Research criteria for the diagnosis of prodromal dementia with Lewy bodies

The prodromal phase of dementia with Lewy bodies (DLB) includes (1) mild cognitive impairment (MCI), (2) delirium-onset, and (3) psychiatric-onset presentations. The purpose of our review is to determine whether there is sufficient information yet available to justify development of diagnostic criteria for each of these. Our goal is to achieve evidence-based recommendations for the recognition of DLB at a predementia, symptomatic stage. We propose operationalized diagnostic criteria for probable and possible mild cognitive impairment with Lewy bodies, which are intended for use in research settings pending validation for use in clinical practice. They are compatible with current criteria for other prodromal neurodegenerative disorders including Alzheimer and Parkinson disease. Although there is still insufficient evidence to propose formal criteria for delirium-onset and psychiatric-onset presentations of DLB, we feel that it is important to characterize them, raising the index of diagnostic suspicion and prioritizing them for further investigation.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.published version, accepted version (12 month embargo

Diagnostic biomarkers for Parkinson's disease at a glance : where are we?

Parkinson's disease (PD) is a neurodegenerative disorder whose aetiology remains unclear: degeneration involves several neurotransmission systems, resulting in a heterogeneous disease characterized by motor and non-motor symptoms. PD causes progressive disability that responds only to symptomatic therapies. Future advances include neuroprotective strategies for use in at-risk populations before the clinical onset of disease, hence the continuing need to identify reliable biomarkers that can facilitate the clinical diagnosis of PD. In this evaluative review, we summarize information on potential diagnostic biomarkers for use in the clinical and preclinical stages of PD

Effects of dance therapy on balance, gait and neuro-psychological performances in patients with Parkinson's disease and postural instability

Postural Instability (PI) is a core feature of Parkinson’s Disease (PD) and a major cause of falls and disabilities. Impairment of executive functions has been called as an aggravating factor on motor performances. Dance therapy has been shown effective for improving gait and has been suggested as an alternative rehabilitative method. To evaluate gait performance, spatial-temporal (S-T) gait parameters and cognitive performances in a cohort of patients with PD and PI modifications in balance after a cycle of dance therapy

Value of cerebrospinal fluid α-synuclein species as biomarker in Parkinson's diagnosis and prognosis.

Since diagnosis of Parkinson's disease (PD) is mostly based on clinical criteria, it is almost impossible to formulate an early diagnosis, as well as a timely differential diagnosis versus other parkinsonisms. A great effort in searching reliable biomarkers both for early diagnosis and prognosis in PD is currently ongoing. Cerebrospinal fluid has been widely investigated as potential source for such biomarkers, with particular emphasis on α-synuclein (α-syn) species. We reviewed all the clinical studies carried out so far on cerebrospinal fluid quantification of α-syn species in PD. Current evidence supports the value of total and oligomeric α-syn in PD diagnosis and in the differential diagnosis of PD and other parkinsonisms. Conversely, the role of α-syn species in PD prognosis remains unsatisfactory

Neurophysiological basis of rapid eye movement sleep behavior disorder:Informing future drug development

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by a history of recurrent nocturnal dream enactment behavior and loss of skeletal muscle atonia and increased phasic muscle activity during REM sleep: REM sleep without atonia. RBD and associated comorbidities have recently been identified as one of the most specific and potentially sensitive risk factors for later development of any of the alpha-synucleinopathies: Parkinson’s disease, dementia with Lewy bodies, and other atypical parkinsonian syndromes. Several other sleep-related abnormalities have recently been identified in patients with RBD/Parkinson’s disease who experience abnormalities in sleep electroencephalographic frequencies, sleep–wake transitions, wake and sleep stability, occurrence and morphology of sleep spindles, and electrooculography measures. These findings suggest a gradual involvement of the brainstem and other structures, which is in line with the gradual involvement known in these disorders. We propose that these findings may help identify biomarkers of individuals at high risk of subsequent conversion to parkinsonism

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

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

Oral and intestinal dysbiosis in Parkinson's disease.

The suspicion of an origin of Parkinson's disease (PD) at the periphery of the body and the involvement of environmental risk factors in the pathogenesis of PD have directed the attention of the scientific community towards the microbiota. The microbiota represents all the microorganisms residing both in and on a host. It plays an essential role in the physiological functioning of the host. In this article, we review the dysbiosis repeatedly demonstrated in PD and how it influences PD symptoms. Dysbiosis is associated with both motor and non-motor PD symptoms. In animal models, dysbiosis only promotes symptoms in individuals genetically susceptible to Parkinson's disease, suggesting that dysbiosis is a risk factor but not a cause of Parkinson's disease. We also review how dysbiosis contributes to the pathophysiology of PD. Dysbiosis induces numerous and complex metabolic changes, resulting in increased intestinal permeability, local and systemic inflammation, production of bacterial amyloid proteins that promote α-synuclein aggregation, as well as a decrease in short-chain fatty acid-producing bacteria that have anti-inflammatory and neuroprotective potential. In addition, we review how dysbiosis decreases the efficacy of dopaminergic treatments. We then discuss the interest of dysbiosis analysis as a biomarker of Parkinson's disease. Finally, we give an overview of how interventions modulating the gut microbiota such as dietary interventions, pro-biotics, intestinal decontamination and fecal microbiota transplantation could influence the course of PD