The thalamus as a putative biomarker in neurodegenerative disorders

Objective: This review provides a brief account of the clinically relevant functional neuroanatomy of the thalamus, before considering the utility of various modalities utilised to image the thalamus and technical challenges therein, and going on to provide an overview of studies utilising structural imaging techniques to map thalamic morphology in the spectrum of neurodegenerative disorders. Methods: A systematic search was conducted for peer-reviewed studies involving structural neuroimaging modalities investigating the morphology (shape and/ or size) of the thalamus in the spectrum of neurodegenerative disorders. Results: Whilst the precise role of the thalamus in the healthy brain remains unclear, there is a large body of knowledge accumulating which defines more precisely its functional connectivity within the connectome, and a burgeoning literature implicating its involvement in neurodegenerative disorders. It is proposed that correlation of clinical features with thalamic morphology (as a component of a quantifiable subcortical connectome) will provide a better understanding of neuropsychiatric dysfunction in various neurodegenerative disorders, potentially yielding clinically useful endophenotypes and disease biomarkers. Conclusions: Thalamic biomarkers in the neurodegenerative disorders have great potential to provide clinically meaningful knowledge regarding not only disease onset and progression, but may yield targets of and perhaps a way of gauging response to future disease-modifying modalities

Deep gray matter atrophy in multiple sclerosis: a tensor based morphometry.

Tensor based morphometry (TBM) was applied to determine the atrophy of deep gray matter (DGM) structures in 88 relapsing multiple sclerosis (MS) patients. For group analysis of atrophy, an unbiased atlas was constructed from 20 normal brains. The MS brain images were co-registered with the unbiased atlas using a symmetric inverse consistent nonlinear registration. These studies demonstrate significant atrophy of thalamus, caudate nucleus, and putamen even at a modest clinical disability, as assessed by the expanded disability status score (EDSS). A significant correlation between atrophy and EDSS was observed for different DGM structures: (thalamus: r=-0.51, p=3.85 x 10(-7); caudate nucleus: r=-0.43, p=2.35 x 10(-5); putamen: r=-0.36, p=6.12 x 10(-6)). Atrophy of these structures also correlated with 1) T2 hyperintense lesion volumes (thalamus: r=-0.56, p=9.96 x 10(-9); caudate nucleus: r=-0.31, p=3.10 x 10(-3); putamen: r=-0.50, p=6.06 x 10(-7)), 2) T1 hypointense lesion volumes (thalamus: r=-0.61, p=2.29 x 10(-10); caudate nucleus: r=-0.35, p=9.51 x 10(-4); putamen: r=-0.43, p=3.51 x 10(-5)), and 3) normalized CSF volume (thalamus: r=-0.66, p=3.55 x 10(-12); caudate nucleus: r=-0.52, p=2.31 x 10(-7), and putamen: r=-0.66, r=2.13 x 10(-12)). More severe atrophy was observed mainly in thalamus at higher EDSS. These studies appear to suggest a link between the white matter damage and DGM atrophy in MS

Gray Matter Changes in Parkinson's and Alzheimer's Disease and Relation to Cognition

Purpose of Review We summarize structural (s)MRI findings of gray matter (GM) atrophy related to cognitive impairment in Alzheimer's disease (AD) and Parkinson's disease (PD) in light of new analytical approaches and recent longitudinal studies results. Recent Findings The hippocampus-to-cortex ratio seems to be the best sMRI biomarker to discriminate between various AD subtypes, following the spatial distribution of tau pathology, and predict rate of cognitive decline. PD is clinically far more variable than AD, with heterogeneous underlying brain pathology. Novel multivariate approaches have been used to describe patterns of early subcortical and cortical changes that relate to more malignant courses of PD. New emerging analytical approaches that combine structural MRI data with clinical and other biomarker outcomes hold promise for detecting specific GM changes in the early stages of PD and preclinical AD that may predict mild cognitive impairment and dementia conversion

Disrupted cerebral metabolite levels and lower nadir CD4+ counts are linked to brain volume deficits in 210 HIV-infected patients on stable treatmentpatients on stable treatment

AbstractCognitive impairment and brain injury are common in people with HIV/AIDS, even when viral replication is effectively suppressed with combined antiretroviral therapies (cART). Metabolic and structural abnormalities may promote cognitive decline, but we know little about how these measures relate in people on stable cART. Here we used tensor-based morphometry (TBM) to reveal the 3D profile of regional brain volume variations in 210 HIV+ patients scanned with whole-brain MRI at 1.5T (mean age: 48.6±8.4years; all receiving cART). We identified brain regions where the degree of atrophy was related to HIV clinical measures and cerebral metabolite levels assessed with magnetic resonance spectroscopy (MRS). Regional brain volume reduction was linked to lower nadir CD4+ count, with a 1–2% white matter volume reduction for each 25-point reduction in nadir CD4+. Even so, brain volume measured by TBM showed no detectable association with current CD4+ count, AIDS Dementia Complex (ADC) stage, HIV RNA load in plasma or cerebrospinal fluid (CSF), duration of HIV infection, antiretroviral CNS penetration-effectiveness (CPE) scores, or years on cART, after controlling for demographic factors, and for multiple comparisons. Elevated glutamate and glutamine (Glx) and lower N-acetylaspartate (NAA) in the frontal white matter, basal ganglia, and mid frontal cortex — were associated with lower white matter, putamen and thalamus volumes, and ventricular and CSF space expansion. Reductions in brain volumes in the setting of chronic and stable disease are strongly linked to a history of immunosuppression, suggesting that delays in initiating cART may result in imminent and irreversible brain damage

Clinical Characteristics and Neuroanatomical Predictors of Acute Antidepressant Outcome for Patients with Comorbid Depression and Mild Cognitive Impairment

Background: Older adults presenting with both a depressive disorder (DEP) and cognitive impairment (CI) represent a unique, understudied population. The classification of cognitive impairment severity continues to be debated though it has recently been subtyped into late (LMCI) versus early (EMCI) stages. Previous studies have found associations between treatment outcome and both cortical thickness and white matter hyperintensities (WMH), though report inconsistent directionality and affected regions. In this study, we examined baseline clinical characteristics and neuroanatomical features as prognostic indicators for older adults with comorbid DEP and CI participating in an open antidepressant trial. EMCI is hypothesized to have greater cortical thickness and global cognition than LMCI. Antidepressant treatment remitters and responders are hypothesized to have greater cortical thickness and lower WMH burden than non-remitters and non-responders. Methods: Key inclusion criteria were diagnosis of major depression or dysthymic disorder with Hamilton Depression Rating Scale (HDRS) score \u3e14, and cognitive impairment defined by MMSE score ≥21 and impaired performance on the WMS-R Logical Memory II test. Patients were classified as EMCI or LMCI based on the 1.5 SD cutoff on tests of verbal memory, and compared on baseline clinical, neuropsychological, and anatomical characteristics. All patients underwent a baseline MRI scan and received open antidepressant treatment for 8 weeks. Cortical thickness was extracted using an automated brain segmentation and reconstruction program (FreeSurfer). Vertex-wise analyses were conducted using general linear models to evaluate the relationships between cortical thickness and clinical variables. Results: 79 DEP-CI patients were recruited, of whom 39 met criteria for EMCI and 40 for LMCI. The mean age was 68.9 and mean HDRS was 23.0. LMCI patients had significantly worse global cognition and smaller right hippocampal volume compared to EMCI patients. EMCI patients had thicker right medial orbitofrontal cortex than LMCI. MRI indices of cerebrovascular disease did not differ between MCI subtypes. Remitters had greater deep WMH burden, left medial orbitofrontal gyrus thickness, and right superior frontal gyrus thickness than non-remitters. Greater HDRS depressive severity was positively correlated with right pars triangularis thickness. Stronger ADAS-Cog global cognitive performance was positively correlated with thickness in diffuse cortical areas. Conclusions: Cognitive and neuronal loss markers differed between EMCI and LMCI among patients with DEP-CI, with LMCI being more likely to have the clinical and neuronal loss markers known to be associated with Alzheimer’s disease. Samples of DEP-CI exhibit unique patterns of cortical thickness and WMHs compared to their non-CI peers. Cortical thickness may serve as predictor of treatment remission and relates to both depressive severity and global cognition

Strukturální podklady kognitivního deficitu v zobrazování magnetické rezonance.

Předkládaná dizertační práce se ve své hlavní části zabývá možnostmi detekce strukturálních a difuzních změn v MR zobrazení u pacientů s kognitivním deficitem. V širším kontextu je nejprve zmíněn podklad klinických změn a nálezů při neurozobrazení u pacientů s demencí, a to se zvláštním zaměřením na Alzheimerovu chorobu (ACh) a její diferenciální diagnostiku. Druhá část práce obsahuje čtyři experimentální studie v rámci našeho výzkumu. Hlavním cílem prvních dvou studií bylo získání strukturální a mikrostrukturální informace o neurodegenerativních procesech charakteristických pro ACh - na globální i regionální úrovni. Pro tento účel bylo použito několik komplementárních přístupů se zaměřením především na evaluaci šedé, a následně i bílé hmoty mozku. V následujících částech jsme se zaměřili na popis kontextu mikrostrukturálních změn bílé hmoty u normotenzního hydrocefalu (NPH) a charakteristických vzorců dezintegrace bílé hmoty u epilepsií temporálního laloku (TLE). Nejdůležitějším závěrem, který lze vyvodit z našich studií je, že strukturální a difuzní zobrazování se ukázalo jako užitečné při identifikaci regionálně specifické a disproporcionální ztráty objemu mozku a mikrostruktury u některých patologických procesů, které jsou základem kognitivního zhoršení. Použití několika různých morfometrických...Structural and diffusion imaging patterns that can be evaluated using MRI in patients with cognitive deficits are the central theme of the proposed work. First, the clinical and neuroimaging background of dementias has been reviewed in a broader context, with a special focus on Alzheimer's disease (AD) and differential diagnoses. The second part of this thesis contains four consecutive experimental studies. The primary objective of the first two studies was to obtain structural and microstructural information on the neurodegenerative processes characteristic for AD on global and regional levels. For this purpose, several complementary approaches were used and the focus was shifted from grey to white matter (GM/WM). The following two studies focused on the differential context of WM microstructural alterations in normal pressure hydrocephalus (NPH) and distinctive patterns of WM disintegrity in temporal lobe epilepsy (TLE). The most important conclusion of our studies is that structural and diffusion imaging proved to be useful in identifying regionally specific and disproportionate loss of brain volume and microstructure in several pathological processes underlying cognitive deterioration. The use of distinctive morphometric methods yielded complementary information on AD-related atrophy patterns,...Department of Neurosurgery and Neurooncology First Faculty of Medicine and Central Military HospitalNeurochirurgická a neuroonkologická klinika 1. LF UK a ÚVN1. lékařská fakultaFirst Faculty of Medicin

A study of Clinico-Neuroradiologic Correlation in Patients with Dementia

INTRODUCTION: Dementia is characterized by decline in the cognitive functioning of an individual that significantly affects the quality of life and intrudes into the activity of daily living. The prevalence of dementia is increasing and is on the rise. This is due to the increased longevity that has resulted in increasing proportions of elderly population in whom the prevalence of dementia is higher. Dementia is defined by the DSM 5 criteria as decline from previously established baseline in the at least one of the cognitive domains: Memory and learning, executive function, language, complex attention, social cognition and perceptual motor function and it affects the activities of daily living. The symptoms in these patients do not occur exclusively during delirium and are not explainable by psychiatric disorder. AIM OF THE STUDY: To study the association between clinical deficits in cognitive domains of attention, memory and language in subjects with dementia and the neuroimaging correlates of the corresponding networks. OBJECTIVES: 1. To evaluate clinical deficits in cognitive domains of attention, memory and language in subjects with dementia. 2. To study the neuroimaging findings in subjects of Dementia on MR voxel based morphometry, MR diffusion tensor imaging and 18-Fluorodeoxyglucose Positron Emission Tomography in corresponding networks of attention, language and memory respectively. 3. To determine neuroimaging correlates of deficits in attention, language and memory in subjects with dementia in corresponding networks of attention, language and memory respectively. MATERIALS AND METHODS: Subjects attending dementia and cognitive neurosciences clinic at Rajiv Gandhi Government General Hospital, Chennai (RGGGH) were enrolled in the study. A total of 60 patients and 30 controls were recruited for the study. All the subjects were well informed about the study and the consent forms were obtained prior to the assessments. All the patients in the study underwent clinical examination for establishing the diagnosis of dementia. After the clinical assessment the subjects under investigation underwent four different types of assessments. The assessments include neuropsychological assessments, Voxel based Morphometry, Diffusion Tensor Imaging (for both controls and cases), and FDG-PET (for cases alone). METHODOLOGY: A random sample of 60 patients and 30 age-gender matched controls were selected from dementia and cognitive neurosciences clinic at Rajiv Gandhi Government General Hospital(RGGGH), Chennai during Dec. 2014 – Feb. 2018. The study was approved by Institutional Ethical Committee of Rajiv Gandhi Government General Hospital, Chennai. Neuropsychological tests were performed after obtaining consents from the subjects or caretakers. Patients were selected on the basis of MoCA scores where a case with a MoCA score of below 27 and satisfying the inclusion/exclusion criteria has been treated as a patient and included in the present study. The following clinical assessments were made on each patient: Addenbrooke‘s Cognitive Examination III (ACE III), Wechsler‘s Memory Scale (WMS), Trail Making Test A & B (TMT), Auditory Verbal Learning Test (AVLT) and scores were assessed accordingly. Neuropsychological aspects of both patients and controls were assessed by a single trained clinical psychologist. RESULTS: Before carrying out the major study, a pilot study was conducted taking a random sample of 10 patients and 10 controls. Reliability and validity of the protocols used for carrying out the major study were computed using appropriate statistical tools such as Cronbach‘s alpha for reliability and expert opinion on the validity of the protocols. Reliability analysis was carried out using split half method and the Cronbach alpha for part 1 of the protocol was obtained as 0.913 and for part 2 it was 0.993. The overall reliability of the protocol was 0.937 indicating high reliability of the test schedule used in the present study. CONCLUSIONS: Patients and controls were well differentiated in all the neuro-psychological parameters, MoCA, Addenbrook‘s Cognitive Score, WMS, AVLT, Digit Span, Story Recall, and Complex figure. Patients are found to have low scores in all these aspects compared to controls. Stepwise regression analysis indicates scores in only five parameters, namely attention, memory, AVLT, Digit span, and complex figure are enough to classify a person as having dementia or a normal person with a prediction accuracy of nearly 99 per cent. All these neuro psychological parameters are interrelated to one another. Inter correlations of neuro psychological parameters are very high among patients compared to controls in the present study. Analysis of Diffusion Tensor Imaging indicates that the white matter tract, Superior Longitudinal Fasciculus does not play any major role in attention and language domain. In contrast, Fornix has a major role to play in the memory domain. All the metrics of DTI show significant difference between patients and controls in the white matter tract Fornix on either side of the brain. As far as the DTI metrics are concerned, all the metrics have the same levels on both sides of brain of patients and controls. In most of the white matter tracts, the metrics, RD, MD, and AD are found to be high among patients compared to controls. FA is found to be low among patients in white matter tracts like IFO and Fornix. The analysis of diffusion metrics suggests the varying involvement of the white matter fasciculi of the respective domains. Analysis of FDG PET data indicates that about 70 per cent to 93 per cent of patients have hypometabolism in all the five cortical areas of attention domain- frontal association, posterior cingulate, parietal association, anterior cingulate, and caudate regions on either side of brain. Similarly 77 to 91 per cent of patients have hypometabolism in cortical areas of language domain, frontal association, temporal association and parietal association regions on either side of brain. About 85 to 89 per cent of patients have hypometabolism on either side of anterior cingulate regions. Voxel based Morphometry analysis clearly indicated that the patients and controls are significantly different in the following gray matter hubs of Attention Network : Dorsolateral Prefrontal Cortex, Frontal Eye Field, Occipital Eye Field, Cingulate Cortex and Superior Parietal Lobule. Similar scenario is seen in gray matter hubs of language Network: Broca's Area, Wernicke's Area, and Geschwind‘s Area (Inferior Parietal Lobule). In gray matter hubs of Memory Network: Uncus, Hippocampus, and Nucleus Accumbens areas, patients are found to be significantly different from the controls