Quantitative Electroencephalography and genetics as biomarkers of dementia in Parkinson’s disease

The importance of cognitive decline in Parkinson’s disease (PD), which eventually progresses to dementia (PD-D) in the majority of surviving patients, has been widely recognised during the last decade. PD-D is associated with a twofold increase in mortality, increased caregiver strain and increased healthcare costs. Thus, early and correct identification of the PD patients with a risk of dementia is a challenging problem of neurology, which has led to the suggestion of various markers of cognitive decline in PD. If validated, these markers would offer the opportunity for disease modification and therapeutic intervention at a critical early stage of the illness, when the viable neuronal population is greater. The focus of this thesis was to assess how various factors - quantitative electroencephalography (qEEG) changes, genetics, deep brain stimulation (DBS), olfactory function, etc. – may be related with the risk of cognitive decline in PD patients. We performed four clinical studies with various design. These studies included PD patients who were dementia-free on inclusion, and control participants. Principal findings are the following: (1) increase of global median relative power theta (4–8 Hz), executive and working memory dysfunction are independent prognostic markers of severe cognitive decline in PD patients over a period of 3 years. (2) DBS of the subthalamic nuclei in a group of PD patients with mean age 63.2 years, in comparison with a group of younger patients (52.9 years), causes higher incidence of psychiatric events over 2 years of observation. However, these events were transient and did not outweigh the benefits of surgery. (3) Worsening of verbal fluency performance is an early cognitive outcome of DBS of the subthalamic nuclei in PD patients. (4) Among early appearing non-motor signs of Parkinson’s disease, alteration of olfaction but not EEG spectrum correlates with motor function. (5) A composite score approach seems to be a realistic goal in the search for biomarkers of severe cognitive decline

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

Early diagnosis of Alzheimer's disease: the role of biomarkers including advanced EEG signal analysis. Report from the IFCN-sponsored panel of experts

Alzheimer's disease (AD) is the most common neurodegenerative disease among the elderly with a progressive decline in cognitive function significantly affecting quality of life. Both the prevalence and emotional and financial burdens of AD on patients, their families, and society are predicted to grow significantly in the near future, due to a prolongation of the lifespan. Several lines of evidence suggest that modifications of risk-enhancing life styles and initiation of pharmacological and non-pharmacological treatments in the early stage of disease, although not able to modify its course, helps to maintain personal autonomy in daily activities and significantly reduces the total costs of disease management. Moreover, many clinical trials with potentially disease-modifying drugs are devoted to prodromal stages of AD. Thus, the identification of markers of conversion from prodromal form to clinically AD may be crucial for developing strategies of early interventions. The current available markers, including volumetric magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebral spinal fluid (CSF) analysis are expensive, poorly available in community health facilities, and relatively invasive. Taking into account its low cost, widespread availability and non-invasiveness, electroencephalography (EEG) would represent a candidate for tracking the prodromal phases of cognitive decline in routine clinical settings eventually in combination with other markers. In this scenario, the present paper provides an overview of epidemiology, genetic risk factors, neuropsychological, fluid and neuroimaging biomarkers in AD and describes the potential role of EEG in AD investigation, trying in particular to point out whether advanced analysis of EEG rhythms exploring brain function has sufficient specificity/sensitivity/accuracy for the early diagnosis of AD

Clinical and neuroimaging prognostic markers in Alzheimer's Disease and Lewy Body Dementia: The role of muscle status and nutrition

Alzheimer's Disease and Lewy body dementia are the two most common neurodegenerative dementias. They have a progressive course with devastating consequences for the people living with these diseases and their families, but there are large individual variations. Finding early markers and markers of progression and prognosis could promote actions to improve the quality of life of the people affected with these diseases. Nutrition and muscle status are closely related and have systemic functions and interactions that affect the brain. This thesis describes the role of nutritional and muscle status biomarkers in the prognosis of people diagnosed with mild Alzheimer's disease, Lewy body dementia, and mild subjective cognitive decline. Methods For the aim of this thesis, I used data from 2 community-based prospective Norwegian multicenter cohort studies: DemVest (The Dementia Study of Western Norway) and DDI (Dementia Disease Initiation). In DemVest, patients with mild dementia, defined as a Mini-Mental Status Examination (MMSE) score; equal or higher to 20 or Clinical Dementia Rating (CDR) global score equal to 1, with different types of dementia, were included. The DDI study was designed to investigate early cognitive impairment and dementia markers. DDI participants included in this thesis were those classified as having Subjective cognitive decline (SCD) according to the SCD-I framework. Comprehensive clinical assessments, including measures of cognition, daily functioning and anthropometric measurement, blood samples, and brain MRI were performed in both studies. Brain morphology was studied using FreeSurfer segmentation and muscle morphology using slice O-Matic software. Results This thesis findings first indicate that nutritional status has an essential role in the 5-year prognosis of people living with dementia in the capacity to perform daily life activities and mortality. Second, the quality of the muscle, here the muscle of the tongue, and its amount of fat infiltration were associated with malnutrition onset in people with dementia. Finally, in patients with SCD, muscle function measured with the timed up and go test (TUG) was associated with cognitive decline. TUG, in addition, was associated with cortical thickness in areas related with cognitive and motor functioning. Conclusion Nutritional and muscular status predict prognosis in people with SCD and with dementia. These findings suggest that interventions focused on these areas may improve outcomes such as cognition, function, and survival in these groups

Abnormal reactivity of resting-state EEG alpha rhythms during eyes open in patients with Alzheimer's and Lewy body diseases

Previous studies suggest that resting-state electroencephalographic (rsEEG) rhythms recorded in old patients with dementia due to different neurodegenerative diseases have a significant heuristic and clinical potential in identifying peculiar abnormalities of the ascending activating systems and reciprocal thalamocortical circuits in which oscillatory (de)synchronizing signals dynamically underpin cortical arousal in the regulation of quiet vigilance. In the present PhD program, a new methodological approach based on rsEEG cortical source estimation and individually-based frequency bands was used to test the hypothesis of significant abnormalities in the neurophysiological oscillatory mechanisms underlying the regulation of the quiet vigilance during the transition from an eyes-closed to an eyes-open condition in patients with the most prevalent neurodegenerative dementing disorders such as Alzheimer’s disease and Lewy Body and Parkinson’s diseases and initial abnormalities in the prodromal stage of ADD, characterized by mild cognitive impairment. Three rsEEG studies were performed for that purpose. In the first study, we tested if the reactivity of posterior rsEEG alpha rhythms from the eye- closed to the eyes-open condition may differ in patients with dementia due to Lewy Bodies (DLB) and Alzheimer’s disease (ADD) as a functional probe of the dominant neural synchronization mechanisms regulating the vigilance in posterior visual systems. We used clinical, demographical, and rsEEG datasets in 28 healthy elderly (Healthy) seniors, 42 DLB, and 48 ADD participants. The eLORETA freeware estimated rsEEG cortical sources at individual delta, theta, and alpha frequencies. Results showed a substantial (> -10%) reduction in the posterior alpha activities during the eyes-open condition in 24 Healthy, 26 ADD, and 22 DLB subjects. There were lower reductions in the posterior alpha activities in the ADD and DLB groups than in the Healthy group. The reduction in the occipital region was lower in the DLB than in the ADD group. These results suggest that DLB patients may suffer a greater alteration in the neural synchronization mechanisms regulating vigilance in occipital cortical systems compared to ADD patients. In the second study, we hypothesized that the vigilance dysregulation seen in PDD patients might be reflected by altered reactivity of posterior rsEEG alpha rhythms during the vigilance transition from an eyes-closed to an eyes-open condition. We used clinical, demographical, and rsEEG datasets in 28 healthy elderly (Healthy), 73 PDD, and 35 ADD participants. We have applied the same methodology used for the first study. Results showed substantial (> -10%) reduction (reactivity) in the posterior alpha source activities from the eyes-closed to the eyes-open condition in 88% of the Healthy seniors, 57% of the ADD patients, and only 35% of the PDD patients. In these alpha-reactive participants, there was lower reactivity in the parietal alpha source activities in the PDD group than in the Healthy and the ADD groups. These results suggest that PDD is characterized by poor reactivity of mechanisms desynchronizing posterior rsEEG alpha rhythms in response to visual inputs. This finding could be an interesting biomarker of impaired vigilance regulation in quiet wakefulness in PDD patients. Indeed, such biomarkers may provide endpoints for pharmacological intervention and brain electromagnetic stimulations to improve the PDD patients’ general ability to regulate vigilance and primary visual consciousness in the activities of daily living. In the third study, we tested the exploratory hypothesis that rsEEG alpha rhythms may predict and be sensitive to mild cognitive impairment due to AD (ADMCI) progression at a 6-month follow- up (a relevant feature for intervention clinical trials). Clinical, neuroimaging, and rsEEG datasets in 52 ADMCI and 60 Healthy seniors were used. We applied the same methodology used for the first and the second studies. Results showed a substantial (> -10%) reduction in the posterior alpha source activities during the eyes-open condition in about 90% and 70% of the Healthy and ADMCI participants, respectively. In the younger ADMCI patients (mean age of 64.3±1.1) with “reactive” rsEEG alpha source activities, posterior alpha source activities during the eyes closed condition predicted the global cognitive status at the 6-month follow-up. In all ADMCI participants with “reactive” rsEEG alpha source activities, posterior alpha source activities during the eyes-closed condition reduced in magnitude at that follow-up. These effects could not be explained by neuroimaging and neuropsychological biomarkers of AD. These results suggest that in ADMCI patients, the true (“reactive”) posterior rsEEG alpha rhythms, when present, predict (in relation to younger age) and are quite sensitive to the effects of the disease progression on neurophysiological mechanisms underpinning vigilance regulation. The results of the three studies unveiled the significant extent to which the well-known impairments in the cholinergic and dopaminergic neuromodulatory ascending systems could affect the brain neurophysiological oscillatory mechanisms underpinning the reactivity of rsEEG alpha rhythms during eyes open and, then, the regulation of quiet vigilance in ADD, PDD, and DLB patients, thus enriching the neurophysiological model underlying their known difficulties to remain awake in quiet environmental conditions during daytime

Predicting cognitive impairment in Parkinson's disease using neurophysiology and biochemical parameters as biomarkers

PhD ThesisParkinson’s disease (PD) is a common neurodegenerative condition with multiple associated non-motor symptoms. Of these, dementia is a frequent debilitating complication of the disorder, with significant morbidity and mortality. Some forms of mild cognitive impairment in PD (PD-MCI) may represent a pre-dementia state and certain clinical, laboratory and neurophysiological parameters may increase the accuracy of prediction of cognitive decline. If validated, these markers would offer the opportunity for disease modification and therapeutic intervention at a critical early stage of the illness, when the viable neuronal population is greater. The key aim of this thesis was to characterise cognitive impairment in PD in a cohort of newly diagnosed cases, and evaluate how a panel of biomarkers correlated with cognitive phenotypes to predict risk of future cognitive decline. The main findings were that PD-MCI was common, and was associated with a distinct clinical phenotype. Memory impairment was the most common single domain affected, although the majority of those with PD-MCI were classified as nonamnestic single domain subtype. A significant correlation was found between pattern recognition memory, sensitive to temporal lobe impairments, and cerebrospinal amyloid-β 1-42 levels, thought to represent amyloid-β metabolism and deposition Both amyloid-β 1-42 and 1-40 levels were significantly lower in those with impaired cognition. In addition, short latency afferent inhibition, a neurophysiological in vivo non-invasive measurement of cholinergic function, was also reduced in participants with mild cognitive impairment. These findings suggest that cholinergic dysfunction and amyloid deposition may contribute to the underlying pathophysiology of early PD- MCI. The major conclusion from this thesis is that PD-MCI is heterogeneous and more frequent than previously reported in early disease. This is associated with abnormalities of amyloid processing and cholinergic dysfunction, and may highlight those at risk of developing dementia. Longitudinal assessment of these individuals will enable us to determine and better model those measures predictive of cognitive decline at an early disease stage.Parkinson’s UK, The Michael J Fox Foundation, Newcastle University Lockhart Fun

Validation of brief cognitive tests in mild cognitive impairment, Alzheimer's disease and dementia with Lewy bodies.

Background It is estimated that 34 million people suffer from dementia, costing society US$422 billion each year. Alzheimer’s disease (AD) is the most common dementia and the global prevalence is predicted to increase to over 100 million people by the year 2050, with the greatest increase in developing countries. Therefore, inexpensive and efficient instruments are required for investigation and evaluation. Aim To evaluate the brief cognitive tests cube copying, clock drawing, the Mini-Mental State Examination (MMSE) and A Quick Test of Cognitive Speed (AQT) in the early diagnosis, treatment evaluation and differential diagnosis of dementias. Populations I. 85 patients with AD. II. 33 patients with dementia with Lewy bodies (DLB) and 66 with AD. III. 75 patients with AD. IV. 99 patients with mild cognitive impairment (MCI). Findings I. Cube copying was found useful for evaluating treatment with acetylcholinesterase inhibitors (AChEI) in patients with AD. II. Easy and quick interpretations of the MMSE, clock drawing and cube copying differentiated patients with DLB from patients with AD. III. AQT was twice as sensitive as the MMSE in detecting treatment response to AChEI in patients with AD. IV. The MMSE, AQT and clock drawing were as accurate as cerebrospinal fluid biomarkers (tau, Aβ42 and P-tau) in predicting development of AD and dementia in mild cognitive impairment during an average of five years. Conclusion This thesis has improved the validity of brief cognitive tests and contributed with results that can be clinically relevant for evaluating treatment of AD, differentiating DLB from AD, and predicting development of AD and other dementias