Abstract
Background
Dementia 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.
Discussion
The 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.
Conclusion
DLB 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.
Background
The nosologic relationship, as defined by DSM-5 [1, 2], between dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), both of which are major neurocognitive disorders with α-synuclein (αSyn) deposition/Lewy bodies (LB), is continuously being debated [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22].
The clinical features of DLB and PDD are similar and include dementia, cognitive fluctuations, and (visual) hallucinations in the setting of clinical or latent parkinsonism. The cognitive domains of both disorders overlap, with progressive executive dysfunctions, visual-spatial abnormalities, and memory disorders [10]. Based on international consensus, DLB is diagnosed when cognitive impairment precedes parkinsonian motor signs or begins within 1 year from its onset [23], whereas in PDD, cognitive impairment develops in the setting of well-established Parkinson’s disease (PD) [24]. DLB patients will also develop parkinsonism of increasing severity over the years, although 25% of them never develop parkinsonian symptoms [25]. Despite different temporal sequences of motor and cognitive deficits and several quantitative clinical differences, both disorders show largely convergent, albeit locally and quantitatively divergent neuropathological lesions, associated with increased Aβ and tau loads in DLB [9, 26,27,28,29,30]. The overlap of clinical and morphological features has led to the debate of whether DLB and PDD are the same disease [17], different phenotypic expressions of the same αSyn/Lewy body disease (LBD) spectrum, or distinct ‘diseases’ [3, 31] sharing genetic risk features with PD and Alzheimer’s disease (AD) [10, 32], despite recent studies indicating a regional overlap of pathologies [33,34,35,36,37]. The present paper will critically review the major current findings in DLB and PDD, their possible nosologic interrelations, and the available biological markers and therapies. Of note, this review does not include mild cognitive impairment in LBD (see [8, 38,39,40,41,42,43,44,45,46]).
Clinical features and diagnostic criteria of DLB
The presenting features of DLB can be broadly placed into three categories, namely cognitive impairment, behavioral/psychiatric phenomena, and physical symptoms [47]. Essential for its diagnosis are dementia with moderate memory impairment, deficits in attention, executive dysfunction and visuoperceptual ability, fluctuating cognition (presumably related to thalamic damage and cholinergic imbalance [48]), and recurrent visual hallucinations that are well formed and detailed [2]. Hallucinations in DLB may occur spontaneously, independent of visuospatial and perceptional impairment [49], and possibly related to LBs in the temporal lobe [50], while in PDD they typically occur after dopaminergic therapy [10, 23, 51]. Nevertheless, hallucinations had been reported prior to the levodopa era [52] as well as in drug-naive PD patients even in the premotor phase [53]. Language impairment tends to be mild, with verbal and semantic fluency deficits. Spontaneous parkinsonian features, such as bradykinesia and rigidity, are common in DLB (over 85%) [31], while rest tremor is less frequent [54]. 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]. Further, the rate of cognitive decline is reportedly faster in DLB than in PDD and AD [63, 64] (Table 1).
Supporting clinical features for the diagnosis of probable or possible DLB are repeated falls, syncopes, hyposmia, severe autonomic dysfunction, hypersomnia, hallucinations in non-visual modalities, apathy, depression, and severe sensitivity to antipsychotic agents [2, 65]. However, since these changes also occur in advanced PD, they cannot differentiate DLB from PDD, e.g., the prevalence of neuroleptic sensitivity does not differ significantly between them [66].
A diagnosis of clinically probable DLB requires (1) two or more core clinical features to be present, with or without indicative biomarkers, or (2) the presence of only one core clinical feature but with one or more indicative biomarkers [2]. Although the diagnostic specificity of these criteria is high (range 79–100%), the sensitivity can be low (12–88%), improving with additional supporting features such as biomarkers [67,68,69,70]. A recent meta-analysis reported a pooled sensitivity, specificity, and accuracy of 60.2% (95% CI 30.9–83.7%), 93.8% (83.8–97.6%), and 79.7% (62.6–90.7%), respectively, for the diagnostic [23] criteria of DLB [68]. Thus, currently, approximately 20% of DLB diagnoses are incorrect [68, 69].
Clinical features and diagnostic guidelines of PDD
The clinical features of PDD are in many respects similar to those seen in DLB, although, by definition [23, 71], the occurrence of parkinsonism distinguishes one from the other. Rigidity and akinesia occur both in PDD and DLB [62]. Cognitive impairments in PDD are common and are similar in quality to those of DLB [8]. However, the timing, profile, and rate of cognitive decline vary widely; indeed, the average time to dementia after PD diagnosis is almost 10 years, but may be as long as 20 years [39]. Consensus criteria for PDD [24, 72, 73] require cognitive impairment across multiple domains, mood disturbances, and visual-spatial impairment similar to that seen in DLB. Attentional fluctuations, which are characteristic of DLB, are less frequent in PDD [72] but are clinically indistinguishable in the two conditions [74]. Executive functions are probably more impaired in PDD, while language deficits are rare [71]. Visual symptoms, common in PDD [75] likely due to a reduced metabolism in both dorsal and ventral visual pathways [76], include visual hallucinations, although they are less common than in DLB [77]; yet, the phenomenology of hallucinations is similar in both disorders [78]. Other non-motor features, including autonomic dysfunctions and sleep disorders, may occur disproportionally to the severity of dementia [24, 72], while mood disturbances have a similar frequency as in DLB. The psychosis spectrum of PD has recently been reviewed [79]. RBD can evolve in PDD and DLB [80] in up to 90% of patients after > 10 years [81]. Finally, clinical validation efforts for PDD have shown variable diagnostic sensitivity and specificity [82, 83] and should be considered using the Movement Disorder Society criteria for the diagnosis of PDD [84].
Epidemiology and natural history of DLB and PDD
Approximately 1–2% of those aged above 65 years are diagnosed with DLB worldwide [16], affecting approximately 5% of all dementia cases in those over the age of 75 [85]. Its incidence is 0.7–1.4 new cases/100,000 person-years [16] or 3.5/100,000 person-years [86]. For PDD, the cumulative prevalence is of 75% of PD patients surviving more than 10 years [87], 83% after 20 years [88], and up to 95% by age 90 years [16], with an overall prevalence of 31.1% (95% CI 20.1–42.1) and incidence rates from 0.43 to 1.13/100,000 person-years [89], indicating that, annually, approximately 10% of a PD population will develop dementia [24]. The data concerning age at disease or dementia onset are highly variable. Whereas in the Olmsted County study [86] DLB patients were younger at symptom onset than those with PDD and had more hallucinations and cognitive fluctuations, others have reported younger age at disease onset in PDD [27, 90, 91], or no essential differences between disorders [14, 37, 92, 93].
Individuals with DLB or PDD have an increased mortality compared with the general population [94]. DLB patients with a cerebrospinal fluid (CSF) AD profile and structural MRI changes (hippocampal atrophy) have a shorter survival [95, 96]; similarly, dementia and/or neuritic AD pathology in PD are related to a significantly shorter survival [97]. PDD is associated with high mortality, advancing death by approximately 4 years [98]. For typical DLB, the average survival time from the beginning of symptoms is 5–8 years [99], while rapidly progressing cases have a mean duration of 9 months [100]. In both disorders, older age, hallucinations, and fluctuating dementia at onset are the best predictors of poor outcome [101, 102].
Diagnostic tests (Table 2)
Neuroimaging
The neuroimaging characteristics have been reviewed in a quest for multimodal methods able to improve ante mortem diagnosis [103, 104]. Studies using 123I-β-CIT (DaTScan) SPECT or 18Fluorodopa PET demonstrated reduced dopamine transport binding in caudate and posterior putamen in DLB compared to AD, but observed no differences between DLB and PDD [105, 106]. Further, lower 123I–ioflupane-CIT has been observed in caudate nucleus in DLB and a greater asymmetry of uptake was seen in the posterior putamen in PDD [104, 107]. Dopamine uptake in striatum is significantly lower in PDD compared to DLB (P < 0.04), consistent with dopaminergic cell loss in substantia nigra pars compacta and the severity of parkinsonism [108]. The disruption of dopaminergic pathways impacts the modulation of intrinsic brain networks, resulting in poor motor and cognitive performance [109].
SPECT imaging using 123I–metaiodobenzylguanidine, a marker of postganglionic sympathetic innervation, showed reduced cardiac uptake in both DLB and PDD as compared with AD [110, 111]. The sensitivity, specificity, and accuracy for the diagnosis of probable DLB is 82.4%, 96.3%, and 92.5%, respectively [112]; yet, although specific data on PDD are not available, 123I–metaiodobenzylguanidine imaging is unlikely to differentiate PDD from DLB.
Voxel-based morphometric MRI studies revealed greater grey matter loss in frontotemporal, occipital, and parietal areas in DLB compared to PDD [113,114,115,116,117,118]. Decreased grey matter volumes in association areas (left precuneus and inferior temporal lobe) are correlated with visual hallucinations in DLB [119], and atrophy of caudate, putamen, and pallidum have been observed in DLB but not in PDD [120,121,122,123]. However, since greater volume loss in various brain regions has not been statistically confirmed [124], these differences cannot be used for individual diagnoses.
White matter hyperintensities (WMH) on T2-weighted MRI have been observed in parieto-occipital areas in PDD cases with low CSF Aβ levels [125], without significant difference of progression between PDD and DLB [126], but more severe WMHs have been observed in the temporal lobe in DLB [127]. Thus, evaluation of WMH and medial temporal lobe atrophy using MRI may be a powerful diagnostic tool to investigate the progression of AD-related pathology in DLB and perhaps to distinguish DLB from PDD [126, 128]. Magnetic resonance spectroscopy studies found relatively normal N-acetylaspartate/creatinine ratios in DLB, with similar reductions being observed in PDD and AD [129].
PET, perfusion SPECT, and arterial spin labelling MRI studies showed parietal, frontal, temporal, and occipital hypoperfusion common to both entities [104, 130,131,132,133,134,135]. Further, 11C PIB-PET imaging showed increased Aβ brain deposition in more than 50% of DLB cases, with more modest and less frequent Aβ accumulation in PDD [106, 136,137,138,139], while others reported increased cortical Aβ binding without dissimilarity between PDD and DLB [140]. Tau-PET imaging, along with temporal atrophy, may indicate co-existing AD pathology in DLB with variable cortical tau 18F–AV-1451 uptake, which appears more common than in PDD [141, 142]. Preliminary tau-PET studies suggest a gradient of tau binding from PD/non-demented (minimal) to PDD (low), DLB (intermediate), and AD (highest) [143]. Finally, the recently described additional 18F–AV-1451 binding to (neuro)melanin [144] deserves further investigation.
Electrophysiology and other studies
EEG abnormalities from posterior leads have been observed in all DLB cases and in three-quarters of those with PDD [145]. Further, a multicenter study supported the validity of quantitative EEG analysis as a tool for diagnosis of both disorders and their distinction from AD [146, 147], although some components may be reduced more in PDD than in DLB [148]. Finally, transcranial sonographic hyperechogenicity was inconclusive in differentiating DLB from PDD [149]; a comparative electro-oculographic study showed similar impairment in all tasks in both disorders [150].
Genetics
Both DLB and PD are primarily sporadic diseases, yet genetic factors may be involved in their causation. Recent studies have uncovered certain genetic differences between PDD and DLB, albeit none of which is diagnostic. There is a substantial genetic contribution to DLB, heritability being estimated at about 36% [151, 152], while different genetic markers within the α-Syn gene (SNCA) may be associated with PDD [153, 154], although this is not unexpected in PD (Table 3). Analyses of SNCA expression in PDD and DLB showed an overlap of αSyn biology, indicating that they have distinct genetic etiologies and predicting that several mechanisms may be specific [154]. Genome-wide association studies (GWAS) identified variants in the GBA, SNCA, APOE, and MAPT loci influencing the individual risk for DLB, suggesting that it has shared genetic risk features with PD and AD [32, 155], while the APOE4 haplotype may be an indication of PDD [156]. However, to date, the genetic differences between both entities have not been studied in detail [157]; further studies will increase our understanding of the pathophysiology of these diseases [158].
Fluid biomarkers
The development of broadly applicable CSF and other biomarkers for both DLB and PDD remains elusive, with only few biomarker candidates having been shown to specifically reflect the underlying disease process [159,160,161] (Table 2). A CSF AD profile is more common in DLB [162], while cortical atrophy in PDD is associated with increased total CSF αSyn and t-tau [159]. However, cognitive impairment in GBA-associated PD does not seem to be associated with Aβ and tau profiles in CSF [163]. The elevated tau/Aβ42 index in the order PD < PDD < DLB < AD may be related to an increased AD pathology [164]. Further, levels of αSyn oligomers in CSF are increased in PDD but not in DLB [165,166,167]. Although many CSF and some plasma markers have been identified in both disorders, very few studies have examined samples from both disorders simultaneously, and only a minority have been confirmed by post mortem studies [167, 168].
Neuropathology
The pathological substrates of DLB and PDD have been extensively investigated [9, 27, 29, 30, 35,36,37, 41, 169,170,171,172,173,174,175,176,177,178,179,180,181]. The most difficult problem in defining DLB and PDD at autopsy is their relationship with AD. DLB is, in part, conceived as a variant of AD (‘Lewy body variant of AD’) [182] and significant AD pathology is a consistent but not universal finding in both disorders [181]. Cerebral neurofibrillary tangle burden, along with αSyn and Aβ plaque pathology, are the strongest predictors of a shorter interval between motor and dementia symptom onset and shorter survival [183].
The pathological substrate of PDD includes (1) Lewy/αSyn pathology in cortical, limbic, and brainstem structures, (2) AD-related pathologies, and (3) a combination of these lesions that has been shown to most robustly correlate with the severity of cognitive impairment [41, 169, 173, 174]. Approximately 50% of PDD patients showed Braak LB stages 4–6 plus severe AD-type pathology [92, 174], which may act synergistically [9, 27, 35, 172,173,174, 184, 185], influencing clinical features including a shorter duration or a more malignant course [169, 172]. AD neuropathology seems to be a more specific correlate of dementia than cortical αSyn pathology [169, 173]. Substantia nigra cell loss is more severe in PDD than in DLB [15], consistent with more advanced parkinsonism.
Multiple neurotransmitter deficits occur in PDD [29, 172], including loss of limbic and cortically projecting dopaminergic neurons in the mesocortical limbic system [172] and involvement of the cholinergic system with loss of neurons in the nucleus basalis of Meynert leading to cortical cholinergic denervation [9, 171, 186]. Severe pathology also involves the noradrenergic locus coeruleus, causing dysfunction of the related circuitry [170]. Pedunculopontine cholinergic cell loss occurs in hallucinating PDD patients but not in DLB, which may indicate a different pattern of degeneration of cholinergic input structures [187].
DLB is featured by the co-occurrence of Lewy/αSyn pathology involving cortical and limbic areas (Braak LB stages 3–6) and AD-related pathologies. While some authors suggest that high cortical LB burden is the only independent predictor of dementia in DLB [177], others consider AD-related pathology to be more important [188]; however, studies have shown a strong correlation between both cortical pathologies [169, 173].
The DLB clinical syndrome is positively correlated to the extent of LB pathology (LBP) and negatively to the severity of neuritic AD pathology, while Aβ load has no effect [189]. A subgroup with the clinical picture of DLB was shown to have minimal cerebral amyloid deposition [190]. The higher cortical LB load in the temporal and parietal regions, which seems to be a distinguishing feature of DLB, may account for the shorter latency to dementia and could be accelerated by the APOE ε4 allele [177]. Further, αSyn is an important predictor of disease duration both independently and synergistically with tau and Aβ load [191].
Other co-occurring pathologies (cerebrovascular lesions, cerebral amyloid angiopathy, hippocampal sclerosis, argyrophilic grain disease, and TDP-43 deposits) in PDD (19%) and DLB-AD (31.3%) brains appear to be of minor importance [35, 172, 192,193,194], although they may influence the development of dementia [195]. Cerebrovascular lesions in DLB are relatively mild, showing an inverse relationship with the severity of LBP [196,197,198]. Cerebral microbleeds are more frequent in DLB than in PDD [199], with highest densities in the occipital lobe [200], but they appear to be independent of cerebral amyloid angiopathy [201].
Morphological overlap
Both PDD and DLB may show similar neuropathological features, with a variable mixture of αSyn/LB and AD-related pathologies (Table 4). A common pathophysiological factor is synaptic dysfunction due to the initial aggregation of αSyn in the presynapses causing functional disconnection [202] due to interference with axonal transport and neurotransmitter deprivation [178, 180, 203, 204]. The relationship between phosphorylated αSyn and tau accumulation to Aβ deposition in the cerebral cortex [205, 206] suggests that there is an overlap in the pathology between AD and DLB, and that Aβ promotes the accumulation of both αSyn and tau [35,36,37]. Thus, cognitive decline and related symptoms are not a consequence of αSyn-induced neurodegeneration alone since Aβ and tau pathologies also contribute to the overall deficits [33, 35,36,37, 207].
Morphological differences
Despite many similarities, several morphological differences have been demonstrated, including higher Aβ load in striatum [34, 208], cortex, and claustrum [33, 177, 197, 209,210,211] and in the entorhinal cortex, amygdala, and putamen in DLB [27]. The presence of Aβ in DLB and less so in PDD, along with its great sensitivity to differentiate between the disorders, have been extensively investigated [33, 34, 177, 209], with a hierarchy PD < PDD < DLB in both Aβ and tau burden [143] (Table 4).
Further differences include a more severe αSyn load in hippocampal subarea C2 in DLB [29] and in amygdala in DLB compared to in PDD (78.7% vs. 36% and 92% vs. 30%, respectively) [212], whereas αSyn loads in PD are highest in the cingulate cortex [33]. Other deviations include the severity and distribution pattern of lesions in substantia nigra pars compacta (predominant neuronal loss in the ventrolateral parts in PDD versus more severe damage in the dorsolateral parts in DLB) and less marked nigral neuronal loss causing less severe postsynaptic dopaminergic upregulation [209, 213]. Additionally, significantly higher 5-HT1A receptor binding density in the cortex was seen in DLB compared to PDD [214]. The heterogeneous neurochemistry of both DLB and PDD, which depends on differences in pathology, suggests that these αSyn-related disorders and AD share a common, underlying molecular pathogenesis; however, this needs further elucidation.
Pathogenic aspects
The clinicopathological features of DLB, PDD, and other synucleinopathies are highly variable and heterogeneous [9, 29, 215,216,217], although the spread of LBP was originally suggested to be uniformly ordered according to the Braak scheme [218, 219]. There are three current major staging systems in use for LB disorders, including one for PD [218, 219], one for DLB [23], and revised guidelines for LB disease [2, 220, 221]. Based on semiquantitative assessment of LBs in large autopsy series, a staging of the chronological spread of LBP was proposed to designate its predictable caudo-rostral sequence in the CNS, which, however, is not identical with the spreading and location of αSyn pathology [222, 223]. Cases with severe LBP (Braak ‘neocortical’ stages 5 and 6) that show overlap or transition between PD and DLB are frequently associated with cognitive impairment, which increases with progressing neuropathological changes [223].
The validity of the Braak staging scheme, which corresponds roughly to the classification of LB disorders as either a (1) predominantly brainstem pathology, (2) limbic system (limbic/transitional type) pathology, or (3) diffuse neocortical pathology [224], has gained wide support as a standard for assessment of LBDs [98, 225, 226], but has also been a matter of vigorous debate [216, 227,228,229,230,231]. The Braak staging scheme often, but not consistently, shows acceptable correlations between morphological findings and clinical data, mainly in a subgroup with early onset and prolonged disease duration [232], whereas a new unified staging system allows the classification of all cases of LBDs, including PD, PDD, DLB, incidental LBD, and DLB-AD [220].
According to the Braak scheme, αSyn aggregates, forming the major components of LBs, and Lewy neurites appear first in the olfactory structures and enteric nervous system and then progressively spread into the brain, moving from cell to cell (neuron to neuron) and through neuronal circuits in a ‘prion-like’ manner, thus contributing to synaptic failure [233] due to impaired axonal transport and accounting for the progression of LBP [234,235,236]. More recently, it has been hypothesized that αSyn itself may be a critical factor in mediating transmission of disease pathology by such a ‘prion-like’ process, which appears essential for the pathogenesis of both PDD and DLB [237]. It remains to be seen if the species of aggregates of αSyn responsible for propagation and neurodegeneration are different and whether the various strains of αSyn fibrils underlie the differences in cellular and regional distribution of lesions in different synucleinopathies, as has been observed following the injection of αSyn aggregates in animal models [238, 239].
An essential problem in distinguishing between DLB and PDD is the impact of AD-related pathology and its co-occurrence with LBP, although both types of lesion have been shown to be strongly correlated with one another [169, 173]. However, recent clinicopathological studies showed that the clinical features of DLB are the consequence of multiple regional pathologies that are less pronounced in PDD [9, 27, 30, 73]. Nevertheless, the genetic and molecular mechanisms responsible for the, at least partially, different pathogenetic factors of both disorders await further elucidation.
Therapy
Currently, there are no disease-modifying therapies for LBDs available (however, see [240]), although robust evidence supports the use of cholinesterase inhibitors (ChEIs) to treat these disorders [241, 242], related to the reduction of cholinergic markers in both PDD and DLB [243, 244]. Meta-analyses have indicated beneficial effects of both donepezil and rivastigmine for cognitive and psychiatric symptoms in both disorders [245,246,247,248], while only one study found an effect of memantine in PDD [249]. The efficacy of memantine in DLB is thus less clear, but may have benefits either as monotherapy or as adjunctive to a ChEI [241]; further, it induced longer survival in patients with DLB and PDD [250]. Although the effects were relatively small, ChEIs gave a better response of cognitive impairment in DLB and PDD than in AD [251], and may produce reduction in apathy, visual hallucinations, and delusions [252]. The use of antipsychotics should be avoided given the risk of serious reactions in DLB [2, 253]. When atypical antipsychotic agents are needed, quetiapine, and particularly clozapine, are less likely exacerbate parkinsonism [251]. Levodopa is generally well tolerated, but produces significantly less motor response in DLB than in PD and may be associated with an increased risk of psychosis [242, 254, 255]. Additionally, strategies to decrease the level of αSyn, to prevent cell-to-cell transmission of misfolded αSyn, and deep brain stimulation of the cholinergic nucleus basalis of Meynert have been discussed [39, 256]. Future therapeutic strategies should include disease-modifying strategies, possibly based on recent vaccination trials against αSyn, Aβ, and tau proteins [257, 258]. Preliminary results of anti-αSyn-immunotherapy in a combined model of synucleinopathy [259] may open the way to potential new treatments. A recent review of non-pharmacological interactions for DLB gave no definite results [260], while bilateral deep brain stimulation of the NBM for PDD showed potential improvement of neuropsychiatric symptoms [261].
Conclusions
DLB and PDD are major neurocognitive disorders with LBD, sharing many clinical, genetic, pathophysiological, imaging, and morphological features. Thus far, a clear and objective distinction between the two entities, other than the arbitrary timing of the appearance of cognitive and motor impairments (1-year rule), has not been established [5, 10, 15, 220], while others maintain that the two entities may merge [262] or may become the same disease [17]. The revised Movement Disorder Society clinical definition of PD, considering DLB with presence of parkinsonism a ‘DLB subtype of PD’ [18, 31], was criticized since it would confuse rather than clarify the distinction between both entities [3]. However, the 1-year time period may not be the optimal method for diagnostic distinction between both disorders [3] since cognitive decline has been reported to start as early as 6 years prior to PD diagnosis [263]. Yet, it appears questionable whether this and other recent clinical studies on impaired cognition years before manifestation of parkinsonism [264] may blur the distinction between PD and DLB, which has been supported by recent neuroimaging and postmortem studies indicating that, in addition to predominant LB/αSyn pathology, AD-related lesions may contribute to the timing of dementia onset relative to motor signs [177].
The clinical pictures of both phenotypes, characterized by recent diagnostic criteria (for DLB [2] and for PDD [24, 72, 84]), despite individual variability, show many overlapping and distinguishing features [3, 8, 126, 265] (Table 1).
Several genetic markers have been shown to be risk factors for DLB and/or PDD, with some differences among them (Table 3). However, it appears premature to recommend genetic testing for clinical diagnosis and differentiation between DLB and PDD. A number of indicative and supportive biomarkers may contribute to the clinical diagnosis of probable DLB and PDD (Table 2).
Despite considerable overlap between DLB and PDD, recent neuroimaging and postmortem studies have demonstrated differences in the quantity and distribution pattern of LB/αSyn and AD-related pathologies between these two entities (Table 4). A correlation between these lesions suggests (1) a synergistic/additive or triggering effect between these protein pathologies [266], with increasing levels of AD pathology inducing an increasing burden of αSyn pathology; (2) an overlap in the pathology between DLB and AD; and (3) that the cognitive decline and related symptoms are not a consequence of αSyn-induced neurodegeneration alone, but of mixed pathologies contributing to the overall deficits [30, 35, 37, 183, 207, 266].
A possible interpretation of the available data would be that PDD and DLB are sub/phenotypes or two ends of the LBD spectrum [19], in which DLB may reside at the more severe side next to AD, while incidental LBD would be on the other (initiating) end [267]. The suggested spectrum is as follows: incidental LBD > PD/non-demented > PDD > DLB > DLB/AD nearing AD. Recent GWAS studies suggested, as another possibility, that DLB and PDD would be distinct diseases with shared genetic risk features with PD and AD [32]. Although some genetic factors that predispose to the development of dementia may differ in PDD and DLB, further extensive GWAS studies in autopsy-confirmed cohorts are warranted.
Future perspectives
DLB and PDD are clinically similar illnesses, distinguished on the basis of the relative timing of dementia and parkinsonism (the 1-year rule). In view of the heterogeneity of the clinical course and symptomatology of both disorders that share the same pathophysiology [30], the question of whether this is a biologically valid distinction, or whether they are merely subtypes in a continuum of LBDs remains to be elucidated based on the results of combined biomarkers, new molecular imaging tracers [268, 269], and multimodal imaging [106]. Their distinction would be useful for further diagnostics and, in particular, new and disease-specific preventive and curative measurements.
At present, neuropathological (differential) diagnosis of DLB and PDD with no or insufficient clinical data would be difficult [181]. However, according to the preliminary criteria proposed in Table 5 (which need further validation and reproducibility), this may be possible. In view of the recent data on the clinical diagnostic criteria for DLB [68], their accuracy remains limited, while, to the best of our knowledge, no comparable studies are available for PDD. In order to support the notion that DLB and PDD are separate diseases, a unique pathogenic process should be identified for either one or the other. Therefore, at present, they cannot be strictly separated as distinct, whereas clinical, imaging, and morphological parameters can distinguish DLB from AD and frontotemporal dementia. The solution of this problem – if at all possible – warrants extensive multidisciplinary studies designed to shed further light on the relationship between PDD and DLB, including identifying genetic and environmental risk factors, and improving our understanding of the biological mechanisms responsible for their pathogenesis such that preventative or curative management can be developed [270].
Nevertheless, the wide acceptance of the term DLB is evidence of its clinical utility, which is likely to result in the maintenance of the term; it is useful in the differential diagnosis of cases presenting with cognitive decline. Whether such patients are likely to develop extrapyramidal symptoms (DLB) or not (AD, etc.) has prognostic value and indicates the type of therapy (e.g., typical or atypical neuroleptics) and is thus of clinical importance. Although we favor the concept of a continuum between DLB and PDD, it must be recognized that biological factors must exist that determine whether the synucleinopathy will present earlier with cognitive decline or with extrapyramidal features. Identifying such factors is important scientifically and may lead to the development of disease-modifying therapies.
References
American Psychiatric Association. Diagnostic and statistical manual of mental disorders 5th Ed. (DSM–5). Arlington, VA: American Psychiatric Publishing; 2013.
McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor JP, Weintraub D, et al. Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB consortium. Neurology. 2017;89:88–100.
Boeve BF, Dickson DW, Duda JE, Ferman TJ, Galasko DR, Galvin JE, et al. Arguing against the proposed definition changes of PD. Mov Disord. 2016;31:1619–22.
Aarsland D, Londos E, Ballard C. Parkinson’s disease dementia and dementia with Lewy bodies: different aspects of one entity. Int Psychogeriatr. 2009;21:216–9.
Aarsland D, Ballard CG, Halliday G. Are Parkinson’s disease with dementia and dementia with Lewy bodies the same entity? J Geriatr Psychiatry Neurol. 2004;17:137–45.
Burn DJ. Cortical Lewy body disease and Parkinson’s disease dementia. Curr Opin Neurol. 2006;19:572–9.
Dodel R, Csoti I, Ebersbach G, Fuchs G, Hahne M, Kuhn W, et al. Lewy body dementia and Parkinson’s disease with dementia. J Neurol. 2008;255(Suppl 5):39–47.
Gomperts SN. Lewy body dementias: dementia with Lewy bodies and Parkinson disease dementia. Continuum (Minneap Minn). 2016;22:435–63.
Jellinger KA. Significance of brain lesions in Parkinson disease dementia and Lewy body dementia. Front Neurol Neurosci. 2009;24:114–25.
Lippa CF, Duda JE, Grossman M, Hurtig HI, Aarsland D, Boeve BF, et al. DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers. Neurology. 2007;68:812–9.
McKeith I. Dementia with Lewy bodies and Parkinson’s disease with dementia: where two worlds collide. Pract Neurol. 2007;7:374–82.
McKeith IG, Mosimann UP. Dementia with Lewy bodies and Parkinson’s disease. Parkinsonism Relat Disord. 2004;10(Suppl 1):S15–8.
Mosimann UP, McKeith I. Dementia with Lewy bodies and Parkinson’s disease dementia - two synucleinopathies. ACNR. 2003;3:8–10.
Noe E, Marder K, Bell KL, Jacobs DM, Manly JJ, Stern Y. Comparison of dementia with Lewy bodies to Alzheimer’s disease and Parkinson’s disease with dementia. Mov Disord. 2004;19:60–7.
Tsuboi Y, Dickson DW. Dementia with Lewy bodies and Parkinson’s disease with dementia: are they different? Parkinsonism Relat Disord. 2005;11(Suppl 1):S47–51.
Rongve A, Aarsland D. Dementia in Parkinson’s disease and dementia with Lewy bodies. In: Dening T, Thomas A, Dening T, As T, editors. Oxford textbook of old age psychiatry. Oxford: Oxford University Press; 2013. p. 469–78.
Friedman JH. Dementia with Lewy bodies and Parkinson disease dementia: it is the same disease! Parkinsonism Relat Disord. 2018;46(Suppl 1):S6–9. https://doi.org/10.1016/j.parkreldis.2017.07.013.
Postuma RB, Berg D. The new diagnostic criteria for Parkinson’s disease. Int Rev Neurobiol. 2017;132:55–78.
Richard IH, Papka M, Rubio A, Kurlan R. Parkinson’s disease and dementia with Lewy bodies: one disease or two? Mov Disord. 2002;17:1161–5.
Barker RA, Williams-Gray CH. The spectrum of clinical features seen with alpha synuclein pathology. Neuropathol Appl Neurobiol. 2016;42:6–19.
Litvan I, MacIntyre A, Goetz CG, Wenning GK, Jellinger K, Verny M, et al. Accuracy of the clinical diagnoses of Lewy body disease, Parkinson disease, and dementia with Lewy bodies: a clinicopathologic study. Arch Neurol. 1998;55:969–78.
Jellinger KA. Dementia with Lewy bodies and Parkinson's disease-dementia: current concepts and controversies. J Neural Transm. 2017; https://doi.org/10.1007/s00702-017-1821-9.
McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB consortium. Neurology. 2005;65:1863–72.
Emre M, Aarsland D, Brown R, Burn DJ, Duyckaerts C, Mizuno Y, et al. Clinical diagnostic criteria for dementia associated with Parkinson's disease. Mov Disord. 2007;22:1689–707.
Kim WS, Kagedal K, Halliday GM. Alpha-synuclein biology in Lewy body diseases. Alzheimers Res Ther. 2014;6:73.
Garcia-Esparcia P, Lopez-Gonzalez I, Grau-Rivera O, Garcia-Garrido MF, Konetti A, Llorens F, et al. Dementia with Lewy bodies: molecular pathology in the frontal cortex in typical and rapidly progressive forms. Front Neurol. 2017;8:89.
Hepp DH, Vergoossen DL, Huisman E, Lemstra AW, Berendse HW, Rozemuller AJ, et al. Distribution and load of amyloid-beta pathology in Parkinson disease and dementia with Lewy bodies. J Neuropathol Exp Neurol. 2016;75:936–45.
Paleologou KE, Kragh CL, Mann DM, Salem SA, Al-Shami R, Allsop D, et al. Detection of elevated levels of soluble alpha-synuclein oligomers in post-mortem brain extracts from patients with dementia with Lewy bodies. Brain. 2009;132:1093–101.
Jellinger KA. Neuropathology of Parkinson’s disease. In: Thomas M, Thomas M, editors. Inflammation in Parkinson’s disease: scientific and clinical aspects. New York: Springer; 2014. p. 25–47.
Walker Z, Possin KL, Boeve BF, Aarsland D. Lewy body dementias. Lancet. 2015;386:1683–97.
Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, et al. MDS clinical diagnostic criteria for Parkinson's disease. Mov Disord. 2015;30:1591–601.
Walton RL, Soto-Ortolaza AI, Murray ME, Lorenzo-Betancor O, Ogaki K, Heckman MG, et al. TREM2 p.R47H substitution is not associated with dementia with Lewy bodies. Neurol Genet. 2016;2:e85.
Walker L, McAleese KE, Thomas AJ, Johnson M, Martin-Ruiz C, Parker C, et al. Neuropathologically mixed Alzheimer's and Lewy body disease: burden of pathological protein aggregates differs between clinical phenotypes. Acta Neuropathol. 2015;129:729–48.
Halliday GM, Song YJ, Harding AJ. Striatal beta-amyloid in dementia with Lewy bodies but not Parkinson’s disease. J Neural Transm. 2011;118:713–9.
Colom-Cadena M, Grau-Rivera O, Planellas L, Cerquera C, Morenas E, Helgueta S, et al. Regional overlap of pathologies in Lewy body disorders. J Neuropathol Exp Neurol. 2017;76:216–24.
Colom-Cadena M, Gelpi E, Charif S, Belbin O, Blesa R, Marti MJ, et al. Confluence of alpha-synuclein, tau, and beta-amyloid pathologies in dementia with Lewy bodies. J Neuropathol Exp Neurol. 2013;72:1203–12.
Howlett DR, Whitfield D, Johnson M, Attems J, O'Brien JT, Aarsland D, et al. Regional multiple pathology scores are associated with cognitive decline in Lewy body dementias. Brain Pathol. 2015;25:401–8.
Goldman JG, Williams-Gray C, Barker RA, Duda JE, Galvin JE. The spectrum of cognitive impairment in Lewy body diseases. Mov Disord. 2014;29:608–21.
Aarsland D, Creese B, Politis M, Chaudhuri KR, Ffytche DH, Weintraub D, et al. Cognitive decline in Parkinson disease. Nat Rev Neurol. 2017;13:217–31.
McKeith I, Taylor JP, Thomas A, Donaghy P, Kane J. Revisiting DLB diagnosis: a consideration of prodromal DLB and of the diagnostic overlap with Alzheimer disease. J Geriatr Psychiatry Neurol. 2016;29:249–53.
Jellinger KA. Neurobiology of cognitive impairment in Parkinson’s disease. Expert Rev Neurother. 2012;12:1451–66.
Jellinger KA. Mild cognitive impairment in Parkinson disease: heterogenous mechanisms. J Neural Transm. 2013;120:157–67.
Bronnick K, Breitve MH, Rongve A, Aarsland D. Neurocognitive deficits distinguishing mild dementia with Lewy bodies from mild Alzheimer’s disease are associated with parkinsonism. J Alzheimers Dis. 2016;53:1277–85.
Yoon JH, Lee JE, Yong SW, Moon SY, Lee PH. The mild cognitive impairment stage of dementia with Lewy bodies and Parkinson disease: a comparison of cognitive profiles. Alzheimer Dis Assoc Disord. 2014;28:151–5.
Korczyn AD. Parkinson’s and Alzheimer’s diseases: focus on mild cognitive impairment. Parkinsonism Relat Disord. 2016;22(Suppl 1):S159–61.
McDermott KL, Fisher N, Bradford S, Camicioli R. Parkinson’s disease mild cognitive impairment classifications and neurobehavioral symptoms. Int Psychogeriatr. 2017; https://doi.org/10.1017/S1041610217002265.
Donaghy PC, McKeith IG. The clinical characteristics of dementia with Lewy bodies and a consideration of prodromal diagnosis. Alzheimers Res Ther. 2014;6:46.
Delli Pizzi S, Franciotti R, Taylor JP, Thomas A, Tartaro A, Onofrj M, et al. Thalamic involvement in fluctuating cognition in dementia with Lewy bodies: magnetic resonance evidences. Cereb Cortex. 2015;25:3682–9.
Cagnin A, Gnoato F, Jelcic N, Favaretto S, Zarantonello G, Ermani M, et al. Clinical and cognitive correlates of visual hallucinations in dementia with Lewy bodies. J Neurol Neurosurg Psychiatry. 2013;84:505–10.
Harding AJ, Broe GA, Halliday GM. Visual hallucinations in Lewy body disease relate to Lewy bodies in the temporal lobe. Brain. 2002;125:391–403.
Goetz CG, Vogel C, Tanner CM, Stebbins GT. Early dopaminergic drug-induced hallucinations in parkinsonian patients. Neurology. 1998;51:811–4.
Fénelon G, Goetz CG, Karenberg A. Hallucinations in Parkinson disease in the prelevodopa era. Neurology. 2006;66:93–8.
Pagonabarraga J, Martinez-Horta S, Fernandez de Bobadilla R, Perez J, Ribosa-Nogue R, Marin J, et al. Minor hallucinations occur in drug-naive Parkinson's disease patients, even from the premotor phase. Mov Disord. 2016;31:45–52.
Fritz NE, Kegelmeyer DA, Kloos AD, Linder S, Park A, Kataki M, et al. Motor performance differentiates individuals with Lewy body dementia, Parkinson’s and Alzheimer’s disease. Gait Posture. 2016;50:1–7.
Ferman TJ, Boeve BF, Smith GE, Lin SC, Silber MH, Pedraza O, et al. Inclusion of RBD improves the diagnostic classification of dementia with Lewy bodies. Neurology. 2011;77:875–82.
Dugger BN, Boeve BF, Murray ME, Parisi JE, Fujishiro H, Dickson DW, et al. Rapid eye movement sleep behavior disorder and subtypes in autopsy-confirmed dementia with Lewy bodies. Mov Disord. 2012;27:72–8.
Iaccarino L, Marelli S, Iannaccone S, Magnani G, Ferini-Strambi L, Perani D. Severe brain metabolic decreases associated with rem sleep behavior disorder in dementia with Lewy bodies. J Alzheimers Dis. 2016;52:989–97.
Burchell JT, Panegyres PK. New cerebrospinal fluid biomarkers in Alzheimer’s disease. Future Neurol. 2017;12:53–6.
Boeve BF. Idiopathic REM sleep behaviour disorder in the development of Parkinson's disease. Lancet Neurol. 2013;12:469–82.
Fields JA. Cognitive and neuropsychiatric features in Parkinson's and Lewy body dementias. Arch Clin Neuropsychol. 2017;32:786–801.
Park KW, Kim HS, Cheon SM, Cha JK, Kim SH, Kim JW. Dementia with Lewy bodies versus Alzheimer’s disease and Parkinson’s disease dementia: a comparison of cognitive profiles. J Clin Neurol. 2011;7:19–24.
Takemoto M, Sato K, Hatanaka N, Yamashita T, Ohta Y, Hishikawa N, et al. Different clinical and neuroimaging characteristics in early stage Parkinson’s disease with dementia and dementia with Lewy bodies. J Alzheimers Dis. 2016;52:205–11.
Blanc F, Mahmoudi R, Jonveaux T, Galmiche J, Chopard G, Cretin B, et al. Long-term cognitive outcome of Alzheimer’s disease and dementia with Lewy bodies: dual disease is worse. Alzheimers Res Ther. 2017;9:47.
Kramberger MG, Auestad B, Garcia-Ptacek S, Abdelnour C, Olmo JG, Walker Z, et al. Long-term cognitive decline in dementia with Lewy bodies in a large multicenter, international cohort. J Alzheimers Dis. 2017;57:787—95.
Karantzoulis S, Galvin JE. Update on dementia with Lewy bodies. Curr Transl Geriatr Exp Gerontol Rep. 2013;2:196–204.
Aarsland D, Perry R, Larsen JP, McKeith IG, O'Brien JT, Perry EK, et al. Neuroleptic sensitivity in Parkinson’s disease and parkinsonian dementias. J Clin Psychiatry. 2005;66:633–7.
Huang Y, Halliday G. Can we clinically diagnose dementia with Lewy bodies yet? Transl Neurodegener. 2013;2:4.
Rizzo G, Arcuti S, Copetti M, Alessandria M, Savica R, Fontana A, et al. Accuracy of clinical diagnosis of dementia with Lewy bodies: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2017; https://doi.org/10.1136/jnnp-2017-316844.
Skogseth RE, Hortobagyi T, Soennesyn H, Chwiszczuk L, Ffytche D, Rongve A, et al. Accuracy of clinical diagnosis of dementia with Lewy bodies versus neuropathology. J Alzheimers Dis. 2017;59(4):1139–52.
Svenningsson P, Westman E, Ballard C, Aarsland D. Cognitive impairment in patients with Parkinson's disease: diagnosis, biomarkers, and treatment. Lancet Neurol. 2012;11:697–707.
Meireles J, Massano J. Cognitive impairment and dementia in Parkinson's disease: clinical features, diagnosis, and management. Front Neurol. 2012;3:88.
Goetz CG, Emre M, Dubois B. Parkinson’s disease dementia: definitions, guidelines, and research perspectives in diagnosis. Ann Neurol. 2008;64(Suppl 2):S81–92.
Garcia-Ptacek S, Kramberger MG. Parkinson disease and dementia. J Geriatr Psychiatry Neurol. 2016;29:261–70.
Varanese S, Perfetti B, Monaco D, Thomas A, Bonanni L, Tiraboschi P, et al. Fluctuating cognition and different cognitive and behavioural profiles in Parkinson's disease with dementia: comparison of dementia with Lewy bodies and Alzheimer's disease. J Neurol. 2010;257:1004–11.
Archibald NK, Clarke MP, Mosimann UP, Burn DJ. Visual symptoms in Parkinson's disease and Parkinson's disease dementia. Mov Disord. 2011;26:2387–95.
Lenka A, Jhunjhunwala KR, Saini J, Pal PK. Structural and functional neuroimaging in patients with Parkinson's disease and visual hallucinations: a critical review. Parkinsonism Relat Disord. 2015;21:683–91.
Anang JB, Gagnon JF, Bertrand JA, Romenets SR, Latreille V, Panisset M, et al. Predictors of dementia in Parkinson disease: a prospective cohort study. Neurology. 2014;83:1253–60.
Frei K, Truong DD. Hallucinations and the spectrum of psychosis in Parkinson's disease. J Neurol Sci. 2017;374:56–62.
Ffytche DH, Creese B, Politis M, Chaudhuri KR, Weintraub D, Ballard C, et al. The psychosis spectrum in Parkinson disease. Nat Rev Neurol. 2017;13:81–95.
Gagnon JF, Vendette M, Postuma RB, Desjardins C, Massicotte-Marquez J, Panisset M, et al. Mild cognitive impairment in rapid eye movement sleep behavior disorder and Parkinson's disease. Ann Neurol. 2009;66:39–47.
Iranzo A, Santamaria J, Tolosa E. Idiopathic rapid eye movement sleep behaviour disorder: diagnosis, management, and the need for neuroprotective interventions. Lancet Neurol. 2016;15:405–19.
Dujardin K, Dubois B, Tison F, Durif F, Bourdeix I, Pere JJ, et al. Parkinson's disease dementia can be easily detected in routine clinical practice. Mov Disord. 2010;25:2769–76.
Martinez-Martin P, Falup-Pecurariu C, Rodriguez-Blazquez C, Serrano-Duenas M, Carod Artal FJ, Rojo Abuin JM, et al. Dementia associated with Parkinson's disease: applying the Movement Disorder Society task force criteria. Parkinsonism Relat Disord. 2011;17:621–4.
Dubois B, Burn D, Goetz C, Aarsland D, Brown RG, Broe GA, et al. Diagnostic procedures for Parkinson's disease dementia: recommendations from the movement disorder society task force. Mov Disord. 2007;22:2314–24.
Hogan DB, Fiest KM, Roberts JI, Maxwell CJ, Dykeman J, Pringsheim T, et al. The prevalence and incidence of dementia with Lewy bodies: a systematic review. Can J Neurol Sci. 2016;43(Suppl 1):S83–95.
Savica R, Grossardt BR, Bower JH, Boeve BF, Ahlskog JE, Rocca WA. Incidence of dementia with Lewy bodies and Parkinson disease dementia. JAMA Neurol. 2013;70:1396–402.
Aarsland D, Kurz MW. The epidemiology of dementia associated with Parkinson disease. J Neurol Sci. 2010;289:18–22.
Hely MA, Reid WG, Adena MA, Halliday GM, Morris JG. The Sydney multicenter study of Parkinson's disease: the inevitability of dementia at 20 years. Mov Disord. 2008;23:837–44.
Marder K. Cognitive impairment and dementia in Parkinson's disease. Mov Disord. 2010;25(Suppl 1):S110–6.
Biundo R, Weis L, Antonini A. Cognitive decline in Parkinson's disease: the complex picture. NPJ Parkinsons Dis. 2016;2:16018.
Fereshtehnejad SM, Religa D, Westman E, Aarsland D, Lokk J, Eriksdotter M. Demography, diagnostics, and medication in dementia with Lewy bodies and Parkinson's disease with dementia: data from the Swedish dementia quality registry (SveDem). Neuropsychiatr Dis Treat. 2013;9:927–35.
Jellinger KA. Lewy body disorders. In: MBH Y, Riederer P, Mandel SA, Battistin L, Lajtha A, MBH Y, Riederer P, Mandel SA, Battistin L, As L, editors. Degenerative diseases of the nervous system. New York: Springer Science; 2007. p. 267–343.
Seppi K, Jellinger K, Litvan I, Ransmayr G, Mueller J, Ulmer H, et al. Impact of disease progression upon accuracy of the McKeith criteria for dementia with Lewy bodies: a clinicopatholgic study (abstr.). Neurology. 2001;56(Suppl 3):A127.
Savica R, Grossardt BR, Bower JH, Ahlskog JE, Boeve BF, Graff-Radford J, et al. Survival and causes of death among people with clinically diagnosed synucleinopathies with parkinsonism: a population-based study. JAMA Neurol. 2017;74:839–46.
Lemstra AW, de Beer MH, Teunissen CE, Schreuder C, Scheltens P, van der Flier WM, et al. Concomitant AD pathology affects clinical manifestation and survival in dementia with Lewy bodies. J Neurol Neurosurg Psychiatry. 2017;88:113–8.
Graff-Radford J, Lesnick TG, Boeve BF, Przybelski SA, Jones DT, Senjem ML, et al. Predicting survival in dementia with Lewy bodies with hippocampal volumetry. Mov Disord. 2016;31:989–94.
Jellinger KA, Seppi K, Wenning GK, Poewe W. Impact of coexistent Alzheimer pathology on the natural history of Parkinson's disease. J Neural Transm. 2002;109:329–39.
Kempster PA, O'Sullivan SS, Holton JL, Revesz T, Lees AJ. Relationships between age and late progression of Parkinson's disease: a clinico-pathological study. Brain. 2010;133:1755–62.
Williams MM, Xiong C, Morris JC, Galvin JE. Survival and mortality differences between dementia with Lewy bodies vs Alzheimer disease. Neurology. 2006;67:1935–41.
Gaig C, Valldeoriola F, Gelpi E, Ezquerra M, Llufriu S, Buongiorno M, et al. Rapidly progressive diffuse Lewy body disease. Mov Disord. 2011;26:1316–23.
Jellinger KA, Wenning GK, Seppi K. Predictors of survival in dementia with Lewy bodies and Parkinson dementia. Neurodegener Dis. 2007;4:428–30.
Graff-Radford J, Aakre J, Savica R, Boeve B, Kremers WK, Ferman TJ, et al. Duration and pathologic correlates of Lewy body disease. JAMA Neurol. 2017;74:310–5.
Saeed U, Compagnone J, Aviv RI, Strafella AP, Black SE, Lang AE, et al. Imaging biomarkers in Parkinson's disease and Parkinsonian syndromes: current and emerging concepts. Transl Neurodegener. 2017;6:8.
Mak E, Su L, Williams GB, O'Brien JT. Neuroimaging characteristics of dementia with Lewy bodies. Alzheimers Res Ther. 2014;6:18.
Marquie M, Locascio JJ, Rentz DM, Becker JA, Hedden T, Johnson KA, et al. Striatal and extrastriatal dopamine transporter levels relate to cognition in Lewy body diseases: an (11)C altropane positron emission tomography study. Alzheimers Res Ther. 2014;6:52.
Gomperts SN, Marquie M, Locascio JJ, Bayer S, Johnson KA, Growdon JH. PET radioligands reveal the basis of dementia in Parkinson's disease and dementia with Lewy bodies. Neurodegener Dis. 2016;16:118–24.
Walker Z, Costa DC, Walker RW, Lee L, Livingston G, Jaros E, et al. Striatal dopamine transporter in dementia with Lewy bodies and Parkinson disease: a comparison. Neurology. 2004;62:1568–72.
Colloby SJ, McParland S, O'Brien JT, Attems J. Neuropathological correlates of dopaminergic imaging in Alzheimer's disease and Lewy body dementias. Brain. 2012;135:2798–808.
Christopher L, Duff-Canning S, Koshimori Y, Segura B, Boileau I, Chen R, et al. Salience network and parahippocampal dopamine dysfunction in memory-impaired Parkinson disease. Ann Neurol. 2015;77:269–80.
Yoshita M, Arai H, Arai T, Asada T, Fujishiro H, Hanyu H, et al. Diagnostic accuracy of 123I-meta-iodobenzylguanidine myocardial scintigraphy in dementia with Lewy bodies: a multicenter study. PLoS One. 2015;10:e0120540.
Tiraboschi P, Corso A, Guerra UP, Nobili F, Piccardo A, Calcagni ML, et al. (123) I-2beta-carbomethoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl) nortropane single photon emission computed tomography and (123) I-metaiodobenzylguanidine myocardial scintigraphy in differentiating dementia with Lewy bodies from other dementias: a comparative study. Ann Neurol. 2016;80:368–78.
Sakamoto F, Shiraishi S, Tsuda N, Hashimoto M, Tomiguchi S, Ikeda M, et al. Diagnosis of dementia with Lewy bodies: can 123I-IMP and 123I-MIBG scintigraphy yield new core features? Br J Radiol. 2017;90:20160156.
Beyer MK, Larsen JP, Aarsland D. Gray matter atrophy in Parkinson disease with dementia and dementia with Lewy bodies. Neurology. 2007;69:747–54.
Sanchez-Castaneda C, Rene R, Ramirez-Ruiz B, Campdelacreu J, Gascon J, Falcon C, et al. Correlations between gray matter reductions and cognitive deficits in dementia with Lewy bodies and Parkinson's disease with dementia. Mov Disord. 2009;24:1740–6.
Hwang KS, Beyer MK, Green AE, Chung C, Thompson PM, Janvin C, et al. Mapping cortical atrophy in Parkinson's disease patients with dementia. J Parkinsons Dis. 2013;3:69–76.
Pagonabarraga J, Corcuera-Solano I, Vives-Gilabert Y, Llebaria G, Garcia-Sanchez C, Pascual-Sedano B, et al. Pattern of regional cortical thinning associated with cognitive deterioration in Parkinson's disease. PLoS One. 2013;8:e54980.
Rektorova I, Biundo R, Marecek R, Weis L, Aarsland D, Antonini A. Grey matter changes in cognitively impaired Parkinson's disease patients. PLoS One. 2014;9:e85595.
Zarei M, Ibarretxe-Bilbao N, Compta Y, Hough M, Junque C, Bargallo N, et al. Cortical thinning is associated with disease stages and dementia in Parkinson's disease. J Neurol Neurosurg Psychiatry. 2013;84:875–81.
Lee JE, Park B, Song SK, Sohn YH, Park HJ, Lee PH. A comparison of gray and white matter density in patients with Parkinson's disease dementia and dementia with Lewy bodies using voxel-based morphometry. Mov Disord. 2010;25:28–34.
Almeida OP, Burton EJ, McKeith I, Gholkar A, Burn D, O'Brien JT. MRI study of caudate nucleus volume in Parkinson's disease with and without dementia with Lewy bodies and Alzheimer's disease. Dement Geriatr Cogn Disord. 2003;16:57–63.
Barber R, McKeith I, Ballard C, O'Brien J. Volumetric MRI study of the caudate nucleus in patients with dementia with Lewy bodies, Alzheimer's disease, and vascular dementia. J Neurol Neurosurg Psychiatry. 2002;72:406–7.
Watson R, O'Brien JT, Barber R, Blamire AM. Patterns of gray matter atrophy in dementia with Lewy bodies: a voxel-based morphometry study. Int Psychogeriatr. 2012;24:532–40.
Gazzina S, Premi E, Turrone R, Acosta-Cabronero J, Rizzetti MC, Cotelli MS, et al. Subcortical matter in the alpha-synucleinopathies spectrum: an MRI pilot study. J Neurol. 2016;263:1575–82.
Harper L, Bouwman F, Burton EJ, Barkhof F, Scheltens P, O'Brien JT, et al. Patterns of atrophy in pathologically confirmed dementias: a voxelwise analysis. J Neurol Neurosurg Psychiatry. 2017;88:908–16.
Compta Y, Buongiorno M, Bargallo N, Valldeoriola F, Munoz E, Tolosa E, et al. White matter hyperintensities, cerebrospinal amyloid-beta and dementia in Parkinson's disease. J Neurol Sci. 2016;367:284–90.
Burton EJ, McKeith IG, Burn DJ, Firbank MJ, O'Brien JT. Progression of white matter hyperintensities in Alzheimer disease, dementia with lewy bodies, and Parkinson disease dementia: a comparison with normal aging. Am J Geriatr Psychiatry. 2006;14:842–9.
Sarro L, Tosakulwong N, Schwarz CG, Graff-Radford J, Przybelski SA, Lesnick TG, et al. An investigation of cerebrovascular lesions in dementia with Lewy bodies compared to Alzheimer's disease. Alzheimers Dement. 2017;13:257–66.
Nedelska Z, Ferman TJ, Boeve BF, Przybelski SA, Lesnick TG, Murray ME, et al. Pattern of brain atrophy rates in autopsy-confirmed dementia with Lewy bodies. Neurobiol Aging. 2015;36:452–61.
Watson R, Blamire AM, O'Brien JT. Magnetic resonance imaging in Lewy body dementias. Dement Geriatr Cogn Disord. 2009;28:493–506.
Chiba Y, Fujishiro H, Ota K, Kasanuki K, Arai H, Hirayasu Y, et al. Clinical profiles of dementia with Lewy bodies with and without Alzheimer's disease-like hypometabolism. Int J Geriatr Psychiatry. 2015;30:316–23.
Firbank MJ, Burn DJ, McKeith IG, O'Brien JT. Longitudinal study of cerebral blood flow SPECT in Parkinson's disease with dementia, and dementia with Lewy bodies. Int J Geriatr Psychiatry. 2005;20:776–82.
O'Brien JT, Firbank MJ, Davison C, Barnett N, Bamford C, Donaldson C, et al. 18F-FDG PET and perfusion SPECT in the diagnosis of Alzheimer and Lewy body dementias. J Nucl Med. 2014;55:1959–65.
Jokinen P, Scheinin N, Aalto S, Nagren K, Savisto N, Parkkola R, et al. [(11)C]PIB-, [(18)F]FDG-PET and MRI imaging in patients with Parkinson's disease with and without dementia. Parkinsonism Relat Disord. 2010;16:666–70.
Bohnen NI, Koeppe RA, Minoshima S, Giordani B, Albin RL, Frey KA, et al. Cerebral glucose metabolic features of Parkinson disease and incident dementia: longitudinal study. J Nucl Med. 2011;52:848–55.
Yong SW, Yoon JK, An YS, Lee PH. A comparison of cerebral glucose metabolism in Parkinson's disease, Parkinson's disease dementia and dementia with Lewy bodies. Eur J Neurol. 2007;14:1357–62.
Edison P, Rowe CC, Rinne JO, Ng S, Ahmed I, Kemppainen N, et al. Amyloid load in Parkinson's disease dementia and Lewy body dementia measured with [11C]PIB positron emission tomography. J Neurol Neurosurg Psychiatry. 2008;79:1331–8.
Akhtar RS, Xie SX, Brennan L, Pontecorvo MJ, Hurtig HI, Trojanowski JQ, et al. Amyloid-beta positron emission tomography imaging of Alzheimer's pathology in Parkinson's disease dementia. Mov Disord Clin Pract. 2016;3:367–75.
Gomperts SN. Imaging the role of amyloid in PD dementia and dementia with Lewy bodies. Curr Neurol Neurosci Rep. 2014;14:472.
Petrou M, Dwamena BA, Foerster BR, MacEachern MP, Bohnen NI, Muller ML, et al. Amyloid deposition in Parkinson's disease and cognitive impairment: a systematic review. Mov Disord. 2015;30:928–35.
Foster ER, Campbell MC, Burack MA, Hartlein J, Flores HP, Cairns NJ, et al. Amyloid imaging of Lewy body-associated disorders. Mov Disord. 2010;25:2516–23.
Gomperts SN, Locascio JJ, Makaretz SJ, Schultz A, Caso C, Vasdev N, et al. Tau positron emission tomographic imaging in the Lewy body diseases. JAMA Neurol. 2016;73:1334–41.
Brooks DJ. Imaging amyloid in Parkinson’s disease dementia and dementia with Lewy bodies with positron emission tomography. Mov Disord. 2009;24(Suppl 2):S742–S7.
Bohnen NI, Muller M, Frey KA. Molecular imaging and updated diagnostic criteria in Lewy body dementias. Curr Neurol Neurosci Rep. 2017;17:73.
Marquie M, Verwer EE, Meltzer AC, Kim SJW, Aguero C, Gonzalez J, et al. Lessons learned about [F-18]-AV-1451 off-target binding from an autopsy-confirmed Parkinson's case. Acta Neuropathol Commun. 2017;5:75.
Bonanni L, Thomas A, Tiraboschi P, Perfetti B, Varanese S, Onofrj M. EEG comparisons in early Alzheimer's disease, dementia with Lewy bodies and Parkinson's disease with dementia patients with a 2-year follow-up. Brain. 2008;131:690–705.
Bonanni L, Franciotti R, Nobili F, Kramberger MG, Taylor JP, Garcia-Ptacek S, et al. EEG markers of dementia with Lewy bodies: a multicenter cohort study. J Alzheimers Dis. 2016;54:1649–57.
Garn H, Coronel C, Waser M, Caravias G, Ransmayr G. Differential diagnosis between patients with probable Alzheimer's disease, Parkinson's disease dementia, or dementia with Lewy bodies and frontotemporal dementia, behavioral variant, using quantitative electroencephalographic features. J Neural Transm. 2017;124:569–81.
Seer C, Lange F, Georgiev D, Jahanshahi M, Kopp B. Event-related potentials and cognition in Parkinson's disease: an integrative review. Neurosci Biobehav Rev. 2016;71:691–714.
Walter U, Dressler D, Wolters A, Wittstock M, Greim B, Benecke R. Sonographic discrimination of dementia with Lewy bodies and Parkinson's disease with dementia. J Neurol. 2006;253:448–54.
Mosimann UP, Muri RM, Burn DJ, Felblinger J, O'Brien JT, McKeith IG. Saccadic eye movement changes in Parkinson's disease dementia and dementia with Lewy bodies. Brain. 2005;128:1267–76.
Guerreiro R, Escott-Price V, Darwent L, Parkkinen L, Ansorge O, Hernandez DG, et al. Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Parkinson's and Alzheimer's diseases. Neurobiol Aging. 2016;38:214.e7–214.e10.
Guerreiro R, Ross OA, Kun-Rodrigues C, Hernandez DG, Orme T, Eicher JD, et al. Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study. Lancet Neurol. 2018;17:64–74.
Collins LM, Williams-Gray CH. The genetic basis of cognitive impairment and dementia in Parkinson's disease. Front Psychiatry. 2016;7:89.
Guella I, Evans DM, Szu-Tu C, Nosova E, Bortnick SF, Goldman JG, et al. Alpha-synuclein genetic variability: a biomarker for dementia in Parkinson disease. Ann Neurol. 2016;79:991–9.
Desikan RS, Schork AJ, Wang Y, Witoelar A, Sharma M, McEvoy LK, et al. Genetic overlap between Alzheimer's disease and Parkinson's disease at the MAPT locus. Mol Psychiatry. 2015;20:1588–95.
Li L, Liu MS, Li GQ, Tang J, Liao Y, Zheng Y, et al. Relationship between apolipoprotein superfamily and Parkinson's disease. Chin Med J. 2017;130:2616–23.
Weil RS, Lashley TL, Bras J, Schrag AE, Schott JM. Current concepts and controversies in the pathogenesis of Parkinson's disease dementia and dementia with Lewy bodies. F1000Res. 2017;6:1604.
Vergouw LJM, van Steenoven I, van de Berg WDJ, Teunissen CE, van Swieten JC, Bonifati V, et al. An update on the genetics of dementia with Lewy bodies. Parkinsonism Relat Disord. 2017;43:1–8.
Lin CH, Wu RM. Biomarkers of cognitive decline in Parkinson's disease. Parkinsonism Relat Disord. 2015;21:431–43.
Mollenhauer B, Parnetti L, Rektorova I, Kramberger MG, Pikkarainen M, Schulz-Schaeffer WJ, et al. Biological confounders for the values of cerebrospinal fluid proteins in Parkinson's disease and related disorders. J Neurochem. 2016;139(Suppl 1):290–317.
Johar I, Mollenhauer B, Aarsland D. Cerebrospinal fluid biomarkers of cognitive decline in Parkinson's disease. Int Rev Neurobiol. 2017;132:275–94.
van Steenoven I, Aarsland D, Weintraub D, Londos E, Blanc F, van der Flier WM, et al. Cerebrospinal fluid Alzheimer's disease biomarkers across the spectrum of Lewy body diseases: results from a large multicenter cohort. J Alzheimers Dis. 2016;54:287–95.
Lerche S, Schulte C, Srulijes K, Pilotto A, Rattay TW, Hauser AK, et al. Cognitive impairment in glucocerebrosidase (GBA)-associated PD: not primarily associated with cerebrospinal fluid Abeta and tau profiles. Mov Disord. 2017;32(12):1780–3.
Vranova HP, Henykova E, Kaiserova M, Mensikova K, Vastik M, Mares J, et al. Tau protein, beta-amyloid 1-42 and clusterin CSF levels in the differential diagnosis of Parkinsonian syndrome with dementia. J Neurol Sci. 2014;343:120–4.
Hansson O, Hall S, Ohrfelt A, Zetterberg H, Blennow K, Minthon L, et al. Levels of cerebrospinal fluid alpha-synuclein oligomers are increased in Parkinson's disease with dementia and dementia with Lewy bodies compared to Alzheimer's disease. Alzheimers Res Ther. 2014;6:25.
Simonsen AH, Kuiperij B, El-Agnaf OM, Engelborghs S, Herukka SK, Parnetti L, et al. The utility of alpha-synuclein as biofluid marker in neurodegenerative diseases: a systematic review of the literature. Biomark Med. 2016;10:19–34.
Stuendl A, Kunadt M, Kruse N, Bartels C, Moebius W, Danzer KM, et al. Induction of alpha-synuclein aggregate formation by CSF exosomes from patients with Parkinson's disease and dementia with Lewy bodies. Brain. 2016;139:481–94.
Eusebi P, Giannandrea D, Biscetti L, Abraha I, Chiasserini D, Orso M, et al. Diagnostic utility of cerebrospinal fluid alpha-synuclein in Parkinson's disease: a systematic review and meta-analysis. Mov Disord. 2017;32:1389–400.
Compta Y, Parkkinen L, O'Sullivan SS, Vandrovcova J, Holton JL, Collins C, et al. Lewy- and Alzheimer-type pathologies in Parkinson's disease dementia: which is more important? Brain. 2011;134:1493–505.
Del Tredici K, Braak H. Dysfunction of the locus coeruleus-norepinephrine system and related circuitry in Parkinson's disease-related dementia. J Neurol Neurosurg Psychiatry. 2013;84:774–83.
Hall H, Reyes S, Landeck N, Bye C, Leanza G, Double K, et al. Hippocampal Lewy pathology and cholinergic dysfunction are associated with dementia in Parkinson's disease. Brain. 2014;137:2493–508.
Halliday GM, Leverenz JB, Schneider JS, Adler CH. The neurobiological basis of cognitive impairment in Parkinson's disease. Mov Disord. 2014;29:634–50.
Irwin DJ, White MT, Toledo JB, Xie SX, Robinson JL, Van Deerlin V, et al. Neuropathologic substrates of Parkinson disease dementia. Ann Neurol. 2012;72:587–98.
Irwin DJ, Lee VM, Trojanowski JQ. Parkinson's disease dementia: convergence of alpha-synuclein, tau and amyloid-beta pathologies. Nat Rev Neurosci. 2013;14:626–36.
Oinas M, Polvikoski T, Sulkava R, Myllykangas L, Juva K, Notkola IL, et al. Neuropathologic findings of dementia with Lewy bodies (DLB) in a population-based Vantaa 85+ study. J Alzheimers Dis. 2009;18:677–89.
Prakash KG, Bannur BM, Chavan MD, Saniya K, Sailesh KS, Rajagopalan A. Neuroanatomical changes in Parkinson's disease in relation to cognition: an update. J Adv Pharm Technol Res. 2016;7:123–6.
Ruffmann C, Calboli FC, Bravi I, Gveric D, Curry LK, de Smith A, et al. Cortical Lewy bodies and Abeta burden are associated with prevalence and timing of dementia in Lewy body diseases. Neuropathol Appl Neurobiol. 2016;42:436–50.
Seidel K, Mahlke J, Siswanto S, Kruger R, Heinsen H, Auburger G, et al. The brainstem pathologies of Parkinson's disease and dementia with Lewy bodies. Brain Pathol. 2015;25:121–35.
Sierra M, Gelpi E, Marti MJ, Compta Y. Lewy- and Alzheimer-type pathologies in midbrain and cerebellum across the Lewy body disorders spectrum. Neuropathol Appl Neurobiol. 2016;42:451–62.
Schulz-Schaeffer WJ. The synaptic pathology of alpha-synuclein aggregation in dementia with Lewy bodies, Parkinson's disease and Parkinson's disease dementia. Acta Neuropathol. 2010;120:131–43.
Ince PG. Dementia with Lewy bodies and Parkinson's disease dementia. In: Dickson DW, Weller RO, Dickson DW, ROs W, editors. Neurodegeneration: the molecular pathology of dementia and movement disorders, 2nd edition. Oxford: Blackwell Publishing Ltd; 2011. p. 224–37.
Hansen LA, Daniel SE, Wilcock GK, Love S. Frontal cortical synaptophysin in Lewy body diseases: relation to Alzheimer's disease and dementia. J Neurol Neurosurg Psychiatry. 1998;64:653–6.
Irwin DJ, Grossman M, Weintraub D, Hurtig HI, Duda JE, Xie SX, et al. Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis. Lancet Neurol. 2017;16:55–65.
Lashley T, Holton JL, Gray E, Kirkham K, O'Sullivan SS, Hilbig A, et al. Cortical alpha-synuclein load is associated with amyloid-beta plaque burden in a subset of Parkinson's disease patients. Acta Neuropathol. 2008;115:417–25.
Kotzbauer PT, Cairns NJ, Campbell MC, Willis AW, Racette BA, Tabbal SD, et al. Pathologic accumulation of alpha-synuclein and Abeta in Parkinson disease patients with dementia. Arch Neurol. 2012;69:1326–31.
Colloby SJ, McKeith IG, Burn DJ, Wyper DJ, O'Brien JT, Taylor JP. Cholinergic and perfusion brain networks in Parkinson disease dementia. Neurology. 2016;87:178–85.
Hepp DH, Ruiter AM, Galis Y, Voorn P, Rozemuller AJ, Berendse HW, et al. Pedunculopontine cholinergic cell loss in hallucinating Parkinson disease patients but not in dementia with Lewy bodies patients. J Neuropathol Exp Neurol. 2013;72:1162–70.
Deramecourt V, Bombois S, Maurage CA, Ghestem A, Drobecq H, Vanmechelen E, et al. Biochemical staging of synucleinopathy and amyloid deposition in dementia with Lewy bodies. J Neuropathol Exp Neurol. 2006;65:278–88.
Tiraboschi P, Attems J, Thomas A, Brown A, Jaros E, Lett DJ, et al. Clinicians' ability to diagnose dementia with Lewy bodies is not affected by beta-amyloid load. Neurology. 2015;84:496–9.
Hely MA, Reid WG, Halliday GM, McRitchie DA, Leicester J, Joffe R, et al. Diffuse Lewy body disease: clinical features in nine cases without coexistent Alzheimer's disease. J Neurol Neurosurg Psychiatry. 1996;60:531–8.
Ferman TJ, Aoki N, Crook JE, Murray ME, Graff-Radford NR, van Gerpen JA, et al. The limbic and neocortical contribution of α-synuclein, tau, and amyloid β to disease duration in dementia with Lewy bodies. Alzheimers Dement. 2017; https://doi.org/10.1016/j.jalz.2017.09.014.
Aoki N, Murray ME, Ogaki K, Fujioka S, Rutherford NJ, Rademakers R, et al. Hippocampal sclerosis in Lewy body disease is a TDP-43 proteinopathy similar to FTLD-TDP type a. Acta Neuropathol. 2015;129:53–64.
Homma T, Mochizuki Y, Takahashi K, Komori T. Medial temporal regional argyrophilic grain as a possible important factor affecting dementia in Parkinson's disease. Neuropathology. 2015;35:441–51.
McAleese KE, Walker L, Erskine D, Thomas AJ, McKeith IG, Attems J. TDP-43 pathology in Alzheimer's disease, dementia with Lewy bodies and ageing. Brain Pathol. 2017;27:472–9.
Nakashima-Yasuda H, Uryu K, Robinson J, Xie SX, Hurtig H, Duda JE, et al. Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta Neuropathol. 2007;114:221–9.
Fukui T, Oowan Y, Yamazaki T, Kinno R. Prevalence and clinical implication of microbleeds in dementia with lewy bodies in comparison with microbleeds in Alzheimer's disease. Dement Geriatr Cogn Dis Extra. 2013;3:148–60.
Jellinger KA, Attems J. Prevalence and impact of vascular and Alzheimer pathologies in Lewy body disease. Acta Neuropathol. 2008;115:427–36.
Ghebremedhin E, Rosenberger A, Rub U, Vuksic M, Berhe T, Bickeboller H, et al. Inverse relationship between cerebrovascular lesions and severity of Lewy body pathology in patients with Lewy body diseases. J Neuropathol Exp Neurol. 2010;69:442–8.
Kim SW, Chung SJ, Oh YS, Yoon JH, Sunwoo MK, Hong JY, et al. Cerebral microbleeds in patients with dementia with Lewy bodies and Parkinson disease dementia. AJNR Am J Neuroradiol. 2015;36:1642–7.
Gungor I, Sarro L, Graff-Radford J, Zuk SM, Tosakulwong N, Przybelski SA, et al. Frequency and topography of cerebral microbleeds in dementia with Lewy bodies compared to Alzheimer's disease. Parkinsonism Relat Disord. 2015;21:1101–4.
De Reuck J, Deramecourt V, Cordonnier C, Leys D, Pasquier F, Maurage CA. Prevalence of cerebrovascular lesions in patients with Lewy body dementia: a neuropathological study. Clin Neurol Neurosurg. 2013;115:1094–7.
Bellucci A, Mercuri NB, Venneri A, Faustini G, Longhena F, Pizzi M, et al. Parkinson's disease: from synaptic loss to connectome dysfunction. Neuropathol Appl Neurobiol. 2016;42:77–94.
Lamberts JT, Hildebrandt EN, Brundin P. Spreading of alpha-synuclein in the face of axonal transport deficits in Parkinson's disease: a speculative synthesis. Neurobiol Dis. 2015;77:276–83.
Uchihara T. An order in Lewy body disorders: retrograde degeneration in hyperbranching axons as a fundamental structural template accounting for focal/multifocal Lewy body disease. Neuropathology. 2017;37:129–49.
Obi K, Akiyama H, Kondo H, Shimomura Y, Hasegawa M, Iwatsubo T, et al. Relationship of phosphorylated alpha-synuclein and tau accumulation to Abeta deposition in the cerebral cortex of dementia with Lewy bodies. Exp Neurol. 2008;210:409–20.
Swirski M, Miners JS, de Silva R, Lashley T, Ling H, Holton J, et al. Evaluating the relationship between amyloid-ß and a-synuclein phosphorylated at Ser129 in dementia with Lewy bodies and Parkinson’s disease. Alzheimers Res Ther. 2014;6:77.
Kapasi A, DeCarli C, Schneider JA. Impact of multiple pathologies on the threshold for clinically overt dementia. Acta Neuropathol. 2017;134(2):171–86.
Jellinger KA, Attems J. Does striatal pathology distinguish Parkinson disease with dementia and dementia with Lewy bodies? Acta Neuropathol. 2006;112:253–60.
Ballard C, Ziabreva I, Perry R, Larsen JP, O'Brien J, McKeith I, et al. Differences in neuropathologic characteristics across the Lewy body dementia spectrum. Neurology. 2006;67:1931–4.
Fujishiro H, Iseki E, Higashi S, Kasanuki K, Murayama N, Togo T, et al. Distribution of cerebral amyloid deposition and its relevance to clinical phenotype in Lewy body dementia. Neurosci Lett. 2010;486:19–23.
Tsuboi Y, Uchikado H, Dickson DW. Neuropathology of Parkinson's disease dementia and dementia with Lewy bodies with reference to striatal pathology. Parkinsonism Relat Disord. 2007;13(Suppl 3):S221–4.
Kalaitzakis ME, Pearce RK, Gentleman SM. Clinical correlates of pathology in the claustrum in Parkinson's disease and dementia with Lewy bodies. Neurosci Lett. 2009;461:12–5.
Jellinger KA. Pathological substrate of dementia in Parkinson's disease – its relation to DLB and DLBD. Parkinsonism Relat Disord. 2006;12:119–20.
Francis PT, Perry EK. Cholinergic and other neurotransmitter mechanisms in Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies. Mov Disord. 2007;22(Suppl 17):S351–7.
Halliday GM, Holton JL, Revesz T, Dickson DW. Neuropathology underlying clinical variability in patients with synucleinopathies. Acta Neuropathol. 2011;122:187–204.
Jellinger KA. A critical evaluation of current staging of alpha-synuclein pathology in Lewy body disorders. Biochim Biophys Acta. 1792;2009:730–40.
Jellinger KA. The pathomechanisms underlying Parkinson's disease. Expert Rev Neurother. 2014;14:199–215.
Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2003;24:197–211.
Braak H, Bohl JR, Muller CM, Rub U, de Vos RA, Del Tredici K. Stanley Fahn lecture 2005: the staging procedure for the inclusion body pathology associated with sporadic Parkinson's disease reconsidered. Mov Disord. 2006;21:2042–51.
Beach TG, Adler CH, Lue L, Sue LI, Bachalakuri J, Henry-Watson J, et al. Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol. 2009;117:613–34.
Zaccai J, Brayne C, McKeith I, Matthews F, Ince PG. Patterns and stages of alpha-synucleinopathy: relevance in a population-based cohort. Neurology. 2008;70:1042–8.
Alafuzoff I, Ince PG, Arzberger T, Al-Sarraj S, Bell J, Bodi I, et al. Staging/typing of Lewy body related alpha-synuclein pathology: a study of the BrainNet Europe consortium. Acta Neuropathol. 2009;117:635–52.
Braak H, Del Tredici K. Nervous system pathology in sporadic Parkinson disease. Neurology. 2008;70:1916–25.
Kosaka K, Tsuchiya K, Yoshimura M. Lewy body disease with and without dementia: a clinicopathological study of 35 cases. Clin Neuropathol. 1988;7:299–305.
Dickson DW, Uchikado H, Fujishiro H, Tsuboi Y. Evidence in favor of Braak staging of Parkinson's disease. Mov Disord. 2010;25(Suppl 1):S78–82.
Halliday GM, Del Tredici K, Braak H. Critical appraisal of brain pathology staging related to presymptomatic and symptomatic cases of sporadic Parkinson's disease. J Neural Transm Suppl. 2006;70:99–103.
Halliday G, McCann H, Shepherd C. Evaluation of the Braak hypothesis: how far can it explain the pathogenesis of Parkinson's disease? Expert Rev Neurother. 2012;12:673–86.
Burke RE, Dauer WT, Vonsattel JP. A critical evaluation of the Braak staging scheme for Parkinson's disease. Ann Neurol. 2008;64:485–91.
Muller CM, de Vos RA, Maurage CA, Thal DR, Tolnay M, Braak H. Staging of sporadic Parkinson disease-related alpha-synuclein pathology: inter- and intra-rater reliability. J Neuropathol Exp Neurol. 2005;64:623–8.
Kalaitzakis ME, Graeber MB, Gentleman SM, Pearce RK. Controversies over the staging of alpha-synuclein pathology in Parkinson's disease. Acta Neuropathol. 2008;116:125–8.
Parkkinen L, Pirttila T, Alafuzoff I. Applicability of current staging/categorization of alpha-synuclein pathology and their clinical relevance. Acta Neuropathol. 2008;115:399–407.
Halliday G, Hely M, Reid W, Morris J. The progression of pathology in longitudinally followed patients with Parkinson's disease. Acta Neuropathol. 2008;115:409–15.
Longhena F, Faustini G, Missale C, Pizzi M, Spano P, Bellucci A. The contribution of α-synuclein spreading to Parkinson's disease synaptopathy. Neural Plast. 2017;2017:5012129.
Braak H, Del Tredici K. Potential pathways of abnormal tau and α-synuclein dissemination in sporadic Alzheimer's and Parkinson's diseases. Cold Spring Harb Perspect Biol. 2016;8(11) https://doi.org/10.1101/cshperspect.a023630.
Hasegawa M, Nonaka T, Masuda-Suzukake M. α-Synuclein: Experimental pathology. Cold Spring Harb Perspect Med. 2016;6(9).
Rey NL, George S, Brundin P. Spreading the word: precise animal models and validated methods are vital when evaluating prion-like behaviour of alpha-synuclein. Neuropathol Appl Neurobiol. 2016;42:51–76.
Visanji NP, Brooks PL, Hazrati LN, Lang AE. The prion hypothesis in Parkinson’s disease: Braak to the future. Acta Neuropathol Commun. 2013;1:2.
Brundin P, Melki R. Prying into the prion hypothesis for Parkinson's disease. J Neurosci. 2017;37:9808–18.
Goedert M, Masuda-Suzukake M, Falcon B. Like prions: the propagation of aggregated tau and alpha-synuclein in neurodegeneration. Brain. 2017;140:266–78.
Korczyn AD, Hassin-Baer S. Can the disease course in Parkinson's disease be slowed? BMC Med. 2015;13:295.
Wang HF, Yu JT, Tang SW, Jiang T, Tan CC, Meng XF, et al. Efficacy and safety of cholinesterase inhibitors and memantine in cognitive impairment in Parkinson's disease, Parkinson's disease dementia, and dementia with Lewy bodies: systematic review with meta-analysis and trial sequential analysis. J Neurol Neurosurg Psychiatry. 2015;86:135–43.
Galasko D. Lewy body disorders. Neurol Clin. 2017;35:325–38.
Klein JC, Eggers C, Kalbe E, Weisenbach S, Hohmann C, Vollmar S, et al. Neurotransmitter changes in dementia with Lewy bodies and Parkinson disease dementia in vivo. Neurology. 2010;74:885–92.
Shimada H, Hirano S, Shinotoh H, Aotsuka A, Sato K, Tanaka N, et al. Mapping of brain acetylcholinesterase alterations in Lewy body disease by PET. Neurology. 2009;73:273–8.
Tsuno N. The potential role of donepezil for the treatment of dementia with Lewy bodies. J Alzheimers Dis Parkinsonism. 2016;6:214.
Boot BP. Comprehensive treatment of dementia with Lewy bodies. Alzheimers Res Ther. 2015;7:45.
Ikeda M, Mori E, Matsuo K, Nakagawa M, Kosaka K. Donepezil for dementia with Lewy bodies: a randomized, placebo-controlled, confirmatory phase III trial. Alzheimers Res Ther. 2015;7:4.
Mori E, Ikeda M, Nakagawa M, Miyagishi H, Kosaka K. Pretreatment cognitive profile likely to benefit from donepezil treatment in dementia with Lewy bodies: pooled analyses of two randomized controlled trials. Dement Geriatr Cogn Disord. 2016;42:58–68.
Aarsland D, Ballard C, Walker Z, Bostrom F, Alves G, Kossakowski K, et al. Memantine in patients with Parkinson's disease dementia or dementia with Lewy bodies: a double-blind, placebo-controlled, multicentre trial. Lancet Neurol. 2009;8:613–8.
Stubendorff K, Larsson V, Ballard C, Minthon L, Aarsland D, Londos E. Treatment effect of memantine on survival in dementia with Lewy bodies and Parkinson's disease with dementia: a prospective study. BMJ Open. 2014;4:e005158.
Connolly BS, Fox SH. Drug treatments for the neuropsychiatric complications of Parkinson's disease. Expert Rev Neurother. 2012;12:1439–49.
Sobow T. Parkinson's disease-related visual hallucinations unresponsive to atypical antipsychotics treated with cholinesterase inhibitors: a case series. Neurol Neurochir Pol. 2007;41:276–9.
Burghaus L, Eggers C, Timmermann L, Fink GR, Diederich NJ. Hallucinations in neurodegenerative diseases. CNS Neurosci Ther. 2012;18:149–59.
Molloy S, McKeith IG, O'Brien JT, Burn DJ. The role of levodopa in the management of dementia with Lewy bodies. J Neurol Neurosurg Psychiatry. 2005;76:1200–3.
Goldman JG, Goetz CG, Brandabur M, Sanfilippo M, Stebbins GT. Effects of dopaminergic medications on psychosis and motor function in dementia with Lewy bodies. Mov Disord. 2008;23:2248–50.
Zhang Q, Kim YC, Narayanan NS. Disease-modifying therapeutic directions for Lewy body dementias. Front Neurosci. 2015;9:293.
Bergstrom AL, Kallunki P, Fog K. Development of passive immunotherapies for synucleinopathies. Mov Disord. 2016;31:203–13.
Schneeberger A, Tierney L, Mandler M. Active immunization therapies for Parkinson's disease and multiple system atrophy. Mov Disord. 2016;31:214–24.
Spencer B, Valera E, Rockenstein E, Overk C, Mante M, Adame A, et al. Anti-alpha-synuclein immunotherapy reduces alpha-synuclein propagation in the axon and degeneration in a combined viral vector and transgenic model of synucleinopathy. Acta Neuropathol Commun. 2017;5:7.
Connors MH, Quinto L, McKeith I, Brodaty H, Allan L, Bamford C, et al. Non-pharmacological interventions for Lewy body dementia: a systematic review. Psychol Med. 2017; https://doi.org/10.1017/S0033291717003257.
Gratwicke J, Zrinzo L, Kahan J, Peters A, Beigi M, Akram H, et al. Bilateral deep brain stimulation of the nucleus basalis of Meynert for Parkinson disease dementia: a randomized clinical trial. JAMA Neurol. 2017; https://doi.org/10.1001/jamaneurol.2017.3762.
Berg D, Postuma RB, Bloem B, Chan P, Dubois B, Gasser T, et al. Time to redefine PD? Introductory statement of the MDS task force on the definition of Parkinson's disease. Mov Disord. 2014;29:454–62.
Darweesh SKL, Wolters FJ, Postuma RB, Stricker BH, Hofman A, Koudstaal PJ, et al. Association between poor cognitive functioning and risk of incident parkinsonism: the Rotterdam study. JAMA Neurol. 2017;74(12):1431–8.
Brown EG, Tanner CM. Impaired cognition and the risk of Parkinson disease: trouble in mind. JAMA Neurol. 2017; https://doi.org/10.1001/jamaneurol.2017.1474.
Elder GJ, Mactier K, Colloby SJ, Watson R, Blamire AM, O'Brien JT, et al. The influence of hippocampal atrophy on the cognitive phenotype of dementia with Lewy bodies. Int J Geriatr Psychiatry. 2017;32(11):1182–9.
Spires-Jones TL, Attems J, Thal DR. Interactions of pathological proteins in neurodegenerative diseases. Acta Neuropathol. 2017;134:187–205.
Frigerio R, Fujishiro H, Ahn TB, Josephs KA, Maraganore DM, Delledonne A, et al. Incidental Lewy body disease: do some cases represent a preclinical stage of dementia with Lewy bodies? Neurobiol Aging. 2011;32:857–63.
Bauckneht M, Arnaldi D, Nobili F, Aarsland D, Morbelli S. New tracers and new perspectives for molecular imaging in Lewy body diseases. Curr Med Chem. 2017; https://doi.org/10.2174/0929867324666170609080000.
Strafella AP, Bohnen NI, Perlmutter JS, Eidelberg D, Pavese N, Van Eimeren T, et al. Molecular imaging to track Parkinson's disease and atypical parkinsonisms: new imaging frontiers. Mov Disord. 2017;32:181–92.
Stinton C, McKeith I, Taylor JP, Lafortune L, Mioshi E, Mak E, et al. Pharmacological management of Lewy body dementia: a systematic review and meta-analysis. Am J Psychiatry. 2015;172:731–42.
Clark LN, Kartsaklis LA, Wolf Gilbert R, Dorado B, Ross BM, Kisselev S, et al. Association of glucocerebrosidase mutations with dementia with Lewy bodies. Arch Neurol. 2009;66:578–83.
Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med. 2009;361:1651–61.
Creese B, Bell E, Johar I, Francis P, Ballard C, Aarsland D. Glucocerebrosidase mutations and neuropsychiatric phenotypes in Parkinson's disease and Lewy body dementias: review and meta-analyses. Am J Med Genet B Neuropsychiatr Genet. 2017; https://doi.org/10.1002/ajmg.b.32549.
Liu G, Boot B, Locascio JJ, Jansen IE, Winder-Rhodes S, Eberly S, et al. Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's. Ann Neurol. 2016;80:674–85.
Seto-Salvia N, Clarimon J, Pagonabarraga J, Pascual-Sedano B, Campolongo A, Combarros O, et al. Dementia risk in Parkinson disease: disentangling the role of MAPT haplotypes. Arch Neurol. 2011;68:359–64.
Liu Z, Guo J, Wang Y, Li K, Kang J, Wei Y, et al. Lack of association between IL-10 and IL-18 gene promoter polymorphisms and Parkinson's disease with cognitive impairment in a Chinese population. Sci Rep. 2016;6:19021.
Davis MY, Johnson CO, Leverenz JB, Weintraub D, Trojanowski JQ, Chen-Plotkin A, et al. Association of GBA mutations and the E326K polymorphism with motor and cognitive progression in Parkinson disease. JAMA Neurol. 2016;73:1217–24.
Alcalay RN, Caccappolo E, Mejia-Santana H, Tang M, Rosado L, Orbe Reilly M, et al. Cognitive performance of GBA mutation carriers with early-onset PD: the CORE-PD study. Neurology. 2012;78:1434–40.
Seto-Salvia N, Pagonabarraga J, Houlden H, Pascual-Sedano B, Dols-Icardo O, Tucci A, et al. Glucocerebrosidase mutations confer a greater risk of dementia during Parkinson's disease course. Mov Disord. 2012;27:393–9.
Winder-Rhodes SE, Evans JR, Ban M, Mason SL, Williams-Gray CH, Foltynie T, et al. Glucocerebrosidase mutations influence the natural history of Parkinson's disease in a community-based incident cohort. Brain. 2013;136:392–9.
Chahine LM, Qiang J, Ashbridge E, Minger J, Yearout D, Horn S, et al. Clinical and biochemical differences in patients having Parkinson disease with vs without GBA mutations. JAMA Neurol. 2013;70:852–8.
Oeda T, Umemura A, Mori Y, Tomita S, Kohsaka M, Park K, et al. Impact of glucocerebrosidase mutations on motor and nonmotor complications in Parkinson's disease. Neurobiol Aging. 2015;36:3306–13.
Mata IF, Leverenz JB, Weintraub D, Trojanowski JQ, Chen-Plotkin A, Van Deerlin VM, et al. GBA variants are associated with a distinct pattern of cognitive deficits in Parkinson's disease. Mov Disord. 2016;31:95–102.
Labbè C, Heckman MG, Lorenzo-Betancor O, Soto-Ortolaza AI, Walton RL, Murray ME, et al. MAPT haplotype H1G is associated with increased risk of dementia with Lewy bodies. Alzheimers Dement. 2016;12:1297–304.
Goris A, Williams-Gray CH, Clark GR, Foltynie T, Lewis SJ, Brown J, et al. Tau and alpha-synuclein in susceptibility to, and dementia in. Parkinson's disease Ann Neurol. 2007;62:145–53.
Simon-Sanchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, Berg D, et al. Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat Genet. 2009;41:1308–12.
Morley JF, Xie SX, Hurtig HI, Stern MB, Colcher A, Horn S, et al. Genetic influences on cognitive decline in Parkinson's disease. Mov Disord. 2012;27:512–8.
Nombela C, Rowe JB, Winder-Rhodes SE, Hampshire A, Owen AM, Breen DP, et al. Genetic impact on cognition and brain function in newly diagnosed Parkinson's disease: ICICLE-PD study. Brain. 2014;137:2743–58.
Winder-Rhodes SE, Hampshire A, Rowe JB, Peelle JE, Robbins TW, Owen AM, et al. Association between MAPT haplotype and memory function in patients with Parkinson's disease and healthy aging individuals. Neurobiol Aging. 2015;36:1519–28.
Geiger JT, Ding J, Crain B, Pletnikova O, Letson C, Dawson TM, et al. Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies. Neurobiol Dis. 2016;94:55–62.
Huang X, Chen P, Kaufer DI, Troster AI, Poole C. Apolipoprotein E and dementia in Parkinson disease: a meta-analysis. Arch Neurol. 2006;63:189–93.
Mata IF, Leverenz JB, Weintraub D, Trojanowski JQ, Hurtig HI, Van Deerlin VM, et al. APOE, MAPT, and SNCA genes and cognitive performance in Parkinson disease. JAMA Neurol. 2014;71:1405–12.
Tsuang D, Leverenz JB, Lopez OL, Hamilton RL, Bennett DA, Schneider JA, et al. APOE epsilon4 increases risk for dementia in pure synucleinopathies. JAMA Neurol. 2013;70:223–8.
Williams-Gray CH, Goris A, Saiki M, Foltynie T, Compston DA, Sawcer SJ, et al. Apolipoprotein E genotype as a risk factor for susceptibility to and dementia in Parkinson's disease. J Neurol. 2009;256:493–8.
Mengel D, Dams J, Ziemek J, Becker J, Balzer-Geldsetzer M, Hilker R, et al. Apolipoprotein E epsilon4 does not affect cognitive performance in patients with Parkinson's disease. Parkinsonism Relat Disord. 2016;29:112–6.
Kurz MW, Dekomien G, Nilsen OB, Larsen JP, Aarsland D, Alves G. APOE alleles in Parkinson disease and their relationship to cognitive decline: a population-based, longitudinal study. J Geriatr Psychiatry Neurol. 2009;22:166–70.
Inzelberg R, Chapman J, Treves TA, Asherov A, Kipervasser S, Hilkewicz O, et al. Apolipoprotein E4 in Parkinson disease and dementia: new data and meta-analysis of published studies. Alzheimer Dis Assoc Disord. 1998;12:45–8.
Lockhart PJ, Kachergus J, Lincoln S, Hulihan M, Bisceglio G, Thomas N, et al. Multiplication of the alpha-synuclein gene is not a common disease mechanism in Lewy body disease. J Mol Neurosci. 2004;24:337–42.
Johnson J, Hague SM, Hanson M, Gibson A, Wilson KE, Evans EW, et al. SNCA multiplication is not a common cause of Parkinson disease or dementia with Lewy bodies. Neurology. 2004;63:554–6.
Somme JH, Gomez-Esteban JC, Molano A, Tijero B, Lezcano E, Zarranz JJ. Initial neuropsychological impairments in patients with the E46K mutation of the alpha-synuclein gene (PARK 1). J Neurol Sci. 2011;310:86–9.
Nishioka K, Hayashi S, Farrer MJ, Singleton AB, Yoshino H, Imai H, et al. Clinical heterogeneity of alpha-synuclein gene duplication in Parkinson's disease. Ann Neurol. 2006;59:298–309.
Nishioka K, Hattori N. Relationship between alpha-synuclein and Parkinson's disease. Brain Nerve. 2007;59:825–30.
Konno T, Ross OA, Puschmann A, Dickson DW, Wszolek ZK. Autosomal dominant Parkinson's disease caused by SNCA duplications. Parkinsonism Relat Disord. 2016;22(Suppl 1):S1–6.
Elia AE, Petrucci S, Fasano A, Guidi M, Valbonesi S, Bernardini L, et al. Alpha-synuclein gene duplication: marked intrafamilial variability in two novel pedigrees. Mov Disord. 2013;28:813–7.
Fuchs J, Nilsson C, Kachergus J, Munz M, Larsson EM, Schule B, et al. Phenotypic variation in a large Swedish pedigree due to SNCA duplication and triplication. Neurology. 2007;68:916–22.
Ikeuchi T, Kakita A, Shiga A, Kasuga K, Kaneko H, Tan CF, et al. Patients homozygous and heterozygous for SNCA duplication in a family with parkinsonism and dementia. Arch Neurol. 2008;65:514–9.
Williams-Gray CH, Evans JR, Goris A, Foltynie T, Ban M, Robbins TW, et al. The distinct cognitive syndromes of Parkinson's disease: 5 year follow-up of the CamPaIGN cohort. Brain. 2009;132:2958–69.
Foltynie T, Goldberg TE, Lewis SG, Blackwell AD, Kolachana BS, Weinberger DR, et al. Planning ability in Parkinson's disease is influenced by the COMT val158met polymorphism. Mov Disord. 2004;19:885–91.
Williams-Gray CH, Hampshire A, Barker RA, Owen AM. Attentional control in Parkinson's disease is dependent on COMT val 158 met genotype. Brain. 2008;131:397–408.
Wu K, O'Keeffe D, Politis M, O'Keeffe GC, Robbins TW, Bose SK, et al. The catechol-O-methyltransferase Val(158)met polymorphism modulates fronto-cortical dopamine turnover in early Parkinson's disease: a PET study. Brain. 2012;135:2449–57.
Arias-Vasquez A, de Lau L, Pardo L, Liu F, Feng BJ, Bertoli-Avella A, et al. Relationship of the Ubiquilin 1 gene with Alzheimer's and Parkinson's disease and cognitive function. Neurosci Lett. 2007;424:1–5.
Kurz MW, Schlitter AM, Klenk Y, Mueller T, Larsen JP, Aarsland D, et al. FMR1 alleles in Parkinson's disease: relation to cognitive decline and hallucinations, a longitudinal study. J Geriatr Psychiatry Neurol. 2007;20:89–92.
Kun-Rodrigues C, Ross OA, Orme T, Shepherd C, Parkkinen L, Darwent L, et al. Analysis of C9orf72 repeat expansions in a large international cohort of dementia with Lewy bodies. Neurobiol Aging. 2017;49:214.e13–5.
Healy DG, Falchi M, O'Sullivan SS, Bonifati V, Durr A, Bressman S, et al. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurol. 2008;7:583–90.
Srivatsal S, Cholerton B, Leverenz JB, Wszolek ZK, Uitti RJ, Dickson DW, et al. Cognitive profile of LRRK2-related Parkinson's disease. Mov Disord. 2015;30:728–33.
Shanker V, Groves M, Heiman G, Palmese C, Saunders-Pullman R, Ozelius L, et al. Mood and cognition in leucine-rich repeat kinase 2 G2019S Parkinson's disease. Mov Disord. 2011;26:1875–80.
Nichols WC, Pankratz N, Hernandez D, Paisan-Ruiz C, Jain S, Halter CA, et al. Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease. Lancet. 2005;365:410–2.
Goldwurm S, Zini M, Di Fonzo A, De Gaspari D, Siri C, Simons EJ, et al. LRRK2 G2019S mutation and Parkinson's disease: a clinical, neuropsychological and neuropsychiatric study in a large Italian sample. Parkinsonism Relat Disord. 2006;12:410–9.
Aasly JO, Toft M, Fernandez-Mata I, Kachergus J, Hulihan M, White LR, et al. Clinical features of LRRK2-associated Parkinson's disease in central Norway. Ann Neurol. 2005;57:762–5.
Marras C, Alcalay RN, Caspell-Garcia C, Coffey C, Chan P, Duda JE, et al. Motor and nonmotor heterogeneity of LRRK2-related and idiopathic Parkinson's disease. Mov Disord. 2016;31:1192–202.
Thaler A, Mirelman A, Gurevich T, Simon E, Orr-Urtreger A, Marder K, et al. Lower cognitive performance in healthy G2019S LRRK2 mutation carriers. Neurology. 2012;79:1027–32.
Gatt AP, Jones EL, Francis PT, Ballard C, Bateman JM. Association of a polymorphism in mitochondrial transcription factor a (TFAM) with Parkinson's disease dementia but not dementia with Lewy bodies. Neurosci Lett. 2013;557 Pt B:177–80.
Hodges K, Brewer SS, Labbe C, Soto-Ortolaza AI, Walton RL, Strongosky AJ, et al. RAB39B gene mutations are not a common cause of Parkinson's disease or dementia with Lewy bodies. Neurobiol Aging. 2016;45:107–8.
Acknowledgements
The authors thank Mr. E. Mitter-Ferstl, PhD, for secretarial and editorial work.
Funding
The study was partially funded by the Society for the Promotion of Research in Experimental Neurology, Vienna, Austria.
Availability of data and materials
Not applicable.
Author information
Authors and Affiliations
Contributions
KAJ and ADK contributed to the conception of the manuscript; KAJ contributed literature research, drafted the manuscript, prepared tables and figure. Both authors contributed to the final editing of the manuscript and prepared it.
Corresponding author
Ethics declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
About this article
Cite this article
Jellinger, K.A., Korczyn, A.D. Are dementia with Lewy bodies and Parkinson’s disease dementia the same disease?. BMC Med 16, 34 (2018). https://doi.org/10.1186/s12916-018-1016-8
Received:
Accepted:
Published:
DOI: https://doi.org/10.1186/s12916-018-1016-8