Biomarker and pathology studies in neurodegenerative cognitive impairment

Background: Dementia is a major cause of functional impairment and early death in older age groups. Neurodegenerative disorders are the most common cause of dementia. The most frequent neuropathological lesions include neurofibrillary tangles and senile plaques, hallmark lesions for Alzheimer´s disease (AD), and Lewy body pathology, which characterize Lewy body disease (LBD). Clinically, the neuropathological entity LBD can present as either Parkinson´s disease (PD) or dementia with Lewy bodies (DLB), differentiated on the basis of the presenting symptoms being either motor or cognitive. While the majority of LBD patients develop both motor symptoms and cognitive impairment, some patients with clinical PD will never experience cognitive impairment and likewise some patients with DLB will never develop motor symptoms. Similarly the clinical presentation of AD is also heterogeneous, for instance, the highly variable occurrence of neuropsychiatric symptoms and rate of progression. These differences have a major impact on quality of life for patients and carers, as well as health care costs, but their mechanisms and neuropathological underpinnings are poorly understood. Furthermore the correlation between clinical diagnosis and neuropathological findings is relatively low, and LBD patients presenting with cognitive impairment particularly risk being misclassified as AD. This highlight the need for more precise biomarkers for these clinical syndromes that can be implemented at the start of and during the course of the disease. Biomarkers may inform about disease pathology, thus paving the way for new treatment, they increase diagnostic accuracy and aid in setting a prognosis. Biomarkers are needed in the selection of patients for treatment studies and to identify which patients should benefit from new treatment when available. The cerebrospinal fluid (CSF) biomarkers beta-amyloid 42 (abeta42), total tau (t-tau) and tau protein phosphorylated at amino acid 181 (p-tau181) reflect key AD pathologies. The Lewy bodies found in LBD are composed mainly of the protein !-synuclein. !-synuclein is reduced in CSF in LBD, but with considerable overlap between LBD, controls and other disease groups. Aim: The main aim of this thesis was to increase understanding of pathological mechanisms underlying important clinical features in neurodegenerative cognitive impairment, by exploring the associations between clinical presentation and biomarkers and pathology. The first objective was to explore the association between AD pathology CSF markers and neuropsychiatric symptoms in newly diagnosed AD patients; secondly to assess the association between CSF markers of AD and LBD pathology and early cognitive impairment in PD; thirdly to examine the correlation between clinical diagnosis of DLB and Lewy body pathology at autopsy. Methods: This is a clinical translational neuroscience project based on two clinical cohort studies. The dementia Study of Western Norway (Demvest) included newly diagnosed dementia patients from specialist clinics in geriatric medicine and old age psychiatry in Western Norway. The Parkinson´s Progression Markers Initiative (PPMI) is an international multicentre study, including newly diagnosed PD patients and healthy controls. A comprehensive battery of neuropsychological tests, a structured neuropsychiatric evaluation, clinical examination, and imaging were part of both studies. CSF sampling was done according to standardized protocols and CSF was analysed using commercially available immunoassays. In the Demvest study, participants were recruited for brain donation, and autopsy results were obtained applying commonly used neuropathological protocols and diagnostic criteria. Results: We undertook three specific studies to investigate objective I, II and III. In study I, apathy in patients with early Alzheimer´s disease correlated with t-tau and ptau181 concentrations in CSF, higher values being associated with more severe apathy. There were no associations between depression or psychosis and agitation and CSF markers. In study II, decreased CSF !-synuclein in newly diagnosed PD-patients without dementia correlated with impaired global cognition and impairment of executive functions and attention. CSF abeta42 was decreased in PD with mild cognitive impairment compared with controls after adjusting for covariates. No correlations were found between memory or visuospatial functions and CSF markers. Study III examined autopsy results of 56 patients followed from dementia diagnosis to death. 20 patients received a pathological diagnosis of LBD; the corresponding clinical diagnosis were probable DLB (n=11), Parkinson´s disease with dementia (PDD) (n=5) and probable or possible AD (n=4). Of the 56, 14 patients received a clinical diagnosis of probable DLB, 11 of these had pathological LBD and three AD. Sensitivity, specificity, positive and negative predictive values of a clinical DLB diagnosis were 73%, 93%, 70%, and 90% respectively. Conclusions and implications: We have reported a novel association between neuropsychiatric symptoms and CSF biomarkers reflecting core AD pathology. The relationship between t-tau and p-tau181 and apathy may reflect an association between neurofibrillary tangle pathology and apathy in early AD. Cognitive impairment in early PD was associated with biomarkers of both Lewy body and AD pathology. 18 of 20 LBD patients in the Demvest study had Braak neurofibrillary tangle stage IV or higher, representing severe AD pathology at autopsy. Thus our findings suggest a role for AD pathology in both early and established LBD. Accurate diagnosis is crucial for clinical practice and research. With a sensitivity of 73%, the clinical 2005 DLB criteria are not sensitive enough. More than one in four DLB patients were not identified even when structured rating scales for core DLB symptoms were applied. We regard a specificity of 93% as satisfactory. Our results illustrate that not all DLB patients fulfil the 2005 DLB criteria at disease presentation, highlighting the need for re-evaluation of the diagnosis if new symptoms appear. Studies applying the most recent 2017 DLB criteria will show if this revision has increased sensitivity without decreasing specificity

Making it count : novel behavioural tasks to quantify symptoms of dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is a neurodegenerative disease and a common cause of dementia in the elderly. The primary pathology of DLB is the mis-folding of the α-synuclein protein, classifying DLB as a synucleinopathy. However, concomitant pathologies are commonly found in post-mortem examination of DLB patients that may complicate diagnosis. Furthermore, DLB is a relatively new disease, first discovered in 1976, while the first official diagnostic criteria released in 1996. Consequently, the diagnostic criteria for DLB have evolved as more is learnt about the clinical and neuropathological profile. Synucleinopathies are also known to be heterogeneous, with no single symptom or biomarker present in all DLB cases. Instead, combinations of common symptoms lead to a diagnosis of probable DLB. Two of the most prominent and debilitating symptoms of DLB are visual hallucinations and cognitive fluctuations. Visual hallucinations (VH) in DLB patients are typically vivid, well-formed percepts and are a major cause of patient and caregiver stress as well as a risk factor for the patient being placed into professional care. Cognitive fluctuations (CF) involve a cycling change in attention and alertness and may occur on a daily or monthly basis, while drops in awareness may last seconds or hours. Currently, the only tools to measure cognitive fluctuations or visual hallucinations are scales or questionnaires that rely on responses from the patient or informant. Furthermore, severity of the symptom is then ranked on an arbitrary ranking system. While this method has advantages in a clinical setting, the subjective nature of the scales combined with the ranking of scores results in a loss of sensitivity. In a research setting, especially imaging or clinical trials, objective measures that are sensitive to changes in symptom severity are highly valued. This allows researchers to assess the relationship between behavioural and fMRI data and clinicians to observe subtle changes in severity. Furthermore, the measures need to be easy to conduct as patients are often severely impaired. The aim of this thesis is to test cognitive function using three paradigms that are novel to DLB patients: Sustained Attention Response Task (SART), the Mental Rotation (MR) task and the Bistable Percept Paradigm (BPP). Overall, this thesis provided the groundwork needed before these three tasks can be utilised in a clinical or research setting. Moreover, as each task was accessible to DLB patients and provided a measure associated with VH or CF, they may prove useful for future neuroimaging/neuropsychological studies

Extended Timed Up and Go assessment as a clinical indicator of cognitive state in Parkinson\u27s disease

Objective: To evaluate a modified extended Timed Up and Go (extended-TUG) assessment against a panel of validated clinical assessments, as an indicator of Parkinson’s disease (PD) severity and cognitive impairment. Methods: Eighty-seven participants with idiopathic PD were sequentially recruited from a Movement Disorders Clinic. An extended-TUG assessment was employed which required participants to stand from a seated position, walk in a straight line for 7 metres, turn 180 degrees and then return to the start, in a seated position. The extended-TUG assessment duration was correlated to a panel of clinical assessments, including the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), Quality of Life (PDQ-39), Scales for Outcomes in Parkinson’s disease (SCOPA-Cog), revised Addenbrooke’s Cognitive Index (ACE-R) and Barratt’s Impulsivity Scale 11 (BIS-11). Results: Extended-TUG time was significantly correlated to MDS-UPDRS III score and to SCOPA-Cog, ACE-R (p\u3c0.001) and PDQ-39 scores (p\u3c0.01). Generalized linear models determined the extended-TUG to be a sole variable in predicting ACE-R or SCOPA-Cog scores. Patients in the fastest extended-TUG tertile were predicted to perform 8.3 and 13.4 points better in the SCOPA-Cog and ACE-R assessments, respectively, than the slowest group. Patients who exceeded the dementia cut-off scores with these instruments exhibited significantly longer extended-TUG times. Conclusions: Extended-TUG performance appears to be a useful indicator of cognition as well as motor function and quality of life in PD, and warrants further evaluation as a first line assessment tool to monitor disease severity and response to treatment. Poor extended-TUG performance may identify patients without overt cognitive impairment form whom cognitive assessment is needed

Multiple system atrophy - a clinicopathological update

Multiple system atrophy (MSA) is a fatal, adult-onset neurodegenerative disorder of uncertain etiology, clinically characterized by various combinations of Levo-dopa-unresponsive parkinsonism, and cerebellar, motor, and autonomic dysfunctions. MSA is an α-synucleinopathy with specific glioneuronal degeneration involving striatonigral, olivopontocerebellar, autonomic and peripheral nervous systems. The pathologic hallmark of this unique proteinopathy is the deposition of aberrant α-synuclein (αSyn) in both glia (mainly oligodendroglia) and neurons forming pathological inclusions that cause cell dysfunction and demise. The major variants are striatonigral degeneration (MSA with predominant parkinsonism / MSA-P) and olivopontocerebellar atrophy (MSA with prominent cerebellar ataxia / MSA-C). However, the clinical and pathological features of MSA are broader than previously considered. Studies in various mouse models and human patients have helped to better understand the molecular mechanisms that underlie the progression of the disease. The pathogenesis of MSA is characterized by propagation of disease-specific strains of αSyn from neurons to oligodendroglia and cell-to-cell spreading in a "prion-like" manner, oxidative stress, proteasomal and mitochondrial dysfunctions, myelin dysregulation, neuroinflammation, decreased neurotrophic factors, and energy failure. The combination of these mechanisms results in neurodegeneration with widespread demyelination and a multisystem involvement that is specific for MSA. Clinical diagnostic accuracy and differential diagnosis of MSA have improved by using combined biomarkers. Cognitive impairment, which has been a non-supporting feature of MSA, is not uncommon, while severe dementia is rare. Despite several pharmacological approaches in MSA models, no effective disease-modifying therapeutic strategies are currently available, although many clinical trials targeting disease modification, including immunotherapy and combined approaches, are under way. Multidisciplinary research to elucidate the genetic and molecular background of the noxious processes as the basis for development of an effective treatment of the hitherto incurable disorder are urgently needed

Neural correlates of attention-executive dysfunction in lewy body dementia and Alzheimer's disease.

Attentional and executive dysfunction contribute to cognitive impairment in both Lewy body dementia and Alzheimer's disease. Using functional MRI, we examined the neural correlates of three components of attention (alerting, orienting, and executive/conflict function) in 23 patients with Alzheimer's disease, 32 patients with Lewy body dementia (19 with dementia with Lewy bodies and 13 with Parkinson's disease with dementia), and 23 healthy controls using a modified Attention Network Test. Although the functional MRI demonstrated a similar fronto-parieto-occipital network activation in all groups, Alzheimer's disease and Lewy body dementia patients had greater activation of this network for incongruent and more difficult trials, which were also accompanied by slower reaction times. There was no recruitment of additional brain regions or, conversely, regional deficits in brain activation. The default mode network, however, displayed diverging activity patterns in the dementia groups. The Alzheimer's disease group had limited task related deactivations of the default mode network, whereas patients with Lewy body dementia showed heightened deactivation to all trials, which might be an attempt to allocate neural resources to impaired attentional networks. We posit that, despite a common endpoint of attention-executive disturbances in both dementias, the pathophysiological basis of these is very different between these diseases.This work was supported by an Intermediate Clinical Fellowship . Grant Number: (WT088441MA) to John‐Paul Taylor the National Institute for Health Research (NIHR), and Newcastle Biomedical Research Unit (BRU) based at Newcastle upon Tyne Hospitals NHS Trust, Newcastle University

Neuropsychiatric and cognitive symptoms in Parkinson’s disease: the contribution to subtype classification, to differential diagnosis, their clinical and instrumental correlations

Il piano di ricerca è volto ad approfondire il contributo dei sintomi neuropsichiatrici e cognitivi nelle diverse fasi della Malattia di Parkinson (MP). In particolare, l’argomento di studio è focalizzato sull’analisi dei sintomi cognitivi e neuropsichiatrici nella MP, affrontando queste tematiche anche mediante l’utilizzo di tecniche di neuroimaging, in pazienti drug-naïve, in fase precoce di malattia ed in fase avanzata. Nei pazienti drug-naïve, la ricerca è stata finalizzata alla caratterizzazione dei sintomi neuropsichiatrici e cognitivi nei sottotipi motori (i.e., tremorigeni vs acinetico-rigidi) e rispetto alla lateralità di esordio degli stessi (i.e., lateralità destra vs lateralità sinistra). Nei pazienti in fase precoce di malattia, è stato indagato il contributo dei sintomi neuropsichiatrici e cognitivi nella diagnosi differenziale tra MP e Paralisi Sopranucleare Progressiva (PSP) in pazienti valutati entro i 24 mesi dall’esordio motorio, finestra temporale in cui spesso si assiste ad un overlapping dei sintomi motori. Nei pazienti in fase avanzata di malattia, la ricerca è stata finalizzata alla caratterizzazione, mediante i sintomi neuropsichiatrici e cognitivi, del Gioco D’Azzardo Patologico (gambling) rispetto agli altri tipi di Disturbi del controllo degli Impulsi (ICDs). Ancora nell’ambito dell’ICDs, è stato sviluppato uno studio di neuroimaging, volto ad identificare i correlati morfostrutturali (spessori corticali e volumi dei nuclei sottocorticali) di tali disturbi. Infine, si sono identificati i sintomi neuropsichiatrici e cognitivi che possono impedire l’esecuzione di un esame di Risonanza Magnetica (RM), al fine, in ambito clinico, di preparare adeguatamente all’esame i pazienti più a rischio di mancato svolgimento e con l’intento di indagare, in ambito di ricerca, la reale rappresentatività campionaria dei pazienti inseriti in studi di RM

The comparative neuropsychology of dementia

PhD ThesisOn the basis of neuropathological, neurochemical, genetic, and clinical profile studies on patients, distinct forms of dementia, such as dementia with Lewy bodies (DLB), have been distinguished which were originally thought to be Alzheimer's disease (AD). Dementia with Lewy bodies is probably the second most common form of dementia in the elderly. In this thesis, a well characterised and investigated cohort of DLB and AD patients were compared to non-demented elderly controls in order to establish profiles of cognitive decline in these groups. Initially, comprehensively matched experimental groups were compared using the Cambridge Neuropsychological Test Automated Battery (CANTAB). The DLB group was less impaired than the AD group on a test of visual pattern recognition memory. However, the DLB group performed worse on a number of cognitive tests. Comparison of larger, carefully matched, experimental groups using the Cognitive Drug Research Computerised Assessment Battery (CDR) also revealed differences in the profile of cognitive impairment in DLB and AD. The DLB group showed more marked deficits in attentional abilities than the AD group. In particular, the DLB group were unable to sustain attention. Conversely, the DLB group were less impaired on a test of visual secondary recognition memory than the AD group. Further division of the DLB group into cases with and without persistent visual hallucinations revealed distinct patterns of cognitive impairment in these two groups. Generally, DLB cases with persistent visual hallucinations showed greater attentional and spatial working memory deficits than the DLB cases without persistent visual hallucinations. A final study compared decline in cognitive function over 1 year in DLB, AD and control groups. Similar rates of cognitive decline were identified in a number of cognitive domains in AD and DLB groups. In addition, disproportionate decline in the ability to sustain attention was identified in the DLB group. A comparative model relating known neuropsychological, neurochemical, and neuropathological features of DLB and AD was proposed

The white matter connectome as an individualized biomarker of language impairment in temporal lobe epilepsy.

ObjectiveThe distributed white matter network underlying language leads to difficulties in extracting clinically meaningful summaries of neural alterations leading to language impairment. Here we determine the predictive ability of the structural connectome (SC), compared with global measures of white matter tract microstructure and clinical data, to discriminate language impaired patients with temporal lobe epilepsy (TLE) from TLE patients without language impairment.MethodsT1- and diffusion-MRI, clinical variables (CVs), and neuropsychological measures of naming and verbal fluency were available for 82 TLE patients. Prediction of language impairment was performed using a robust tree-based classifier (XGBoost) for three models: (1) a CV-model which included demographic and epilepsy-related clinical features, (2) an atlas-based tract-model, including four frontotemporal white matter association tracts implicated in language (i.e., the bilateral arcuate fasciculus, inferior frontal occipital fasciculus, inferior longitudinal fasciculus, and uncinate fasciculus), and (3) a SC-model based on diffusion MRI. For the association tracts, mean fractional anisotropy was calculated as a measure of white matter microstructure for each tract using a diffusion tensor atlas (i.e., AtlasTrack). The SC-model used measurement of cortical-cortical connections arising from a temporal lobe subnetwork derived using probabilistic tractography. Dimensionality reduction of the SC was performed with principal components analysis (PCA). Each model was trained on 49 patients from one epilepsy center and tested on 33 patients from a different center (i.e., an independent dataset). Randomization was performed to test the stability of the results.ResultsThe SC-model yielded a greater area under the curve (AUC; .73) and accuracy (79%) compared to both the tract-model (AUC: .54, p < .001; accuracy: 70%, p < .001) and the CV-model (AUC: .59, p < .001; accuracy: 64%, p < .001). Within the SC-model, lateral temporal connections had the highest importance to model performance, including connections similar to language association tracts such as links between the superior temporal gyrus to pars opercularis. However, in addition to these connections many additional connections that were widely distributed, bilateral and interhemispheric in nature were identified as contributing to SC-model performance.ConclusionThe SC revealed a white matter network contributing to language impairment that was widely distributed, bilateral, and lateral temporal in nature. The distributed network underlying language may be why the SC-model has an advantage in identifying sub-components of the complex fiber networks most relevant for aspects of language performance