α-Synuclein in Lewy Body Diseases: Progress, Remaining Challenges and Future Perspectives.

The Role of NAC in Amyloidogenesis in Alzheimer's Disease

Accepted September 14, 1998. From the Neuropharmacology Unit, Defense and Veterans Head Injury Program, Henry M. Jackson Foundation, and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; Veterans Administration Medical Center GRECC, Bedford, Massachusetts; and Departments of Neurology and Pathology, Boston University Medical School, Boston, Massachusetts. Address correspondence to Dr. Litvan, Neuropharmacology Unit, Defense and Veterans Head Injury Program, Henry M. Jackson Foundation, NINDS, NIH, Federal Building, Room 714, 7550 Wisconsin Avenue, Bethesda, MD 20892-9130; e-mail: litvan1@helix.nih.gov Copyright q 1999 American Psychiatric Press, Inc. Clinicopathologic Case Report

LRP10 in α-synucleinopathies

Despite ongoing debate about whether Parkinson's disease (PD) dementia (PDD) and dementia with Lewy bodies (DLB) are separable diseases or a single Lewy body dementia (LBD) spectrum, there are limited investigations of differences between these conditions. We used fixel-based diffusion magnetic resonance imaging and plasma measures to examine white matter integrity and burden of amyloid pathology (using phosphorylated tau-217 [p-tau217]) in 47 patients with DLB, 21 with PDD, 29 with PD, and 23 age-matched controls. We show reduced fiber cross-section in LBD versus PD, and increased concentrations of plasma neurofilament light chain and p-tau217; with p-tau217 and fiber cross-section associated with cognition. Fiber density was reduced in PDD versus DLB, but neither plasma measures nor fiber cross-section differed between LBD subtypes. Our findings suggest that the presence of dementia in LBD is associated with poorer white matter macrostructure and may relate to pathological protein accumulation. Conversely, differences between DLB and PDD may be driven by other factors. Plasma neurofilament light and phosphorylated tau-217 were increased in Lewy body dementia (LBD) relative to Parkinson's disease (PD) and controls. Magnetic resonance imaging (MRI) white matter macrostructure (fiber cross-section) was reduced in LBD relative to PD. In contrast, MRI white matter microstructure (fiber density) was reduced in PD dementia compared to dementia with Lewy bodies. Differences between dementia with Lewy bodies and PD dementia were distinct compared with those between LBD and Parkinson's with normal cognition. Our findings suggest that dementia with Lewy bodies and Parkinson's dementia differ in underlying processes distinct from those driving dementia.

Memantine for patients with Parkinson's disease dementia or dementia with Lewy bodies: a randomised, double-blind, placebo-controlled trial

Chapter 9 Dementia with Lewy Bodies and Parkinson's Disease Dementia

This study investigated clinical and neuropathological differences between DLB and PDD. 52 PDD and 16 DLB cases from the Queen Square Brain Bank (QSBB) for Neurological disorders were included. Comprehensive clinical data of motor and cognitive features were obtained from medical records. Neuropathological assessment included examination of CAA, Lewy body and AD pathology. CAA was more common in DLB than in PDD (P=0.003). The severity of CAA was greater in DLB than in PDD (P=0.009), with significantly higher CAA scores in the parietal lobe (P=0.043), and the occipital lobe (P=0.008), in DLB than in PDD. The highest CAA scores were observed in cases with APOE ε4/4 and ε2/4. Survival analysis showed worse prognosis in DLB, as DLB reached each clinical milestone sooner than PDD. Absence of dyskinesia in DLB is linked to the significantly lower lifetime cumulative dose of levodopa in comparison with PDD. This is the first study which identified prominent concurrent CAA pathology as a pathological substrate of DLB. More prominent CAA and rapid disease progression as measured by clinical milestones distinguish DLB from PDD.

Are there morphological differences between Parkinson's disease-dementia and dementia with Lewy bodies?

Lewy body (LB) inclusions are one of the pathological hallmarks of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). One way to better understand the process leading to LB formation and associated pathogenesis responsible for neurodegeneration in PD and DLB is to examine the content of LB inclusions. Here, we performed a proteomic investigation of cortical LBs, obtained by laser capture microdissection from neurons in the temporal cortex of dementia patients with cortical LB disease. Analysis of over 2500 cortical LBs discovered 296 proteins; of those, 17 had been associated previously with brainstem and/or cortical LBs. We validated several proteins with immunohistochemical staining followed by confocal microscopy. The results demonstrated that heat shock cognate 71 kDa protein (also known as HSC70, HSP73, or HSPA10) was indeed not only colocalized with the majority of LBs in the temporal cortex but also colocalized to LBs in the frontal cortex of patients with diffuse LB disease. Our investigation represents the first extensive proteomic investigation of cortical LBs, and it is expected that characterization of the proteins in the cortical LBs may reveal novel mechanisms by which LB forms and pathways leading to neurodegeneration in DLB and/or advanced PD. Further investigation of these novel candidates is also necessary to ensure that the potential proteins in cortical LBs are not identified incorrectly because of incomplete current human protein database.

Accumulation of the protein α-synuclein into insoluble intracellular deposits termed Lewy bodies (LBs) is the characteristic neuropathological feature of LB diseases, such as Parkinson’s disease (PD), Parkinson’s disease dementia (PDD) and dementia with LB (DLB). α-Synuclein aggregation is thought to be a critical pathogenic event in the aetiology of LB disease, based on genetic analyses, fundamental studies using model systems, and the observation of LB pathology in post-mortem tissue. However, some monogenic disorders not traditionally characterised as synucleinopathies, such as lysosomal storage disorders, iron storage disorders and mitochondrial diseases, appear disproportionately vulnerable to the deposition of LBs, perhaps suggesting the process of LB formation may be a result of processes perturbed as a result of these conditions. The present review discusses biological pathways common to monogenic disorders associated with LB formation, identifying catabolic processes, particularly related to lipid homeostasis, autophagy and mitochondrial function, as processes that could contribute to LB formation. These findings are discussed in the context of known mediators of α-synuclein aggregation, highlighting the potential influence of impairments to these processes in the aetiology of LB formation.

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) share underlying neuropathology. Despite overlapping biology, therapeutic development has been approached separately for these clinical syndromes and there remains no treatment to slow, stop or prevent progression of clinical symptoms and development disability for people living with PD or DLB. Recent advances in biomarker tools, however, have paved new paths for biologic definition and staging of PD and DLB under a shared research framework. Patient-centered research funding organizations see the opportunity for a novel biological staging system for PD and DLB to accelerate and increase success of therapeutic development for the patient communities they serve. Amid growing momentum in the field to develop biological definitions for these neurodegenerative diseases, 7 international nonprofit organizations focused on PD and DLB came together to drive multistakeholder discussion and input on a biological staging system for research. The impact of these convenings to date can be seen in changes incorporated into a proposed biological staging system and growing alignment within the field to rapidly apply new scientific knowledge and biomarker tools to inform clinical trial design. In working together, likeminded nonprofit partners who were initially catalyzed by the significant potential for a biological staging system also realized the power of a shared voice in calling the field to action and have since worked together to establish a coalition to advance precompetitive progress and reduce hurdles to developing better treatments for PD, DLB and biologically related disorders.

To investigate the extent of medial temporal lobe atrophy (MTA) on MRI in Parkinson disease (PD) with and without dementia compared with Alzheimer disease (AD) and dementia with Lewy bodies (DLB) and to determine whether MTA correlates with cognitive impairment in PD and PD dementia (PDD). Coronal T1-weighted MRI scans were acquired from control subjects (n = 39) and patients with PD (n = 33), PDD (n = 31), DLB (n = 25), and AD (n = 31), diagnosed according to standardized clinical diagnostic criteria. Cognitive function was assessed using the Cambridge Cognitive Examination (CAMCOG), and MTA was rated visually using a standardized (Scheltens) scale. More severe MTA was seen in PDD (p = 0.007), DLB (p < 0.001), and AD (p < 0.001) vs control subjects. PD subjects had greater hippocampal atrophy than control subjects (p = 0.015) but less than subjects with DLB and AD, though not with PDD. MTA correlated with CAMCOG score and memory scores in the DLB group and with age in control, PDD, and AD groups. There were no correlations between MTA and cognitive impairment in PD, PDD, and AD. PDD and DLB had a similar profile of cognitive impairment and MTA. Medial temporal lobe atrophy (MTA) was seen in cognitively intact older subjects with Parkinson disease (PD) and was not more pronounced in Parkinson disease dementia (PDD). Alzheimer disease (AD) and, to a lesser extent, dementia with Lewy bodies (DLB) showed more pronounced MTA. Results suggest early hippocampal involvement in PD and that when dementia develops in PD, anatomic structures apart from the hippocampus are predominantly implicated. Greater hippocampal involvement in AD vs PDD and DLB is consistent with clinical, cognitive, and pathologic differences between the disorders.

Objective To compare the difference in heart rate variability(HRV)between patients with dementia with Lewy bodies(DLB)and those with Parkinson disease dementia(PDD)and to identify the influencing factors. Methods We retrospectively enrolled 30 patients with DLB(DLB group)and 41 patients with PDD(PDD group)at the outpatient and inpatient services of our hospital from January 2010 to December 2017 in this study, and further recruited 119 normal elderly individuals to serve as the control group.HRV was recorded with 24 h dynamic electrocardiogram and compared between the DLB group and the PDD group.Time domain measures including standard deviation of all normal to normal(NN)intervals(SDNN)and square root of the mean squared differences of successive NN intervals(rMSSD)and frequency domain measures including total power(TP), low frequency(LF), and high frequency(HF)were analyzed with a customized program.The levodopa equivalent dose(LED), mini-mental state examination(MMSE), Montreal Cognitive Assessment(MoCA), Hoehn-Yahr stage(H-Y stage)and the unified Parkinson's disease rating scale Ⅲ(UPDRS Ⅲ), and the Alzheimer's disease Cooperative Study-Activities of Daily Living scale(ADCS-ADL)were assessed in DLB and PDD patients to investigate the influencing factors. Results SDNN, TP, and LF in the DLB group and the PDD group were significantly lower than in the control group(F=14.154, 4.742, 4.897, P 0.05). The DLB group and the PDD group did not differ in HF from the control group(P>0.05). There was no significant difference in any HRV indexes between DLB and PDD patients(P>0.05). Correlation analysis showed no correlation of HRV with cognitive level(MMSE, MoCA), motor disturbance degree(UPDRS Ⅲ, H-Yahr stage), daily living ability(ADCS-ADL), or dosage of anti-PD drugs(each P>0.05). Conclusions DLB and PDD patients present similar impairments in autonomic nervous system function, which are not associated with disease severity. Key words: Dementia; Lewy bodies; Parkinson disease; Heart rate variability

Parkin Localizes to the Lewy Bodies of Parkinson Disease and Dementia with Lewy Bodies

Dementia with Lewy bodies (DLB), Parkinson’s disease dementia (PDD), and Parkinson’s disease (PD) collectively known as Lewy body diseases (LBDs) are neuropathologically characterised by α-synuclein deposits (Lewy bodies and Lewy neurites). However, LBDs also exhibit pathology associated with Alzheimer’s disease (AD) (i.e. hyperphosphorylated tau and amyloid β (Aβ). Aβ can be deposited in the walls of blood vessels in the brains of individuals with AD, termed cerebral amyloid angiopathy (CAA). The aim of this study was to investigate the type and distribution of CAA in DLB, PDD, and PD and determine if this differs from AD. CAA type, severity, and topographical distribution was assessed in 94 AD, 30 DLB, 17 PDD, and 11 PD cases, and APOE genotype evaluated in a subset of cases where available. 96.3% AD cases, 70% DLB cases and 82.4% PDD cases exhibited CAA (type 1 or type 2). However only 45.5% PD cases had CAA. Type 1 CAA accounted for 37.2% of AD cases, 10% of DLB cases, and 5.9% of PDD cases, and was not observed in PD cases. There was a hierarchical topographical distribution in regions affected by CAA where AD and DLB displayed the same distribution pattern that differed from PDD and PD. APOE ε4 was associated with severity of CAA in AD cases. Topographical patterns and severity of CAA in DLB more closely resembled AD rather than PDD, and as type 1 CAA is associated with clinical dementia in AD, further investigations are warranted into whether the increased presence of type 1 CAA in DLB compared to PDD are related to the onset of cognitive symptoms and is a distinguishing factor between LBDs. Possible alignment of the the topographical distribution of CAA and microbleeds in DLB warrants further investigation. CAA in DLB more closely resembles AD rather than PDD or PD, and should be taken into consideration when stratifying patients for clinical trials or designing disease modifying therapies.