New cerebrospinal fluid biomarkers in Alzheimer’s disease

Burchell, Jennifer; Panegyres, Peter K.

doi:10.2217/fnl-2017-0009

Cited by 3 publications

(1 citation statement)

References 20 publications

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“…REM sleep behavior disorder (RBD), which shows a high prevalence in DLB and may precede cognitive decline by decades, is now included as a core clinical feature [ 55 ]. RBD may reflect a distinct subtype of DLB with earlier disease onset [ 56 ], associated with severe brain metabolic decreases [ 57 ]; however, as an early manifestation, it is not specific to DLB [ 58 , 59 ]. The pattern of initial cognitive dysfunction differs between DLB and PDD [ 60 ], with greater deficiencies of attention, executive function, and constructive abilities, as well as significantly lower ratings in episodic verbal memory tasks, in DLB [ 61 , 62 ].…”

Section: Introductionmentioning

confidence: 99%

Are dementia with Lewy bodies and Parkinson’s disease dementia the same disease?

Jellinger¹,

Korczyn

2018

BMC Med

283

216

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BackgroundDementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), which share many clinical, neurochemical, and morphological features, have been incorporated into DSM-5 as two separate entities of major neurocognitive disorders with Lewy bodies. Despite clinical overlap, their diagnosis is based on an arbitrary distinction concerning the time of onset of motor and cognitive symptoms, namely as early cognitive impairment in DLB and later onset following that of motor symptoms in PDD. Their morphological hallmarks – cortical and subcortical α-synuclein/Lewy body plus β-amyloid and tau pathologies – are similar, but clinical differences at onset suggest some dissimilar profiles. Based on recent publications, including the fourth consensus report of the DLB Consortium, a critical overview is provided herein.DiscussionThe clinical constellations of DLB and PDD include cognitive impairment, parkinsonism, visual hallucinations, and fluctuating attention. Intravitam PET and postmortem studies have revealed a more pronounced cortical atrophy, elevated cortical and limbic Lewy body pathologies, higher Aβ and tau loads in cortex and striatum in DLB compared to PDD, and earlier cognitive defects in DLB. Conversely, multitracer PET studies have shown no differences in cortical and striatal cholinergic and dopaminergic deficits. Clinical management of both DLB and PDD includes cholinesterase inhibitors and other pharmacologic and non-drug strategies, yet with only mild symptomatic effects. Currently, no disease-modifying therapies are available.ConclusionDLB and PDD are important dementia syndromes that overlap in many clinical features, genetics, neuropathology, and management. They are currently considered as subtypes of an α-synuclein-associated disease spectrum (Lewy body diseases), from incidental Lewy body disease and non-demented Parkinson’s disease to PDD, DLB, and DLB with Alzheimer’s disease at the most severe end. Cognitive impairment in these disorders is induced not only by α-synuclein-related neurodegeneration but by multiple regional pathological scores. Both DLB and PDD show heterogeneous pathology and neurochemistry, suggesting that they share important common underlying molecular pathogenesis with Alzheimer’s disease and other proteinopathies. While we prefer to view DLB and PDD as extremes on a continuum, there remains a pressing need to more clearly differentiate these syndromes and to understand the synucleinopathy processes leading to either one.

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Section: Introductionmentioning

confidence: 99%

Are dementia with Lewy bodies and Parkinson’s disease dementia the same disease?

Jellinger¹,

Korczyn

2018

BMC Med

283

216

View full text Add to dashboard Cite

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Dementia with Lewy bodies and Parkinson’s disease-dementia: current concepts and controversies

Jellinger¹

2017

J Neural Transm

225

181

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Dementia with Lewy bodies (DLB) and Parkinson's disease-dementia (PDD), although sharing many clinical, neurochemical and morphological features, according to DSM-5, are two entities of major neurocognitive disorders with Lewy bodies of unknown etiology. Despite considerable clinical overlap, their diagnosis is based on an arbitrary distinction between the time of onset of motor and cognitive symptoms: dementia often preceding parkinsonism in DLB and onset of cognitive impairment after onset of motor symptoms in PDD. Both are characterized morphologically by widespread cortical and subcortical α-synuclein/Lewy body plus β-amyloid and tau pathologies. Based on recent publications, including the fourth consensus report of the DLB Consortium, a critical overview is given. The clinical features of DLB and PDD include cognitive impairment, parkinsonism, visual hallucinations, and fluctuating attention. Intravitam PET and post-mortem studies revealed more pronounced cortical atrophy, elevated cortical and limbic Lewy pathologies (with APOE ε4), apart from higher prevalence of Alzheimer pathology in DLB than PDD. These changes may account for earlier onset and greater severity of cognitive defects in DLB, while multitracer PET studies showed no differences in cholinergic and dopaminergic deficits. DLB and PDD sharing genetic, neurochemical, and morphologic factors are likely to represent two subtypes of an α-synuclein-associated disease spectrum (Lewy body diseases), beginning with incidental Lewy body disease-PD-nondemented-PDD-DLB (no parkinsonism)-DLB with Alzheimer's disease (DLB-AD) at the most severe end, although DLB does not begin with PD/PDD and does not always progress to DLB-AD, while others consider them as the same disease. Both DLB and PDD show heterogeneous pathology and neurochemistry, suggesting that they share important common underlying molecular pathogenesis with AD and other proteinopathies. Cognitive impairment is not only induced by α-synuclein-caused neurodegeneration but by multiple regional pathological scores. Recent animal models and human post-mortem studies have provided important insights into the pathophysiology of DLB/PDD showing some differences, e.g., different spreading patterns of α-synuclein pathology, but the basic pathogenic mechanisms leading to the heterogeneity between both disorders deserve further elucidation. In view of the controversies about the nosology and pathogenesis of both syndromes, there remains a pressing need to differentiate them more clearly and to understand the processes leading these synucleinopathies to cause one disorder or the other. Clinical management of both disorders includes cholinesterase inhibitors, other pharmacologic and nonpharmacologic strategies, but these have only a mild symptomatic effect. Currently, no disease-modifying therapies are available.

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Developing Effective Alzheimer’s Disease Therapies: Clinical Experience and Future Directions

Elmaleh

Farlow

Conti

et al. 2019

JAD

108

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Alzheimer’s disease (AD) clinical trials, focused on disease modifying drugs and conducted in patients with mild to moderate AD, as well as prodromal (early) AD, have failed to reach efficacy endpoints in improving cognitive function in most cases to date or have been terminated due to adverse events. Drugs that have reached clinical stage were reviewed using web resources (such as clinicaltrials.gov, alzforum.org, company press releases, and peer reviewed literature) to identify late stage (Phase II and Phase III) efficacy clinical trials and summarize reasons for their failure. For each drug, only the latest clinical trials and ongoing trials that aimed at improving cognitive function were included in the analysis. Here we highlight the potential reasons that have hindered clinical success, including clinical trial design and choice of outcome measures, heterogeneity of patient populations, difficulties in diagnosing and staging the disease, drug design, mechanism of action, and toxicity related to the long-term use. We review and suggest approaches for AD clinical trial design aimed at improving our ability to identify novel therapies for this devastating disease.

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New cerebrospinal fluid biomarkers in Alzheimer’s disease

Cited by 3 publications

References 20 publications

Are dementia with Lewy bodies and Parkinson’s disease dementia the same disease?

Are dementia with Lewy bodies and Parkinson’s disease dementia the same disease?

Dementia with Lewy bodies and Parkinson’s disease-dementia: current concepts and controversies

Developing Effective Alzheimer’s Disease Therapies: Clinical Experience and Future Directions

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