Non-tremor motor dysfunction in Lewy body dementias is associated with AD biomarkers.
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ABSTRACT:
SUBMITTER: Walker IM
PROVIDER: S-EPMC10078247 | biostudies-literature | 2022 Jul
REPOSITORIES: biostudies-literature
Publications
Non-tremor motor dysfunction in Lewy body dementias is associated with AD biomarkers.
Walker Ian M IM Cousins Katheryn A KA Siderowf Andrew A Duda John E JE Morley James F JF Dahodwala Nabila N Tropea Thomas T Vaishnavi Sanjeev S Wolk David A DA Chen-Plotkin Alice S AS Shaw Leslie M LM Lee Edward B EB Trojanowski John Q JQ Grossman Murray M Weintraub Daniel D Irwin David J DJ
Parkinsonism & related disorders 20220608
Motor features of Parkinson's disease (PD) are heterogeneous and well-studied; non-tremor features of postural instability and gait dysfunction (PIGD) have been linked to worse outcomes and Alzheimer's disease (AD) co-pathology. However, these features are understudied in Lewy body dementias (LBD). Here we perform retrospective analysis of a unique cohort of LBD (n = 30) with Unified Parkinson's Disease Rating Scale (UPDRS) data collected at baseline in proximity to cerebrospinal fluid collectio ...[more]
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Project description:ObjectiveLewy body dementias (LBD) include both dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD), and the differentiation of LBD from other neurodegenerative dementias can be difficult. Currently, there are few biomarkers which might assist early diagnosis, map onto LBD symptom severity, and provide metrics of treatment response. Traditionally, biomarkers in LBD have focussed on neuroimaging modalities; however, as biomarkers need to be simple, inexpensive and non-invasive, neurophysiological approaches might also be useful as LBD biomarkers.MethodsIn this review, we searched PubMED and PsycINFO databases in a semi-systematic manner in order to identify potential neurophysiological biomarkers in the LBDs.ResultsWe identified 1491 studies; of these, 37 studies specifically examined neurophysiological biomarkers in LBD patients. We found that there was substantial heterogeneity with respect to methodologies and patient cohorts.ConclusionGenerally, many of the findings have yet to be replicated, although preliminary findings reinforce the potential utility of approaches such as quantitative electroencephalography and motor cortical stimulation paradigms.SignificanceVarious neurophysiological techniques have the potential to be useful biomarkers in the LBDs. We recommend that future studies focus on maximising the diagnostic specificity and sensitivity of the most promising neurophysiological biomarkers.
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Project description:Lewy body dementia (LBD) and Alzheimer's disease (AD) are common forms of dementia that have different clinical profiles but are both commonly associated with attentional deficits. The aim of this study was to investigate efficiency of different attentional systems in LBD and AD and its association with brain structural abnormalities. We studied reaction time (RT) data from 45 LBD, 31 AD patients and 22 healthy controls (HCs) using the Attention Network Test (ANT) to assess the efficiency of three different attentional systems: alerting, orienting and executive conflict. Voxel-based morphometry (VBM) was used to investigate relations between different attention components and cortical volume. Both dementia groups showed slower overall RTs than controls, with additional slowing in LBD relative to AD. There was a significant alerting effect in controls which was absent in the dementia groups, the executive conflict effect was greater in both dementia groups compared to controls, but the orienting effect did not differ between groups. Mean RT in AD was negatively correlated with occipital gray matter (GM) volume and in LBD orienting efficiency was negatively related to occipital white matter (WM) volume. Given that previous studies in less impaired patients suggest a maintenance of the alerting effect, the absent alerting effect in our study suggests a loss of alerting efficiency with dementia progression. While orienting was largely preserved, it might be related to occipital structural abnormalities in LBD. Executive function was markedly impaired in both dementia groups, however, the absence of relations to brain volume suggests that it might be more related to functional rather than macrostructural pathophysiological changes.
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Project description:Lewy body dementia (LBD) is one of the most common neurodegenerative dementias. Clinical trials for symptomatic and disease-modifying therapies in LBD remain a national research priority, but there are many challenges in both past and active drug developments in LBD. This review highlights the controversies in picking the appropriate populations, interventions, target selections, and outcome measures, which are all critical components of clinical trial implementation in LBD. The heterogeneity of LBD neuropathology and clinical presentations, limited understanding of core features such as cognitive fluctuations, and lack of validated LBD-specific outcome measures and biomarkers represent some of the major challenges in LBD trials.
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Project description:Lewy body dementias (LBDs) consist of dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), which are clinically similar syndromes that share neuropathological findings with widespread cortical Lewy body deposition, often with a variable degree of concomitant Alzheimer pathology. The objective of this article is to provide an overview of the neuropathological and clinical features, current diagnostic criteria, biomarkers, and management of LBD. Literature research was performed using the PubMed database, and the most pertinent articles were read and are discussed in this paper. The diagnostic criteria for DLB have recently been updated, with the addition of indicative and supportive biomarker information. The time interval of dementia onset relative to parkinsonism remains the major distinction between DLB and PDD, underpinning controversy about whether they are the same illness in a different spectrum of the disease or two separate neurodegenerative disorders. The treatment for LBD is only symptomatic, but the expected progression and prognosis differ between the two entities. Diagnosis in prodromal stages should be of the utmost importance, because implementing early treatment might change the course of the illness if disease-modifying therapies are developed in the future. Thus, the identification of novel biomarkers constitutes an area of active research, with a special focus on α-synuclein markers.
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Project description:IntroductionDementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are characterized by cognitive alterations, visual hallucinations, and motor impairment. Diagnosis is based on type and timing of clinical manifestations; however, determination of clinical subtypes is challenging. The utility of blood DNA methylation as a biomarker for Lewy body disorders (LBD) is mostly unexplored.MethodsWe performed a cross-sectional analysis of blood methylation in 42 DLB and 50 PDD cases applying linear models to compare groups and logistic least absolute shrinkage and selection operator regression to explore the discriminant power of methylation signals.ResultsDLB blood shows differential methylation compared to PDD. Some methylation changes associate with core features of LBD. Sets of probes show high predictive value to discriminate between variants.DiscussionOur study is the first to explore LBD blood methylation. Despite overlapping clinical presentation, we detected differential epigenetic signatures that, if confirmed in independent cohorts, could be developed into useful biomarkers.
| S-EPMC7896631 | biostudies-literature
Project description:Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are characterized by the presence of α-synuclein-containing Lewy bodies and Lewy neurites. However, both dementias also show variable degrees of Alzheimer's disease (AD) pathology (senile plaques and neurofibrillary tangles), particularly in areas of the cortex associated with higher cognitive functions. This study investigates the contribution of the individual and combined pathologies in determining the rate of cognitive decline. Cortical α-synuclein, phosphorylated tau (phosphotau) and Aβ plaque pathology in 34 PDD and 55 DLB patients was assessed semi-quantitatively in four regions of the neocortex. The decline in cognition, assessed by Mini Mental State Examination, correlated positively with the cortical α-synuclein load. Patients also had varying degrees of senile Aβ plaque and phosphotau pathology. Regression analyses pointed to a combined pathology (Aβ plaque plus phosphotau plus α-synuclein-positive features), particularly in the prefrontal cortex (BA9) and temporal lobe neocortex with the superior and middle temporal gyrus (BA21, 22), being a major determining factor in the development of dementia. Thus, cognitive decline in Lewy body dementias is not a consequence of α-synuclein-induced neurodegeneration alone but senile plaque and phosphorylated tau pathology also contribute to the overall deficits.
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Project description:IntroductionAn estimated 50% of patients with Lewy body dementias (LBD), including Parkinson's disease dementia (PDD) and Dementia with Lewy bodies (DLB), have co-occurring Alzheimer's disease (AD) that is associated with worse prognosis. This study tests an automated analysis of natural speech as an inexpensive, non-invasive screening tool for AD co-pathology in biologically-confirmed cohorts of LBD patients with AD co-pathology (SYN + AD) and without (SYN-AD).MethodsWe analyzed lexical-semantic and acoustic features of picture descriptions using automated methods in 22 SYN + AD and 38 SYN-AD patients stratified using AD CSF biomarkers or autopsy diagnosis. Speech markers of AD co-pathology were identified using best subset regression, and their diagnostic discrimination was tested using receiver operating characteristic. ANCOVAs compared measures between groups covarying for demographic differences and cognitive disease severity. We tested relations with CSF tau levels, and compared speech measures between PDD and DLB clinical disorders in the same cohort.ResultsAge of acquisition of nouns (p = 0.034, |d| = 0.77) and lexical density (p = 0.0064, |d| = 0.72) were reduced in SYN + AD, and together showed excellent discrimination for SYN + AD vs. SYN-AD (95% sensitivity, 66% specificity; AUC = 0.82). Lower lexical density was related to higher CSF t-Tau levels (R = -0.41, p = 0.0021). Clinically-diagnosed PDD vs. DLB did not differ on any speech features.ConclusionAD co-pathology may result in a deviant natural speech profile in LBD characterized by specific lexical-semantic impairments, not detectable by clinical disorder diagnosis. Our study demonstrates the potential of automated digital speech analytics as a screening tool for underlying AD co-pathology in LBD.
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Project description:IntroductionWe aimed to identify unique proteomic signatures of Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and Parkinson's disease dementia (PDD).MethodsWe conducted a comparative proteomic analysis of 33 post mortem brains from AD, DLB, and PDD individuals without dementia focusing on prefrontal, cingulate, and parietal cortices, using weighted gene co-expression network analyses with differential enrichment analysis.ResultsNetwork modules revealed hub proteins common to all dementias. Lewy body dementias differed from AD by reduced levels of the autophagy protein p62 (SQSTM1), whereas DLB was distinguished from both AD and PDD by altered TRIM33 and cysteine/glutamate transporter (SLC7A11) across brain regions. An increase in mitochondrial and synaptic proteins was related to better cognition whereas enrichment in the extracellular matrix, complement system, and autophagy proteins was associated with greater cognitive impairment.DiscussionOur study offers valuable insights into the network-based biomarker characterization of molecular signatures of AD, DLB, and PDD.HighlightsReduced levels of the autophagy protein p62 (SQSTM1) differentiated Lewy body dementias from Alzheimer's disease (AD) across multiple brain regions. Dementia with Lewy bodies (DLB) was distinguished from both AD and Parkinson's disease dementia (PDD) by altered TRIM33 and cysteine/glutamate transporter (SLC7A11) levels across brain regions. Key mitochondrial oxidative phosphorylation proteins (e.g., COX7A2, TOMM40L, NDUFV1), and synaptic proteins (e.g., GABRB3, GABRB2, GLUA3, GLUA4, SNAP47, dynamin1) were more abundant in preserved cognitive states. Extracellular matrix proteins and members of the complement system (decorin, biglycan, C4A, C4B) showed a strong positive correlation with cognitive decline.
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Project description:Synucleinopathies are a group of neurodegenerative disorders characterized by pathologic aggregates of neural and glial α-synuclein (α-syn) in the form of Lewy bodies (LBs), Lewy neurites, and cytoplasmic inclusions in both neurons and glia. Two major classes of synucleinopathies are LB disease and multiple system atrophy. LB diseases include Parkinson's disease (PD), PD with dementia, and dementia with LBs. All are increasing in prevalence. Effective diagnostics, disease-modifying therapies, and therapeutic monitoring are urgently needed. Diagnostics capable of differentiating LB diseases are based on signs and symptoms which might overlap. To date, no specific diagnostic test exists despite disease-specific pathologies. Diagnostics are aided by brain imaging and cerebrospinal fluid evaluations, but more accessible biomarkers remain in need. Mechanisms of α-syn evolution to pathologic oligomers and insoluble fibrils can provide one of a spectrum of biomarkers to link complex neural pathways to effective therapies. With these in mind, we review promising biomarkers linked to effective disease-modifying interventions.
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Project description:Co-pathologies are common in dementia with Lewy bodies and other dementia disorders. We investigated cerebrovascular and Alzheimer's disease co-pathologies in patients with dementia with Lewy bodies in comparison with patients with mild cognitive impairment, Alzheimer's disease, mixed dementia, vascular dementia or Parkinson's disease with dementia and cognitively unimpaired participants. We assessed the association of biomarkers of cerebrovascular and Alzheimer's disease co-pathologies with medial temporal atrophy and global cognitive performance. Additionally, we evaluated whether the findings were specific to dementia with Lewy bodies. We gathered a multi-cohort dataset of 4549 participants (dementia with Lewy bodies = 331, cognitively unimpaired = 1505, mild cognitive impairment = 1489, Alzheimer's disease = 708, mixed dementia = 268, vascular dementia = 148, Parkinson's disease with dementia = 120) from the MemClin Study, Karolinska Imaging in Dementia Study, Gothenburg H70 Birth Cohort Studies and the European DLB Consortium. Cerebrovascular co-pathology was assessed with visual ratings of white matter hyperintensities using the Fazekas scale through structural imaging. Alzheimer's disease biomarkers of β-amyloid and phosphorylated tau were assessed in the cerebrospinal fluid for a subsample (N = 2191). Medial temporal atrophy was assessed with visual ratings and global cognition with the mini-mental state examination. Differences and associations were assessed through regression models, including interaction terms. In dementia with Lewy bodies, 43% had a high white matter hyperintensity load, which was significantly higher than that in cognitively unimpaired (14%), mild cognitive impairment (26%) and Alzheimer's disease (27%), but lower than that in vascular dementia (62%). In dementia with Lewy bodies, white matter hyperintensities were associated with medial temporal atrophy, and the interaction term showed that this association was stronger than that in cognitively unimpaired and mixed dementia. However, the association between white matter hyperintensities and medial temporal atrophy was non-significant when β-amyloid was included in the model. Instead, β-amyloid predicted medial temporal atrophy in dementia with Lewy bodies, in contrast to the findings in mild cognitive impairment where medial temporal atrophy scores were independent of β-amyloid. Dementia with Lewy bodies had the lowest performance on global cognition, but this was not associated with white matter hyperintensities. In Alzheimer's disease, global cognitive performance was lower in patients with more white matter hyperintensities. We conclude that white matter hyperintensities are common in dementia with Lewy bodies and are associated with more atrophy in medial temporal lobes, but this association depended on β-amyloid-related pathology in our cohort. The associations between biomarkers were overall stronger in dementia with Lewy bodies than in some of the other diagnostic groups.
| S-EPMC11406466 | biostudies-literature