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Lewy body disorders (LBD) are common neurodegenerative diseases characterized by the presence of aggregated α-synuclein in Lewy bodies and Lewy neurites in the central and peripheral nervous systems. The brains of patients with LBD often display other comorbid pathologies, i.e. insoluble tau, β-amyloid aggregates, TAR DNA-binding protein 43 (TDP-43) deposits, and argyrophilic grain disease (AGD). The incidence and physiological relevance of these concurrent pathological findings remain controversial. We performed a semiquantitative detailed mapping of α-synuclein, tau, β-amyloid (Aβ), TDP-43, and AGD pathologies in 17 areas in 63 LBD cases (44 with Parkinson disease [PD], 28 with dementia, and 19 with dementia with Lewy bodies). APOE and MAPT genetic variants were also investigated. A majority of LBD cases had 2 or 3 concomitant findings, particularly Alzheimer disease-related pathology. Pathological stages of tau, β-amyloid and α-synuclein pathologies were increased in cases with dementia. Aβ score was the best correlate of the time to dementia in PD. In addition, β-amyloid deposition correlated with α-synuclein load in all groups. MAPT H1 haplotype did not influence any assessed pathology in PD. These results highlight the common concurrence of pathologies in patients with LBD that may have an impact on the clinical expression of the diseases.

Currently, the neuropathological diagnosis of Lewy body disease (LBD) may be stated according to several staging systems, which include the Braak Lewy body stages (Braak), the consensus criteria by McKeith and colleagues (McKeith), the modified McKeith system by Leverenz and colleagues (Leverenz), and the Unified Staging System by Beach and colleagues (Beach). All of these systems use semi-quantitative scoring (4- or 5-tier scales) of Lewy pathology (LP; i.e., Lewy bodies and Lewy neurites) in defined cortical and subcortical areas. While these systems are widely used, some suffer from low inter-rater reliability and/or an inability to unequivocally classify all cases with LP. To address these limitations, we devised a new system, the LP consensus criteria (LPC), which is based on the McKeith system, but applies a dichotomous approach for the scoring of LP (i.e., “absent” vs. “present”) and includes amygdala-predominant and olfactory-only stages. α-Synuclein-stained slides from brainstem, limbic system, neocortex, and olfactory bulb from a total of 34 cases with LP provided by the Newcastle Brain Tissue Resource (NBTR) and the University of Pennsylvania brain bank (UPBB) were scanned and assessed by 16 raters, who provided diagnostic categories for each case according to Braak, McKeith, Leverenz, Beach, and LPC systems. In addition, using LP scores available from neuropathological reports of LP cases from UPBB (n = 202) and NBTR (n = 134), JT (UPBB) and JA (NBTR) assigned categories according to all staging systems to these cases. McKeith, Leverenz, and LPC systems reached good (Krippendorff’s α ≈ 0.6), while both Braak and Beach systems had lower (Krippendorff’s α ≈ 0.4) inter-rater reliability, respectively. Using the LPC system, all cases could be unequivocally classified by the majority of raters, which was also seen for 97.1% when the Beach system was used. However, a considerable proportion of cases could not be classified when using Leverenz (11.8%), McKeith (26.5%), or Braak (29.4%) systems. The category of neocortical LP according to the LPC system was associated with a 5.9 OR (p < 0.0001) of dementia in the 134 NBTR cases and a 3.14 OR (p = 0.0001) in the 202 UPBB cases. We established that the LPC system has good reproducibility and allows classification of all cases into distinct categories. We expect that it will be reliable and useful in routine diagnostic practice and, therefore, suggest that it should be the standard future approach for the basic post-mortem evaluation of LP.

Abstract This study was designed to correlate clinical findings with the extent of pathologic a-synuclein (aSyn) in the brain using the Unified Staging System for Lewy Body disorders (USSLB). Data from 280 cases from the Arizona Study of Aging and Neurodegenerative Disorders are presented. Each case had a complete USSLB staging and at least 1 full research clinical assessment, including subspecialty neurologist-administered movement and cognitive evaluation. Of the 280, 25.7% were cognitively normal, 8.6% had mild cognitive impairment, and 65.7% had dementia. All cases could be categorized into 1 of 5 USSLB stages (8.6% stage I—olfactory bulb only; 15.4% IIa—brainstem predominant; 13.6% IIb—limbic predominant; 31.8% III—brainstem and limbic; and 30.7% IV—neocortical) yet using the Braak staging system 70 cases (25.3%) could not be classified. Those with USSLB stages III and IV died at a younger age. Multiple measures of motor parkinsonism, cognitive impairment, hyposmia, and probable RBD were significantly correlated with increasing USSLB stage. We conclude that the USSLB is the most comprehensive staging system for all Lewy body disorders and allows for categorization and ranking of all brains with significant correlations to many motor and nonmotor clinical signs and symptoms.

In Lewy body diseases—including Parkinson’s disease, without or with dementia, dementia with Lewy bodies, and Alzheimer’s disease with Lewy body co-pathology 1 —α-synuclein (α-Syn) aggregates in neurons as Lewy bodies and Lewy neurites 2 . By contrast, in multiple system atrophy α-Syn accumulates mainly in oligodendrocytes as glial cytoplasmic inclusions (GCIs) 3 . Here we report that pathological α-Syn in GCIs and Lewy bodies (GCI-α-Syn and LB-α-Syn, respectively) is conformationally and biologically distinct. GCI-α-Syn forms structures that are more compact and it is about 1,000-fold more potent than LB-α-Syn in seeding α-Syn aggregation, consistent with the highly aggressive nature of multiple system atrophy. GCI-α-Syn and LB-α-Syn show no cell-type preference in seeding α-Syn pathology, which raises the question of why they demonstrate different cell-type distributions in Lewy body disease versus multiple system atrophy. We found that oligodendrocytes but not neurons transform misfolded α-Syn into a GCI-like strain, highlighting the fact that distinct α-Syn strains are generated by different intracellular milieus. Moreover, GCI-α-Syn maintains its high seeding activity when propagated in neurons. Thus, α-Syn strains are determined by both misfolded seeds and intracellular environments. Distinct strains of misfolded α-synuclein proteins, which aggregate in neurons in Lewy body diseases or in oligodendrocytes in multiple system atrophy, are formed as a consequence of differences between intracellular environments.

Progressive aggregation of alpha-synuclein (αS) through formation of amorphous pale bodies to mature Lewy bodies or in neuronal processes as Lewy neurites may be the consequence of conformational protein changes and accumulations, which structurally represents “molecular template”. Focal initiation and subsequent spread along anatomically connected structures embody “structural template”. To investigate the hypothesis that both processes might be closely associated and involved in the progression of αS pathology, which can be observed in human brains, αS amyloidogenic precursors termed “seeds” were experimentally injected into the brain or peripheral nervous system of animals. Although these studies showed that αS amyloidogenic seeds can induce αS pathology, which can spread in the nervous system, the findings are still not unequivocal in demonstrating predominant transsynaptic or intraneuronal spreads either in anterograde or retrograde directions. Interpretation of some of these studies is further complicated by other concurrent aberrant processes including neuroimmune activation, injury responses and/or general perturbation of proteostasis. In human brain, αS deposition and neuronal degeneration are accentuated in distal axon/synapse. Hyperbranching of axons is an anatomical commonality of Lewy-prone systems, providing a structural basis for abundance in distal axons and synaptic terminals. This neuroanatomical feature also can contribute to such distal accentuation of vulnerability in neuronal demise and the formation of αS inclusion pathology. Although retrograde progression of αS aggregation in hyperbranching axons may be a consistent feature of Lewy pathology, the regional distribution and gradient of Lewy pathology are not necessarily compatible with a predictable pattern such as upward progression from lower brainstem to cerebral cortex. Furthermore, “focal Lewy body disease” with the specific isolated involvement of autonomic, olfactory or cardiac systems suggests that spread of αS pathology is not always consistent. In many instances, the regional variability of Lewy pathology in human brain cannot be explained by a unified hypothesis such as transsynaptic spread. Thus, the distribution of Lewy pathology in human brain may be better explained by variable combinations of independent focal Lewy pathology to generate “multifocal Lewy body disease” that could be coupled with selective but variable neuroanatomical spread of αS pathology. More flexible models are warranted to take into account the relative propensity to develop Lewy pathology in different Lewy-prone systems, even without interconnections, compatible with the expanding clinicopathological spectra of Lewy-related disorders. These revised models are useful to better understand the mechanisms underlying the variable progression of Lewy body diseases so that diagnostic and therapeutic strategies are improved.

Aggregation of α-synuclein is a defining molecular feature of Parkinson’s disease, Lewy body dementia, and multiple systems atrophy. Hereditary mutations in α-synuclein are linked to both Parkinson’s disease and Lewy body dementia; in particular, patients bearing the E46K disease mutation manifest a clinical picture of parkinsonism and Lewy body dementia, and E46K creates more pathogenic fibrils in vitro. Understanding the effect of these hereditary mutations on α-synuclein fibril structure is fundamental to α-synuclein biology. We therefore determined the cryo-electron microscopy (cryo-EM) structure of α-synuclein fibrils containing the hereditary E46K mutation. The 2.5-Å structure reveals a symmetric double protofilament in which the molecules adopt a vastly rearranged, lower energy fold compared to wild-type fibrils. We propose that the E46K misfolding pathway avoids electrostatic repulsion between K46 and K80, a residue pair which form the E46-K80 salt bridge in the wild-type fibril structure. We hypothesize that, under our conditions, the wild-type fold does not reach this deeper energy well of the E46K fold because the E46-K80 salt bridge diverts α-synuclein into a kinetic trap—a shallower, more accessible energy minimum. The E46K mutation apparently unlocks a more stable and pathogenic fibril structure.

α-Synuclein (α-syn) phosphorylation at serine 129 (pS129–α-syn) is substantially increased in Lewy body disease, such as Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). However, the pathogenic relevance of pS129–α-syn remains controversial, so we sought to identify when pS129 modification occurs during α-syn aggregation and its role in initiation, progression and cellular toxicity of disease. Using diverse aggregation assays, including real-time quaking-induced conversion (RT-QuIC) on brain homogenates from PD and DLB cases, we demonstrated that pS129–α-syn inhibits α-syn fibril formation and seeded aggregation.We also identified lower seeding propensity of pS129–α-syn in cultured cells and correspondingly attenuated cellular toxicity. To build upon these findings, we developed a monoclonal antibody (4B1) specifically recognizing nonphosphorylated S129–α-syn (WT–α-syn) and noted that S129 residue is more efficiently phosphorylated when the protein is aggregated. Using this antibody, we characterized the time-course of α-syn phosphorylation in organotypic mouse hippocampal cultures and mice injected with α-syn preformed fibrils, and we observed aggregation of nonphosphorylated α-syn followed by later pS129–α-syn. Furthermore, in postmortem brain tissue from PD and DLB patients, we observed an inverse relationship between relative abundance of nonphosphorylated α-syn and disease duration. These findings suggest that pS129–α-syn occurs subsequent to initial protein aggregation and apparently inhibits further aggregation. This could possibly imply a potential protective role for pS129–α-syn, which has major implications for understanding the pathobiology of Lewy body disease and the continued use of reduced pS129–α-syn as a measure of efficacy in clinical trials.

Involvement of the olfactory bulb by Lewy-type α-synucleinopathy (LTS) is known to occur at an early stage of Parkinson’s disease (PD) and Lewy body disorders and is therefore of potential usefulness diagnostically. An accurate estimate of the specificity and sensitivity of this change has not previously been available. We performed immunohistochemical α-synuclein staining of the olfactory bulb in 328 deceased individuals. All cases had received an initial neuropathological examination that included α-synuclein immunohistochemical staining on sections from brainstem, limbic and neocortical regions, but excluded olfactory bulb. These cases had been classified based on their clinical characteristics and brain regional distribution and density of LTS, as PD, dementia with Lewy bodies (DLB), Alzheimer’s disease with LTS (ADLS), Alzheimer’s disease without LTS (ADNLS), incidental Lewy body disease (ILBD) and elderly control subjects. The numbers of cases found to be positive and negative, respectively, for olfactory bulb LTS were: PD 55/3; DLB 34/1; ADLS 37/5; ADNLS 19/84; ILBD 14/7; elderly control subjects 5/64. The sensitivities and specificities were, respectively: 95 and 91% for PD versus elderly control; 97 and 91% for DLB versus elderly control; 88 and 91% for ADLS versus elderly control; 88 and 81% for ADLS versus ADNLS; 67 and 91% for ILBD versus elderly control. Olfactory bulb synucleinopathy density scores correlated significantly with synucleinopathy scores in all other brain regions (Spearman R values between 0.46 and 0.78) as well as with scores on the Mini-Mental State Examination and Part 3 of the Unified Parkinson’s Disease Rating Scale (Spearman R −0.27, 0.35, respectively). It is concluded that olfactory bulb LTS accurately predicts the presence of LTS in other brain regions. It is suggested that olfactory bulb biopsy be considered to confirm the diagnosis in PD subjects being assessed for surgical therapy.

Background Parkinson’s disease (PD) is a progressive neurodegenerative disorder associated with a loss of dopaminergic (DA) neurons. Despite symptomatic therapies, there is currently no disease-modifying treatment to halt neuronal loss in PD. A major hurdle for developing and testing such curative therapies results from the fact that most DA neurons are already lost at the time of the clinical diagnosis, rendering them inaccessible to therapy. Understanding the early pathological changes that precede Lewy body pathology (LBP) and cell loss in PD will likely support the identification of novel diagnostic and therapeutic strategies and help to differentiate LBP-dependent and -independent alterations. Several previous studies identified such specific molecular and cellular changes that occur prior to the appearance of Lewy bodies (LBs) in DA neurons, but a concise map of such early disease events is currently missing. Methods Here, we conducted a literature review to identify and discuss the results of previous studies that investigated cases with incidental Lewy body disease (iLBD), a presumed pathological precursor of PD. Results Collectively, our review demonstrates numerous cellular and molecular neuropathological changes occurring prior to the appearance of LBs in DA neurons. Conclusions Our review provides the reader with a summary of early pathological events in PD that may support the identification of novel therapeutic and diagnostic targets and aid to the development of disease-modifying strategies in PD.

Lewy body dementia (DLB) is a common form of cognitive impairment, accounting for 30% of dementia cases in ages over 65 years. Early diagnosis of DLB has been challenging; particularly in the context of differentiation with Parkinson’s disease dementia and other forms of dementias, such as Alzheimer’s disease and rapidly progressive dementias. Current practice involves the use of [123I]FP-CIT-SPECT, [18F]FDG PET and [123I]MIBG molecular imaging to support diagnostic procedures. Structural imaging techniques have an essential role for excluding structural causes, which could lead to a DLB-like phenotype, as well as aiding differential diagnosis through illustrating disease-specific patterns of atrophy. Novel PET molecular imaging modalities, such as amyloid and tau imaging, may provide further insights into DLB pathophysiology and may aid in early diagnosis. A multimodal approach, through combining various established techniques and possibly using novel radioligands, might further aid towards an in-depth understanding of this highly disabling disease. In this review, we will provide an overview of neuroimaging applications in patients with DLB.