Inter-hemispheric EEG coherence analysis in Parkinson's disease : Assessing brain activity during emotion processing

Parkinson’s disease (PD) is not only characterized by its prominent motor symptoms but also associated with disturbances in cognitive and emotional functioning. The objective of the present study was to investigate the influence of emotion processing on inter-hemispheric electroencephalography (EEG) coherence in PD. Multimodal emotional stimuli (happiness, sadness, fear, anger, surprise, and disgust) were presented to 20 PD patients and 30 age-, education level-, and gender-matched healthy controls (HC) while EEG was recorded. Inter-hemispheric coherence was computed from seven homologous EEG electrode pairs (AF3–AF4, F7–F8, F3–F4, FC5–FC6, T7–T8, P7–P8, and O1–O2) for delta, theta, alpha, beta, and gamma frequency bands. In addition, subjective ratings were obtained for a representative of emotional stimuli. Interhemispherically, PD patients showed significantly lower coherence in theta, alpha, beta, and gamma frequency bands than HC during emotion processing. No significant changes were found in the delta frequency band coherence. We also found that PD patients were more impaired in recognizing negative emotions (sadness, fear, anger, and disgust) than relatively positive emotions (happiness and surprise). Behaviorally, PD patients did not show impairment in emotion recognition as measured by subjective ratings. These findings suggest that PD patients may have an impairment of inter-hemispheric functional connectivity (i.e., a decline in cortical connectivity) during emotion processing. This study may increase the awareness of EEG emotional response studies in clinical practice to uncover potential neurophysiologic abnormalities

Cognition in Multiple sclerosis with special emphasis on MRI findings and cerebrosterol

Multiple sclerosis (MS) is a progressive inflammatory and degenerative disease of the central nervous system (CNS). This thesis focuses on cognition in MS, with special emphasis on long-term magnetic resonance imaging (MRI) findings and cerebrosterol plasma levels. In study I, the effects of MS on a variety of cognitive aspects were evaluated longitudinally over an eight-year follow-up period in 31 patients who had been diagnosed as having relapsing-remitting MS, secondary progressive MS (SP-MS) or primary progressive MS. A selective pattern of decline was found at baseline in the whole group, with marked decline in information-processing speed (IPS). These deficits in IPS at baseline predicted further cognitive decline over the follow-up period. A differential pattern of cognitive decline over time was noticed in the subgroups, with the most pronounced decline in the SP-MS group; in these patients, the deterioration in visual IPS was clearly more marked than that in auditory IPS. A high disability score (on the expanded disability status scale; EDSS) during follow-up was associated with cognitive decline. These findings indicate that tests measuring IPS are especially strong predictors of cognitive decline over longer periods in patients with MS. In Study II, 25 patients with MS and 25 matched control participants were tested with a picture-naming test (Boston Naming Test; BNT) and a letter-word fluency test (using the letters FAS). In the BNT, the MS patients used less distinct descriptions and substitutions and had significantly more off-target substitutions than the control group. The MS patients were significantly less effective in using strategies for retrieval in the word fluency FAS test than the control participants. These results suggest that language function becomes impaired in MS, with semantically nonspecific naming responses and less effective use of strategies for retrieval in word fluency. In Study III, 22 MS patients were given tasks investigating IPS, covering the following aspects: cognitive (symbol digit modalities test; SDMT), sensory (visual and auditory reaction time tests), motor (finger-tapping speed test) and auditory interhemispheric transfer (verbal dichotic listening test; VDL). These parameters were related to the area of the corpus callosum in the brain (CCA), measured with MRI at baseline and at follow-up nine years later. The relative brain volume (RBV) and the T2 lesion load were taken into account. The results showed that the CCA, but not the RBV or the T2 lesion load, was associated with the SDMT score, and that the higher the annual rate of change in the CCA, the poorer the performance in the left ear VDL, with a subsequently more pronounced advantage in the right ear VDL. These results indicate that corpus callosum is related to a clearly cognitive component, rather than a sensory-motor component. Study IV analyzed the relationships between cognitively demanding information processing (measured with the SDMT), clinical status (EDSS), plasma cerebrosterol 24OHC levels, and MRI-normalized measurement of RBV, grey and white matter volumes, and ventricular cerebrospinal fluid volume in a cross-sectional sample of 21 MS patients. The results showed that slow IPS in SDMT was related to neurodegeneration, particularly loss of grey matter volume, and high cerebrosterol plasma concentrations, reflecting membrane turnover in the CNS. Poor EDSS was associated with high plasma cerebrosterol levels, which is hypothetically a biomarker of MS progression. Conclusions: Deterioration in IPS seems to be a central aspect of cognitive decline in MS. Slow IPS occurs already at an early phase in the disease and predicts long term cognitive decline. The MS patients have less effective strategies for lexical substitution and retrieval than healthy persons. The poor lexical processing in the MS patients could putatively be due to slow IPS, especially in the markedly speed demanding word fluency test. CCA in contrast to RBV and the T2 lesion load, appears to be exclusively related to a cognitively demanding IPS task but not to sensory-motor speed tasks, which suggests that CC is especially important for cognitive speed processes. Slow IPS seems to be primarily associated with low grey matter volume and high plasma concentration level of cerebrosterol while disability appears to be related to high plasma level of cerebrosterol. Since there were no interaction between cerebrosterol and the neurodegenerative predictors, it is putative that the cytotoxic properties of the cerebrosterol independently could cause neuronal cell death and thereby affect IPS independently of neurodegeneration

Euphoria in multiple sclerosis: an investigation of constructs and symptons

Includes bibliographical references.In multiple sclerosis (MS), some patients are said to present with unawareness of deficit, and positive mood and optimism that is out of place or incongruous given the patient's circumstances. The history of these symptoms, collectively known as euphoria, however, is characterised by marked inconsistencies regarding a number of aspects of these symptoms. This research attempted to investigate both the constructs, and the symptoms themselves, with the aim of better defining and broadening our understanding of euphoria. Results revealed that a change in the definition of euphoria appears to have occurred since the concept was introduced by Cottrell and Wilson. Different operational definitions appear to be partly responsible for the very different incidence rates reported throughout the literature. Instead of the classical three types of euphoria identified by the classical authors, or the single type utilised in the contemporary literature, the current research revealed two types of euphoria in MS (viz. positivity and unawareness). Positivity appears to be a subjective mood/outlook experienced by the patient and not an outward façade projected by the euphoric individual, and was defined in fairly subtle terms. Unawareness appears to relate to a number of domains (including physical, cognitive and mood or behavioural deficits), and was measured via participant/informant discrepancies on self-report questionnaires. Both positivity and unawareness were represented on a continuum and appeared to have different demographic, disease and cognitive correlates. Positivity was significantly predicted by a medical history of conditions that can affect neuropsychological functioning. Unawareness of physical deficits was associated with a female gender, a younger age, a lower income, relapsing-remitting course, a current disease state of relapse or exacerbation, a shorter disease duration, but a greater disease severity in terms of physical disability. Severity of the disease and the cognitive composite representing cognitive functions sub-served by the orbitobasal frontal cortex were also significant individual predictors of unawareness of physical deficits. Visuospatial ability significantly predicted unawareness of cognitive deficits. No demographic, disease or cognitive correlates of unawareness of mood or behavioural deficits were identified. Finally, no indisputable single cause underlying the two types of euphoria in MS identified by this research was isolated by the exploratory investigations undertaken; however interesting preliminary findings that may tentatively implicate executive dysfunction as well as, possibly, immunological disease processes in the etiology of euphoria in MS were revealed. These results have broadened our understanding of euphoria in MS and may shape both the research and clinical work with euphoric patients going forward

Diagnostic and prognostic aspects of clinical brain dopamine transporter imaging in parkinsonism

Idiopathic Parkinson’s disease (PD) is the most frequent cause of clinical parkinsonism. However, the diagnostic accuracy of PD is suboptimal. One biomarker that assists with the parkinsonism differential diagnostics is functional dopamine transporter (DAT) imaging. The accuracy of DAT single photon emission computed tomography (SPECT) imaging is high for detecting striatal dopamine deficiency associated with neurodegenerative parkinsonism. However, its limitations and associations with clinical characteristics are not yet fully understood, particularly in patients with clinical parkinsonism of uncertain origin. In this thesis, the retrospective studies investigated the associations between striatal dopamine deficiency and structural midbrain atrophy measurements and long-term survival in PD patients. As both visual and semi-quantitative analysis methods are broadly used for DAT SPECT scans, the concordance between these methods was investigated. The cross-sectional clinical and imaging study investigated which of the parkinsonian motor signs are associated with a higher likelihood of striatal DAT deficiency, and whether these signs are associated with DAT loss in certain striatal regions in patients with neurodegenerative parkinsonism. The results showed that there were no associations between the midbrain-to-pons ratios, suggestive of midbrain atrophy, and striatal dopamine deficiency in DP. Expert visual DAT image analyses and the semi-quantitative analyses did not match in 10% of cases; however, none of these patients had neurodegenerative parkinsonism according to the clinical follow-ups. The level of DAT deficiency was not associated with survival in PD. Finally, both upper extremity rigidity and hypomimia were independently associated with a higher likelihood of striatal dopamine deficiency. Hypomimia was specifically associated with caudate nucleus dopamine loss in patients with abnormal striatal DAT binding. The results indicate that midbrain-to-pons ratios cannot be used to estimate the level of striatal DAT deficiency in patients with PD. The scans that showed a discrepancy between the different analysis methods should likely be interpreted as normal. Dopamine deficiency levels cannot be used to predict patient survival in PD. Presence of upper extremity rigidity and hypomimia in clinical neurological examinations may be useful markers in the differential diagnosis of clinically uncertain parkinsonism and tremor as they point to striatal DAT deficiency

Inter-Cohort Validation of SuStaIn Model for Alzheimer's Disease

Alzheimer's disease (AD) is a neurodegenerative disorder which spans several years from preclinical manifestations to dementia. In recent years, interest in the application of machine learning (ML) algorithms to personalized medicine has grown considerably, and a major challenge that such models face is the transferability from the research settings to clinical practice. The objective of this work was to demonstrate the transferability of the Subtype and Stage Inference (SuStaIn) model from well-characterized research data set, employed as training set, to independent less-structured and heterogeneous test sets representative of the clinical setting. The training set was composed of MRI data of 1043 subjects from the Alzheimer's disease Neuroimaging Initiative (ADNI), and the test set was composed of data from 767 subjects from OASIS, Pharma-Cog, and ViTA clinical datasets. Both sets included subjects covering the entire spectrum of AD, and for both sets volumes of relevant brain regions were derived from T1-3D MRI scans processed with Freesurfer v5.3 cross-sectional stream. In order to assess the predictive value of the model, subpopulations of subjects with stable mild cognitive impairment (MCI) and MCIs that progressed to AD dementia (pMCI) were identified in both sets. SuStaIn identified three disease subtypes, of which the most prevalent corresponded to the typical atrophy pattern of AD. The other SuStaIn subtypes exhibited similarities with the previously defined hippocampal sparing and limbic predominant atrophy patterns of AD. Subject subtyping proved to be consistent in time for all cohorts and the staging provided by the model was correlated with cognitive performance. Classification of subjects on the basis of a combination of SuStaIn subtype and stage, mini mental state examination and amyloid-β1-42 cerebrospinal fluid concentration was proven to predict conversion from MCI to AD dementia on par with other novel statistical algorithms, with ROC curves that were not statistically different for the training and test sets and with area under curve respectively equal to 0.77 and 0.76. This study proves the transferability of a SuStaIn model for AD from research data to less-structured clinical cohorts, and indicates transferability to the clinical setting

Use of the Modified Visual Magnetic Resonance Rating Scale in alzheimer’s disease and ıts correlation with cognitive decline

Amaç: Alzheimer hastalığı (AH) araştırmaları için daha ileri nörogörüntüleme teknikleri geliştirilmiş olsa da, yapısal manyetik rezonans görüntüleme (MRG) AH’nin klinik tanısında önemini korumaktadır. Birçok parametreyi değerlendiren kapsamlı görsel MRG derecelendirme ölçeklerinin, hastalığın kognitif ve davranışsal görünümleriyle ilişkisi yeterince araştırılmamıştır. Bu çalışmada, Modifiye Görsel Manyetik Rezonans Derecelendirme Skalası’nın (MGMRDS) 7 alt bölümünün, AH tanısı almış hastaların demografik, kognitif ve davranışsal verileri ile korelasyonunu değerlendirmek amaçlanmıştır. Gereç ve Yöntemler: Retrospektif çalışmamıza beyin MRG ve nöropsikometrik test (NPT) verileri olan, Ruhsal Bozuklukların Tanısal ve Sayımsal Elkitabı (DSM-IV-TR) ölçütleri ile Ulusal Nörolojik ve İletişimsel Bozukluklar ve İnme Enstitüsü & Alzheimer Hastalığı ve İlişkili Bozukluklar Derneği (NINCDS–ADRDA) kriterleri temelinde AH tanısı almış, 50 yaş ve üzeri toplam 42 hasta dahil edildi. Beyin MRG verileri, hasta yaş, cinsiyet ve tanı verilerine kör bir nöroradyolog tarafından MGMRDS kullanılarak değerlendirildi. MGMRDS verilerinin kognitif ve davranışsal test sonuçlarıyla korelasyonu incelendi. Bulgular: Hastaların %61,9’u kadın, yaş ortalaması 75,19±9,26 (53–92) yıl idi. Ortalama eğitim süresi 5,02±4,84 (0–15) yıl, ortalama hastalık süresi 4,52±2,94 yıldı. Ortalama Mini Mental Durum Testi skoru 18,51±5,43 (4–30) iken, ortalama Klinik Demans Derecelendirmesi (KDD) skoru 1,07±0,42 (0,5–2,0) idi. Sulkal atrofi puanları uzun süreli hatırlama ve yüz tanıma ile negatif korele idi; ventriküler atrofi skorları ise öğrenme puanları, meyve–insan ve yüz tanıma değişkenleri ile ters korelasyon gösterdi. Anlık hatırlama, öğrenme puanı, kendiliğinden hatırlama, meyve–insan ve KDD değişkenleri ile mediyal temporal atrofi değişkeni arasında anlamlı ilişki gözlendi. Tartışma ve Sonuç: Beyin MRG’ye dayalı görsel derecelendirme skalaları kullanmak, demans değerlendirmelerinde tanıyı doğrulayıcı, ucuz ve pratik bir yaklaşımdır. MGMRDS, kognitif (yürütücü işlevler, bellek, dikkat, dil) verilerle de anlamlı korelasyon göstermektedir. Bu ölçeği daha geniş hasta gruplarında değişik kognitif bozukluklarda değerlendirecek çalışmalar klinik açıdan faydalı olacaktır.Aim: Although more advanced neuroimaging techniques have been developed for research on Alzheimer’s disease (AD), structural magnetic resonance imaging (MRI) remains important in the clinical diagnosis of AD. The relationship between comprehensive MRI visual rating scales evaluating many parameters and cognitive and behavioral appearances of the disease has not been adequately investigated. In this study, we aimed to evaluate the correlation of the 7 subsections of the Modified Visual Magnetic Resonance Rating Scale (MVMRRS) with demographic, cognitive, and behavioral characteristics of patients diagnosed with AD. Materials and Methods: The retrospective study included a total of 42 patients aged 50 years and older whose brain MRI and neuropsychometric test results were available and who were diagnosed with AD according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSMIV-TR) and of the National Institute of Neurological and Communicative Disorders and Stroke & the Alzheimer’s Disease and Related Disorders Association (NINCDS–ADRDA). By use of the Modified Visual Magnetic Resonance Rating Scale (MVMRRS), the brain MRI data were evaluated by a neuroradiologist blinded to the patient age, sex, and diagnosis data. Correlation of MVMRRS data with cognitive and behavioral test results was analyzed. Results: The mean patient age was 75.19±9.26 (53–92) years and 61.9% of all patients were female. The mean education level was 5.02±4.84 (0–15) years and the mean illness duration was 4.52±2.94 years. The mean Mini-Mental State Examination score was 18.51±5.43 (4–30) while the mean Clinical Dementia Rating (CDR) score was 1.07±0.42 (0.5–2.0). Sulcal atrophy scores were negatively correlated with longterm recall and facial recognition while ventricular atrophy scores were inversely correlated with the learning scores and fruit–human and facial recognition parameters. A significant relationship was observed between the immediate recall, learning score, spontaneous recall, fruit–human, and CDR variables and the medial temporal atrophy variable. Discussion and Conclusion: In dementia assessment, the use of MRI-based visual rating scales is an inexpensive and practical approach that also improves the diagnostic accuracy. Furthermore, the MVMRRS shows significant correlation with cognitive (executive functions, memory, attention, and language) data. Further studies to evaluate this scale in larger groups of patients with different patterns of cognitive impairment would be of clinical benefit

Memory Performance in Children with Temporal Lobe Epilepsy: Neocortical vs. Dual Pathologies

This study investigated memory in children with temporal lobe epilepsy and the ability to discern hippocampal dysfunction with conventional memory tests that are typically used to detect more global memory impairment. All data was obtained retrospectively from the epilepsy surgery program at a local children’s hospital. The research population consisted of 54 children with intractable epilepsy of temporal onset, balanced across pathology types (with and without hippocampal disease) and other demographics. Each was given a clinical battery prior to surgical intervention, which included the WRAML/WRAML2 Verbal Learning subtest from which the dependent variables for this study were extracted. The research hypothesis had predicted that memory retention between verbal learning and recall would be worse for participants with pathology that included hippocampal sclerosis than for those with non-hippocampal temporal lobe pathology. A two-way mixed-design ANOVA was used to test the hypothesis, which allowed incorporation of variables of interest related to memory factors, pathology type, and hemispheric laterality, as well as their various interactions. There was a significant main effect for change in the number of words retained from the final learning trial to the delayed recall. Although the interaction between memory retention and pathology type was not statistically significant, the average of the memory scores as it related to pathology by side did show significance. Thus, results did not support the hypothetical relationship between retention and hippocampal function. However, additional exploratory analyses revealed that the final learning trial by itself was associated with hippocampal pathology, which applied only to those participants with left-hemisphere lesions. Logistic regression with the final learning trial correctly classified 74 percent of participants into the appropriate pathology category, with 81 percent sensitivity to hippocampal dysfunction. Mean participant memory scores were nearly one standard deviation below the normative mean for both delayed recall and total learning scaled scores, regardless of pathology type or lesion hemisphericity. Thus, while the conventionally used indices of the WRAML Verbal Learning test are useful for determining overall memory status, they are not specific to pathological substrate. The within-subject main effect showed an expected loss of information across the time of the delay, but overall the recall score showed no association with hippocampal functioning. This study revealed the possibility of measuring hippocampal function at statistically significant group levels using learning scores from a widely used measure of verbal memory, even in participants with intact contralateral mesial temporal structures. It also indicated that hippocampal structures do not play a role during recall measures given after a standard time delay. Data further demonstrated a role of the hippocampus for encoding and transferring information beyond short term/working memory into long term. During the learning process, the hippocampus appears to work in concert with short-term memory systems, but does not take over the encoding process until enough repetitions have occurred to saturate the working memory buffer. This research represents a small, yet important step forward in our understanding of the hippocampus, with potentially important implications for the future study of memory constructs and mensuration

Huntington disease: natural history, biomarkers and prospects for therapeutics

Huntington disease (HD) can be seen as a model neurodegenerative disorder, in that it is caused by a single genetic mutation and is amenable to predictive genetic testing, with estimation of years to predicted onset, enabling the entire range of disease natural history to be studied. Structural neuroimaging biomarkers show that progressive regional brain atrophy begins many years before the emergence of diagnosable signs and symptoms of HD, and continues steadily during the symptomatic or 'manifest' period. The continued development of functional, neurochemical and other biomarkers raises hopes that these biomarkers might be useful for future trials of disease-modifying therapeutics to delay the onset and slow the progression of HD. Such advances could herald a new era of personalized preventive therapeutics. We describe the natural history of HD, including the timing of emergence of motor, cognitive and emotional impairments, and the techniques that are used to assess these features. Building on this information, we review recent progress in the development of biomarkers for HD, and potential future roles of these biomarkers in clinical trials