the ACE-III but not that of the other tests. CONCLUSIONS: The ACE-III achieved the highest diagnostic accuracy. This better discrimination was more evident in the more educated group.

Addenbrooke's cognitive examination III: diagnostic utility for mild cognitive impairment and dementia and correlation with standardized neuropsychological tests.

BACKGROUND: Addenbrooke's Cognitive Examination III (ACE-III) is a screening test that was recently validated for diagnosing dementia. Since it assesses attention, language, memory, fluency, and visuospatial function separately, it may also be useful for general neuropsychological assessments. The aim of this study was to analyze the tool's ability to detect early stages of Alzheimer's disease and to examine the correlation between ACE-III scores and scores on standardized neuropsychological tests. METHODS: Our study included 200 participants categorized as follows: 25 healthy controls, 48 individuals with subjective memory complaints, 47 patients with amnestic mild cognitive impairment and 47 mild Alzheimer's disease, and 33 patients with other neurodegenerative diseases. RESULTS: The ACE-III memory and language domains were highly correlated with the neuropsychological tests specific to those domains (Pearson correlation coefficient of 0.806 for total delayed recall on the Free and Cued Selective Reminding Test vs. 0.744 on the Boston Naming Test). ACE-III scores discriminated between controls and patients with amnestic mild cognitive impairment (AUC: 0.906), and between controls and patients with mild Alzheimer's disease (AUC: 0.978). CONCLUSION: Our results suggest that ACE-III is a useful neuropsychological test for assessing the cognitive domains of attention, language, memory, and visuospatial function. It also enables detection of Alzheimer's disease in early stages.

Amyloid- and FDG-PET imaging in amyotrophic lateral sclerosis.

PURPOSE: We aimed to study brain metabolism and presence of beta-amyloid deposits using positron emission tomography (PET) in patients with amyotrophic lateral sclerosis (ALS). METHODS: This prospective cross-sectional study included 18 patients with definite or probable ALS according to the revised El Escorial diagnostic criteria, and 24 healthy controls. Patients underwent neurological and neuropsychological assessments, PET with (18)F-fluorodeoxyglucose (FDG), and amyloid-PET with (18)F-florbetaben. RESULTS: Patients with ALS showed hypometabolism in the frontal area and hypermetabolism in the cerebellum compared to healthy controls. Four patients (22 %) displayed cognitive impairment and decreased metabolism in the frontal area extending bilaterally to the parietal regions, and increased metabolism in the posterior area of the cerebellum. In patients with no cognitive impairment, metabolism was lower in the left superior frontal gyrus and higher in the anterior and posterior lobes of the cerebellum. In the individual analysis, six patients (35 %) displayed more anterior involvement with hypometabolism affecting the superior frontal, medial, and inferior gyri; six patients (35 %) exhibited a more posterior pattern with hypometabolism in the precentral and postcentral gyri and in the superior and inferior parietal lobules; two patients (11 %) showed a mixed pattern; and three patients (17 %) showed no alterations in brain metabolism. Three (16 %) showed increased (18)F-florbetaben uptake compared to controls. CONCLUSIONS: We have identified two main patterns of brain metabolism with an association to cognitive status. Only a subgroup of patients showed an increased uptake of the amyloid tracer. Our results suggest that ALS is heterogeneous from a clinical, metabolic, and molecular standpoint.

Validation of the Lille's Apathy Rating Scale in Very Mild to Moderate Dementia.

OBJECTIVE: Apathy is one of the most common and disabling syndromes of dementia and presents at all stages of the disease. Comprehensive and structured methods to assess apathy in dementia are still needed. Lille's Apathy Rating Scale (LARS) has shown good psychometric properties for apathy evaluation in Parkinson disease but has not been validated in dementia. The aim of this study was to validate the LARS in a cohort of patients with very mild to moderate dementia. METHODS: 101 patients with cognitive impairment (Clinical Dementia Rating ≤ 2) and 50 healthy subjects were recruited. Patient diagnoses included 43 individuals with Alzheimer disease, 41 frontotemporal dementia, and 17 primary progressive aphasia. In addition to LARS, the following assessments were administered: Clinical Dementia Rating, Interview for Deterioration in Daily Living Activities in Dementia, Functional Activities Questionnaire, Frontal Behavioral Inventory, Neuropsychiatric Inventory (NPI), and Hamilton Depression Rating Scale. RESULTS: Internal consistency for LARS (Cronbach's alpha) was 0.940. Test-retest intraclass correlation coefficient (ICC) was 0.940 and inter-rater ICC was 0.987. The correlation among LARS and NPI apathy scores (concurrent validity) was 0.834. Receiver operating characteristic analysis estimated an area under the curve of 0.987. The optimal cutoff point was -10. Although total LARS score was influenced by the presence of depression, this disorder was independent with respect to apathy. CONCLUSION: LARS is reliable and valid for detecting and quantifying apathy in patients with dementia, even in very early stages of the disease.

Normative Data for the Spanish Version of the Addenbrooke's Cognitive Examination III.

BACKGROUND: Addenbrooke's Cognitive Examination III (ACE-III) is a cognitive test that has been validated for the diagnosis of cognitive disorders. The aim of this study was to provide normative data for the ACE-III for age, education and gender. METHODS: The Spanish version of the ACE-III was administered to a group of 273 healthy subjects in a multicenter study in Spain. Correlation and determination coefficients for age, education and gender were estimated. The overlapping interval strategy and linear regression analyses were used to provide adjusted norms for demographic factors and to explore the potential influence of these factors in the performance of the test. RESULTS: Age and education correlated significantly with the total score and with all the domains. Gender correlated only with the domains of attention and visuospatial skills. Norms for the total score and for cognitive domains (attention, memory, fluency, language, and visuospatial skills) are provided. CONCLUSION: This study confirms the influence of demographic factors (especially age and education) on the performance in the ACE-III and provides normative data for the Spanish version of the ACE-III.

Visual and statistical analysis of ¹8F-FDG PET in primary progressive aphasia.

PURPOSE: Diagnosing progressive primary aphasia (PPA) and its variants is of great clinical importance, and fluorodeoxyglucose (FDG) positron emission tomography (PET) may be a useful diagnostic technique. The purpose of this study was to evaluate interobserver variability in the interpretation of FDG PET images in PPA as well as the diagnostic sensitivity and specificity of the technique. We also aimed to compare visual and statistical analyses of these images. METHODS: There were 10 raters who analysed 44 FDG PET scans from 33 PPA patients and 11 controls. Five raters analysed the images visually, while the other five used maps created using Statistical Parametric Mapping software. Two spatial normalization procedures were performed: global mean normalization and cerebellar normalization. Clinical diagnosis was considered the gold standard. RESULTS: Inter-rater concordance was moderate for visual analysis (Fleiss' kappa 0.568) and substantial for statistical analysis (kappa 0.756-0.881). Agreement was good for all three variants of PPA except for the nonfluent/agrammatic variant studied with visual analysis. The sensitivity and specificity of each rater's diagnosis of PPA was high, averaging 87.8 and 89.9% for visual analysis and 96.9 and 90.9% for statistical analysis using global mean normalization, respectively. In cerebellar normalization, sensitivity was 88.9% and specificity 100%. CONCLUSION: FDG PET demonstrated high diagnostic accuracy for the diagnosis of PPA and its variants. Inter-rater concordance was higher for statistical analysis, especially for the nonfluent/agrammatic variant. These data support the use of FDG PET to evaluate patients with PPA and show that statistical analysis methods are particularly useful for identifying the nonfluent/agrammatic variant of PPA.

Amyloid PET imaging in multiple sclerosis: an (18)F-florbetaben study.

BACKGROUND: Positron emission tomography (PET) images with amyloid tracers show normal uptake in healthy white matter, which suggests that amyloid tracers are potentially useful for studying such white matter diseases as multiple sclerosis (MS). METHODS: Twelve patients diagnosed with MS (5 with RRMS, 5 with SPMS, and 2 with PPMS) and 3 healthy controls underwent studies with MRI and (18)F-florbetaben-PET imaging. Images were preprocessed using Statistical Parametric Mapping software. We analysed (18)F-florbetaben uptake in demyelinating plaques (appearing as hyperintense lesions in FLAIR sequences), in normal-appearing white matter, and in grey matter. RESULTS: Mean standardized uptake value relative to cerebellum was higher in normally appearing white matter (NAWM) (1.51 ± 0.12) than in damaged white matter (DWM) (1.24 ± 0.12; P = .002). Mean percentage of change between NAWM and DWM was -17.56% ± 6.22%. This percentage of change correlated negatively with EDSS scores (r = -0.61, p < .05) and with age (r = -0.83, p < 0.01). Progressive forms of MS showed a more pronounced reduction of the uptake in DWM in comparison to relapsing-remitting form. CONCLUSIONS: Uptake of (18)F-florbetaben in damaged white matter is lower than that occurring in normally-appearing white matter. These findings indicate that amyloid tracers may be useful in studies of MS, although further research is needed to evaluate the utility of amyloid-PET in monitoring MS progression.

Evaluation of the new consensus criteria for the diagnosis of primary progressive aphasia using fluorodeoxyglucose positron emission tomography.

BACKGROUND: New consensus criteria have been proposed to classify primary progressive aphasia (PPA) into three variants: agrammatic, semantic, and logopenic. Some studies have subsequently addressed the usefulness of these criteria, with controversial results. We aimed to determine the correlation between the clinical diagnosis according to the new criteria and brain topography in (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET). METHODS: Patients meeting the PPA criteria were prospectively recruited in a single center during a period of 18 months. They were clinically classified according to the new criteria and underwent FDG-PET. The cerebral metabolism of each patient was compared to a healthy control group using statistical parametric mapping. The expected variant according to the analysis of PET imaging was compared with the clinical diagnosis using the consensus criteria. RESULTS: 32 patients were included. 90% of them fulfilled the consensus criteria and could be classified into one of the three clinical variants. The correlation with the cerebral metabolism was high: the kappa index was 0.91 in the agrammatic variant, 0.71 in the semantic variant, and 0.74 in the logopenic variant. CONCLUSIONS: A high correlation with the diagnosis obtained using FDG-PET was found. However, an overdiagnosis of the logopenic variant was observed. These results support the use of the new criteria, but some modifications or complementary studies may still be necessary.

Mirrored-self misidentification in a patient without dementia: evidence for right hemispheric and bifrontal damage.

Mirrored-self misidentification, often referred as the 'mirror sign', is a delusion characterized by the inability to recognize one's own reflected image, often associated with the intact capacity to recognize others in the mirror. It has been described mainly in moderate or severe dementia, especially Alzheimer's disease. In the few reported cases without global cognitive impairment, right hemispheric and frontal dysfunctions have been described. We report a 90-year-old man with abrupt onset of the mirror sign after a minor right hemispheric ischemic stroke. Neuropsychological testing revealed preserved cognitive capacities, except for mild to moderate impairment of visuospatial skills, suggesting right hemisphere dysfunction. Neuroimaging showed a small right dorsolateral frontal infarct, and bifrontal encephalomalacia, consistent with a past history of head trauma. Scattered ischemic white matter lesions in posterior periventricular regions were also seen. It seems that the mirror sign is a multifactorial phenomenon that usually requires right hemispheric dysfunction (perceptual abnormalities, loss of familiarity) and frontal damage (loss of judgement and inability to correct wrong beliefs). The right frontal dorsolateral prefrontal cortex seems to have a crucial role in self-recognition.

Development, Spanish Normative Data, and Validation of a Social Cognition Battery in Prodromal Alzheimer's Disease and Multiple Sclerosis.

OBJECTIVES: The assessment of social cognition changes may be challenging, especially in the earliest stages of some neurodegenerative diseases. Our objective was to validate a social cognition battery from a multidomain perspective. In this regard, we aimed to adapt several tests, collect normative data, and validate them in prodromal Alzheimer's disease (AD) and multiple sclerosis (MS). METHODS: A total of 92 healthy controls, 25 prodromal AD, and 39 MS patients were enrolled. Age-, gender-, and education-matched control groups were created for comparisons. Social cognition battery was composed of an emotion-labeling task developed from FACES database, the Story-based Empathy test (SET), the Faux Pas test, and the Interpersonal Reactivity Index. Patients were also evaluated with a comprehensive cognitive battery to evaluate the other cognitive domains. Automatic linear modeling was used to predict each social cognition test's performance using the neuropsychological tests examining other cognitive domains. RESULTS: The reliability of the battery was moderate-high. Significant intergroup differences were found with medium-large effect sizes. Moderate correlations were found between social cognition battery and neuropsychological tests. The emotion labeling task and SET showed moderate correlations with age and education, and age, respectively. Regression-based norms were created considering the relevant demographic variables. Linear regression models including other neuropsychological tests explained between 7.7% and 68.8% of the variance of the social cognition tests performance. CONCLUSIONS: Our study provides a battery for the assessment of social cognition in prodromal AD and MS with Spanish normative data to improve the evaluation in clinical and research settings.

Memory Impairment in Relapsing-Remitting Multiple Sclerosis Using a Challenging Semantic Interference Task.

Objective: Episodic memory is frequently impaired in Multiple Sclerosis (MS), but the cognitive characteristics and neuropsychological processes involved remain controversial. Our aim was to study episodic memory dysfunction in MS, using the LASSI-L, a novel memory-based cognitive stress test that uses a new paradigm that capitalizes on semantic interference. Methods: Cross-sectional study in which 93 patients with MS (relapsing-remitting) and 124 healthy controls were included. The LASSI-L test was administered to all participants, as well as a comprehensive neuropsychological battery including a selective reminding test. MS patients were divided into two groups, with cognitive impairment (CI-MS) and cognitively preserved (CP-MS). Results: Reliability of the LASSI-L test was high (Cronbach's alpha 0.892) and there were less ceiling effects. MS patients scored lower than controls on all LASSI-L subtests, except for maximum storage of the initial target items (CRA2). Effect sizes were moderate-large. A delay in learning, difficulties in retroactive semantic interference, failure to recover from proactive semantic interference, and delayed recall were the most frequent findings in MS patients. Scores associated with maximum storage capacity, and retroactive semantic interference were the most strongly associated with cognitive impairment and employment status. Conclusion: We found that deficits in maximum learning, difficulties in recovery from the effects of proactive semantic interference and retroactive semantic interference are three important breakdowns in episodic memory deficits among patients with MS. The LASSI-L showed good psychometric and diagnostic properties. Overall, our study supports the utility of the LASSI-L, as a new cognitive test, useful for neuropsychological assessment in MS in clinical and research settings.

Amyloid PET findings in multiple sclerosis are associated with cognitive decline at 18 months.

OBJECTIVE: To study the clinical, cognitive, and radiological progression of a cohort of patients with MS, taking into account the amyloid PET with 18F-florbetaben analyses. METHODS: Twenty-nine patients with MS were assessed with longitudinal structural MRI and a clinical and comprehensive neuropsychological protocol, with a mean interval between assessments of 18 ± 3.31 months. 18F-florbetaben PET was performed at baseline. Uptake was analysed in demyelinating plaques (DWM) and normal-appearing white matter (NAWM). Results were correlated with clinical, cognitive and MRI data. RESULTS: Patients with cognitive decline over the follow-up period showed a lower standardised uptake value ratio in NAWM and lower thalamic volume and a higher lesion load in the baseline MRI. Myelin status was correlated with EDSS and cognitive tests mainly evaluating visuospatial function and working memory. Lower uptake in NAWM at baseline was also associated with a growth in white matter lesion volume over time. CONCLUSIONS: Lower white matter uptake in amyloid PET is associated with cognitive decline and an increase in white matter lesion volume during the follow-up. Our study suggests that 18F-florbetaben may be a useful biomarker in assessing myelin status in MS, understanding MS pathophysiology, and predicting cognitive outcomes.

Reading prosody in the non-fluent and logopenic variants of primary progressive aphasia.

BACKGROUND: Primary progressive aphasia (PPA) is a clinical syndrome including a group of neurodegenerative disorders that present with language impairment. We hypothesised that impairment in reading prosody may be present in a subgroup of patients with PPA, and particularly non-fluent PPA (nfvPPA), because of the impairment of key brain regions involved in the pathophysiology of speech dysprosody and reading observed in these patients. METHODS: Ninety-five participants were evaluated using a narrative text comprising several declarative, exclamatory, and interrogative sentences, as well as a comprehensive language protocol. Patients were also examined with 18F-fluorodeoxyglucose positron emission tomography imaging. RESULTS: Impairment was more frequent and more severe in patients with nfvPPA, especially in the subgroup of patients with Apraxia of Speech (AOS). Patients with nfvPPA, mainly those with AOS, showed lower values in several pitch variables. Statistically significant differences were also observed in sentence duration, reading times, and types of error. A regression model including mean length of utterances, time after full stops, number of pauses, and number of pitch variables below the mean, correctly classified 70-71.3% of patients. When combined with sentence repetition task, the percentage of patients correctly classified was 96.2% and 92.4%, respectively, for each classification. The left frontal lobe was the region most strongly correlated with reading prosody parameters. Specific tasks displayed additional correlations with the left parietal and occipital lobes; right frontal lobe, thalamus, and caudate; and right cerebellum. CONCLUSION: Reading prosody is relevant in PPA diagnosis and classification. Because reading prosody may be quantified, it is amenable to use in diagnosis and follow-up. We found neuroimaging correlation with metabolism in the left frontal lobe, as well as in other regions including the right frontal lobe, basal ganglia, and cerebellum, which suggests that these may be the main brain regions involved in prosodic control in patients with PPA.

Machine learning in the clinical and language characterisation of primary progressive aphasia variants.

INTRODUCTION: Primary progressive aphasia (PPA) is a clinical syndrome of neurodegenerative origin with 3 main variants: non-fluent, semantic, and logopenic. However, there is some controversy about the existence of additional subtypes. Our aim was to study the language and cognitive features associated with a new proposed classification for PPA. MATERIAL AND METHODS: Sixty-eight patients with PPA in early stages of the disease and 20 healthy controls were assessed with a comprehensive language and cognitive protocol. They were also evaluated with 18F-FDG positron emision tomography (PET). Patients were classified according to FDG PET regional metabolism, using our previously developed algorithm based on a hierarchical agglomerative cluster analysis with Ward's linkage method. Five variants were found, with both the non-fluent and logopenic variants being split into 2 subtypes. Machine learning techniques were used to predict each variant according to language assessment results. RESULTS: Non-fluent type 1 was associated with poorer performance in repetition of sentences and reading of irregular words than non-fluent type 2. Conversely, the second group showed a higher degree of apraxia of speech. Patients with logopenic variant type 1 performed more poorly on action naming than patients with logopenic type 2. Language assessments were predictive of PET-based subtypes in 86%-89% of cases using clustering analysis and principal components analysis. CONCLUSIONS: Our study supports the existence of 5 variants of PPA. These variants show some differences in language and FDG PET imaging characteristics. Machine learning algorithms using language test data were able to predict each of the 5 PPA variants with a relatively high degree of accuracy, and enable the possibility of automated, machine-aided diagnosis of PPA variants.

Plasma Neurofilament Light Chain in Primary Progressive Aphasia and Related Disorders: Clinical Significance and Metabolic Correlates.

BACKGROUND: Primary progressive aphasia (PPA) is a heterogeneous syndrome that is difficult to diagnose at early stages. Plasma neurofilament light chain (NFL) has been proposed as a potential biomarker for PPA. OBJECTIVE: To examine the diagnostic properties of plasma NFL in PPA and to evaluate its association with clinical stages of the disease and brain metabolism. METHODS: Our study included 80 participants (13 with non-fluent, 12 with semantic, and 16 with logopenic variant PPA; 13 with amnestic Alzheimer's disease [AD]; 13 with behavioral variant frontotemporal dementia; and 13 healthy controls). Plasma NFL concentration was measured using a high-sensitivity enzyme-linked immunosorbent assay (ELISA) kit. PET imaging was performed in a subgroup of patients. RESULTS: NFL discriminated patients from controls with an area under the curve of 0.914 (95% CI, 0.843-0.984; p < 0.001) (cut-off: 76.46 pg/mL; 94% sensitivity, 76.9% specificity). There were no significant differences between clinical syndromes (PPA subtypes), the main clinical forms of dementia (frontotemporal dementia and AD), or the expected pathological groups (frontotemporal lobar degeneration-tau [FTLD-tau], FTLD-TDP43, and AD). NFL levels showed weak to moderate correlations with age and functional scale score. We found no significant correlation with the extent of hypometabolism observed on FDG-PET images. CONCLUSION: Plasma NFL is a non-specific marker of neurodegeneration, and may be helpful in the diagnosis of PPA. However, NFL does not permit differential diagnosis between PPA subtypes and is not correlated with the extent of neurodegeneration.