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Clinical correlates of pathology in the claustrum in Parkinson's disease and dementia with Lewy bodies
Abstract
Dementia and visual hallucinations are common complications of Parkinson's disease (PD), yet their patho-anatomical bases are poorly defined. We studied alpha-synuclein (alphaSyn), tau and amyloid-beta (Abeta) pathology in the claustrum of 20 PD cases without dementia, 12 PD cases with dementia (PDD) and 7 cases with dementia with Lewy bodies (DLB). alphaSyn positivity was observed in 75% of PD cases without dementia and in 100% of PDD and DLB cases. Abeta was observed in the claustrum in 25% of PD, 58% of PDD and 100% of DLB cases. Tau was negligible in all cases restricting further analysis. Compared to PD cases without dementia, PDD cases demonstrated a significantly greater alphaSyn burden in the claustrum (p=0.0003). In addition, DLB cases showed a significantly increased alphaSyn deposition when compared to PDD (p=0.02) and PD without dementia (p=0.0002). A similar hierarchy, PD<PDD<DLB was seen in terms of Abeta burden in the claustrum. Comparison of alphaSyn and Abeta burden in those cases with and without visual hallucinations did not reveal any significant associations (p=0.13 and 0.1, respectively). We demonstrate that pathology in the claustrum, a region of largely obscure physiological function, strongly relates to the presence of dementia in Parkinson's disease and DLB.
... Claustrum lesions are observed in almost all cases of Parkinson's disease [72]. Cognitive complications of Parkinson's disease thought to be mediated by claustrum disfunction are dementia, functional and behavioral impairment [73]. ...
... Claustrum disfunction has been associated with several neurological and clinical pathologies, including Wilson's disease [78], epilepsy [79], Lewy body dementia [3,80], schizophrenia [46], sleep disturbance, depressive symptoms, psychomotor retardation, anhedonia [72]. Some findings show that delusions and hallucinations in schizophrenia can be explained by the claustrum's involvement in consciousness formation [81]. ...
Introduction
The claustrum is a structure involved in formation of several cortical and subcortical neural microcircuits which may be involved in such functions as conscious sensations and rewarding behavior. The claustrum is regarded as a multi-modal information processing network. Pathology of the claustrum is seen in certain neurological disorders. To date, there are not enough comprehensive studies that contain accurate information regarding involvement of the claustrum in development of neurological disorders.
Objective
Our review aims to provide an update on claustrum anatomy, ontogenesis, cytoarchitecture, neural networks and their functional relation to the incidence of neurological diseases.
Materials and methods
A literature review was conducted using the Google Scholar, PubMed, NCBI MedLine, and eLibrary databases.
Results
Despite new methods that have made it possible to study the claustrum at the molecular, genetic and epigenetic levels, its functions and connectivity are still poorly understood. The anatomical location, relatively uniform cytoarchitecture, and vast network of connections suggest a divergent role of the claustrum in integration and processing of input information and formation of coherent perceptions. Several studies have shown changes in the appearance, structure and volume of the claustrum in neurodegenerative diseases, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), autism, schizophrenia, and depressive disorders. Taking into account the structure, ontogenesis, and functions of the claustrum, this literature review offers insight into understanding the crucial role of this structure in brain function and behavior.
... A synergistic interaction between the Alzheimer's disease-related protein aggregates (amyloid-b and tau) and -synuclein-containing inclusions (perikaryal Lewy bodies and Lewy neurites) has also been proposed as a critical determinant (Masliah et al., 2001;Apaydin et al., 2002;Giasson et al., 2003;Pletnikova et al., 2005;Lashley et al., 2008, Clinton et al., 2010, and a link between concomitant Alzheimer's disease pathology and faster progression to dementia has been suggested (Ballard et al., 2006;Halliday et al., 2008;Sabbagh et al., 2009). Subcortical amyloid-b pathology has also been reported in patients with Parkinson's disease and cognitive impairment (Kalaitzakis et al., 2008(Kalaitzakis et al., , 2009), but it remains uncertain whether the striatal amyloid-b deposition alone could drive the progression of dementia in Parkinson's disease independently of cortical amyloid-b lesions and cortical Lewy body burden (Lashley et al., 2008;Dickson et al., 2009). ...
... In our study, we have found that both Lewy body-(-synuclein) and Alzheimer's disease-(amyloid-b and tau) type pathologies are increased in cortical areas of patients with PDD compared to patients with PDND. A number of studies have proposed that limbic and cortical Lewy body pathology is the main and specific pathological correlate of dementia in Parkinson's disease (Hurtig et al., 2000;Mattila et al., 2000;Harding and Halliday, 2001;Kö vari et al., 2003;Aarsland et al., 2005), but other surveys have challenged this view (Apaydin et al., 2002;Colosimo et al., 2003;Pletnikova et al., 2005;Ballard et al., 2006;Kalaitzakis et al., 2008Kalaitzakis et al., , 2009Lashley et al., 2008). Furthermore, some clinicopathological studies favour a role for Alzheimer's disease-type pathological changes driving clinical disease progression to cognitive impairment in Parkinson's disease (Apaydin et al., 2002;Jellinger and Attems, 2008). ...
The relative importance of Lewy- and Alzheimer-type pathologies to dementia in Parkinson's disease remains unclear. We have examined the combined associations of α-synuclein, tau and amyloid-β accumulation in 56 pathologically confirmed Parkinson's disease cases, 29 of whom had developed dementia. Cortical and subcortical amyloid-β scores were obtained, while tau and α-synuclein pathologies were rated according to the respective Braak stages. Additionally, cortical Lewy body and Lewy neurite scores were determined and Lewy body densities were generated using morphometry. Non-parametric statistics, together with regression models, receiver-operating characteristic curves and survival analyses were applied. Cortical and striatal amyloid-β scores, Braak tau stages, cortical Lewy body, Lewy neurite scores and Lewy body densities, but not Braak α-synuclein stages, were all significantly greater in the Parkinson's disease-dementia group (P<0.05), with all the pathologies showing a significant positive correlation to each other (P<0.05). A combination of pathologies [area under the receiver-operating characteristic curve=0.95 (0.88-1.00); P<0.0001] was a better predictor of dementia than the severity of any single pathology. Additionally, cortical amyloid-β scores (r=-0.62; P=0.043) and Braak tau stages (r=-0.52; P=0.028), but not Lewy body scores (r=-0.25; P=0.41) or Braak α-synuclein stages (r=-0.44; P=0.13), significantly correlated with mini-mental state examination scores in the subset of cases with this information available within the last year of life (n=15). High cortical amyloid-β score (P=0.017) along with an older age at onset (P=0.001) were associated with a shorter time-to-dementia period. A combination of Lewy- and Alzheimer-type pathologies is a robust pathological correlate of dementia in Parkinson's disease, with quantitative and semi-quantitative assessment of Lewy pathology being more informative than Braak α-synuclein stages. Cortical amyloid-β and age at disease onset seem to determine the rate to dementia.
... Yamamoto (Yamamoto et al., 2007) LB scores in the claustrum are lower than in the insular and inferior temporal cortices and amygdala, but higher than in the BA17, precentral, postcentral, and transverse temporal cortices Weaker intrinsic functional connectivity (iFC) between the claustrum and dorsal anterior cingulate cortex HIV Smith (Smith et al., 2000) Regional increase in normal white matter in claustrum sub-nuclear white matter HIV-Encephalitis Sevigny (Sevigny et al., 2005) Astrogliosis of the claustrum and other basal ganglia Multiple Sclerosis Klaver (Klaver et al., 2013) Demyelination of the claustrum found in MS patients Parkinson's Kalaitzakis (Kalaitzakis et al., 2009) Claustral αSyn positivity in 75% of non-demented cases, but 100% of patients with dementia (Parkinson's w/dementia or DLB) Schizophrenia Shapleske (Shapleske et al., 2002) White matter excess in the claustrum is correlated with hallucinations in schizophrenia Cascella (Cascella et al., 2011) Severity of delusions is correlated with reduction in left claustral volume Kong (Kong et al., 2012) GM decrease in the claustrum correlates ositively with neurlogical soft signs Seizures Wada (Wada and Kudo, 1997) Lesioning of the left claustrum led to bilateral eyelid twitching, myoclonic jerking, and eventually convulsive seizures Transitory encephalopathy Sperner (Sperner et al., 1996) Epilepsy and psychotic disturbance was associated with bilateral lesions of the claustrum Wilson's disease Sener (Sener, 1998) Bilateral claustrum brighter and thicker in T1 (see also King et al.) Sener (Sener, 1993) T2 hyperintensity in the claustrum-the "bright claustrum sign"-is a marker of the disease changes in the claustrum associated with aging, however, are subtle, appearing several years after those in the cerebral cortex become apparent. The claustrum has also been examined in cases of memory impairment associated with HIV, AIDS, Parkinson's, and Dementia with Lewy Bodies (DLB) (Kozlowski et al., 1997;Yamamoto et al., 2007;Smith et al., 2008;Kalaitzakis et al., 2009). ...
... Yamamoto (Yamamoto et al., 2007) LB scores in the claustrum are lower than in the insular and inferior temporal cortices and amygdala, but higher than in the BA17, precentral, postcentral, and transverse temporal cortices Weaker intrinsic functional connectivity (iFC) between the claustrum and dorsal anterior cingulate cortex HIV Smith (Smith et al., 2000) Regional increase in normal white matter in claustrum sub-nuclear white matter HIV-Encephalitis Sevigny (Sevigny et al., 2005) Astrogliosis of the claustrum and other basal ganglia Multiple Sclerosis Klaver (Klaver et al., 2013) Demyelination of the claustrum found in MS patients Parkinson's Kalaitzakis (Kalaitzakis et al., 2009) Claustral αSyn positivity in 75% of non-demented cases, but 100% of patients with dementia (Parkinson's w/dementia or DLB) Schizophrenia Shapleske (Shapleske et al., 2002) White matter excess in the claustrum is correlated with hallucinations in schizophrenia Cascella (Cascella et al., 2011) Severity of delusions is correlated with reduction in left claustral volume Kong (Kong et al., 2012) GM decrease in the claustrum correlates ositively with neurlogical soft signs Seizures Wada (Wada and Kudo, 1997) Lesioning of the left claustrum led to bilateral eyelid twitching, myoclonic jerking, and eventually convulsive seizures Transitory encephalopathy Sperner (Sperner et al., 1996) Epilepsy and psychotic disturbance was associated with bilateral lesions of the claustrum Wilson's disease Sener (Sener, 1998) Bilateral claustrum brighter and thicker in T1 (see also King et al.) Sener (Sener, 1993) T2 hyperintensity in the claustrum-the "bright claustrum sign"-is a marker of the disease changes in the claustrum associated with aging, however, are subtle, appearing several years after those in the cerebral cortex become apparent. The claustrum has also been examined in cases of memory impairment associated with HIV, AIDS, Parkinson's, and Dementia with Lewy Bodies (DLB) (Kozlowski et al., 1997;Yamamoto et al., 2007;Smith et al., 2008;Kalaitzakis et al., 2009). Other neurological conditions have been examined in the claustrum as well. ...
The claustrum seems to have been waiting for the science of connectomics. Due to its tiny size, the structure has remained remarkably difficult to study until modern technological and mathematical advancements like graph theory, connectomics, diffusion tensor imaging, HARDI, and excitotoxic lesioning. That does not mean, however, that early methods allowed researchers to assess micro-connectomics. In fact, the claustrum is such an enigma that the only things known for certain about it are its histology, and that it is extraordinarily well connected. In this literature review, we provide background details on the claustrum and the history of its study in the human and in other animal species. By providing an explanation of the neuroimaging and histology methods have been undertaken to study the claustrum thus far-and the conclusions these studies have drawn-we illustrate this example of how the shift from micro-connectomics to macro-connectomics advances the field of neuroscience and improves our capacity to understand the brain.
... 29 31 54 Striatal α-synuclein differentiated PDD (29.4% of 17 cases) from DLB (76.5% of 17 cases, p<0.001) in one study. 40 Additionally, in the claustrum, α-synuclein deposition rose progressively from PD without dementia to PDD to DLB. 43 The strong association between extensive α-synuclein pathology and dementia was challenged by some observations. Some large studies found that 15.2%-44.7% of 181 cognitively healthy PD cases had severe, neocortical-type pathology. ...
... Claustrum amyloid-β was comparable between PDD and DLB, but exceeded levels in cognitively healthy PD, while tau was negligible in all three groups. 43 Finally, in cases with comorbid Lewy and Alzheimer pathologies, greater global amyloid-β (significant in the temporal and cingulate cortices) and tau (significant in the frontal and cingulate cortices) was found in those diagnosed clinically with DLB, relative to PDD. 59 ...
Background
Dementia is a common, debilitating feature of late Parkinson’s disease (PD). PD dementia (PDD) is associated with α-synuclein propagation, but coexistent Alzheimer’s disease (AD) pathology may coexist. Other pathologies (cerebrovascular, transactive response DNA-binding protein 43 (TDP-43)) may also influence cognition. We aimed to describe the neuropathology underlying dementia in PD.
Methods
Systematic review of autopsy studies published in English involving PD cases with dementia. Comparison groups included PD without dementia, AD, dementia with Lewy bodies (DLB) and healthy controls.
Results
44 reports involving 2002 cases, 57.2% with dementia, met inclusion criteria. While limbic and neocortical α-synuclein pathology had the strongest association with dementia, between a fifth and a third of all PD cases in the largest studies had comorbid AD. In PD cases with dementia, tau pathology was moderate or severe in around a third, and amyloid-β pathology was moderate or severe in over half. Amyloid-β was associated with a more rapid cognitive decline and earlier mortality, and in the striatum, distinguished PDD from DLB. Positive correlations between multiple measures of α-synuclein, tau and amyloid-β were found. Cerebrovascular and TDP-43 pathologies did not generally contribute to dementia in PD. TDP-43 and amyloid angiopathy correlated with coexistent Alzheimer pathology.
Conclusions
While significant α-synuclein pathology is the main substrate of dementia in PD, coexistent pathologies are common. In particular, tau and amyloid-β pathologies independently contribute to the development and pattern of cognitive decline in PD. Their presence should be assessed in future clinical trials where dementia is a key outcome measure.
Trial registration number
CRD42018088691.
... Although their presence in the substantia nigra is pathognomonic for PD, alpha-Syn pathological lesions have been reported in several extranigral regions as well. In a very elegant study Kalaitzakis and associates have evaluated the alpha-Syn, tau and amyloid-βeta (Aβ) pathologies in claustrum of 20 PD cases without dementia, 12 PD cases with dementia (PDD) and 7 cases with dementia with LBD (Kalaitzakis et al. 2009). An alpha-Syn positivity has been observed in 75% of PD cases without dementia and in 100% of PDD and LBD cases. ...
... This result is in accordance with an article in which the hypofunction of precuneus has been related to memory and executive tasks alterations in PD (Dušek et al. 2012). Such alteration might also contribute to explain poor visuospatial processing (Filoteo et al. 2014) that may prelude to dementia and visual hallucinations previously reported in PD (Kalaitzakis et al. 2009). Several studies have further shown that precuneus is strongly involved in visuomotor processing and learning (Kawashima et al. 1995;Parsons et al. 2005;Culham et al. 2006). ...
The claustrum is a thin grey matter structure which is involved in a wide brain network. Previous studies suggested a link between claustrum and Parkinson’s Disease (PD), showing how α-synuclein pathology may affect claustral neurons as well as how α-synuclein immunoreactivity may correlate with the onset of cognitive dysfunctions. Our aim is to investigate, via diffusion MRI, claustral structural network changes in drug naïve PD patients, with the goal to understand whether such changes may contribute to cognitive decline in PD. 15 drug naïve PD patients and 15 age-matched controls were enrolled; MR protocol was performed on a 3T scanner. Whole brain probabilistic tractography was obtained using Constrained Spherical Deconvolution (CSD) diffusion model. Connectivity matrices were estimated based on a robust anatomical parcellation of structural T1w images. In PD group, impaired subnetworks were correlated with psychological examinations. We found decreased claustral connectivity in PD patients compared to controls, especially with areas mainly involved in visuomotor and attentional systems. Moreover, we found a positive correlation between MoCA and density of pathways connecting ipsilaterally claustrum to left (r = 0.578, p = 0.021) and right (r = 0.640, p = 0.020) Pars Orbitalis. Our results support the hypothesis of claustral involvement in cognitive decline in drug naïve PD patients.
... Moreover, an important contribution of the presence of striatal Aβ in the cognition of PD was shown when compared to cortical β-amyloidopathy alone [75,87]. Other differences include a more severe α-syn load in the amygdala in DLB compared to PDD [88]. In PD, the highest load of α-syn is found in the cingulate cortex, basal forebrain, and hippocampus [69,76,89], with a higher deposition in the claustrum rising progressively from PD without dementia to PDD and DLB [88]. ...
... Other differences include a more severe α-syn load in the amygdala in DLB compared to PDD [88]. In PD, the highest load of α-syn is found in the cingulate cortex, basal forebrain, and hippocampus [69,76,89], with a higher deposition in the claustrum rising progressively from PD without dementia to PDD and DLB [88]. Moreover, hyperphosphorylated tau (p-tau) in LBD has been shown to be significantly lower than in AD but significantly higher than in controls [74], and may display a different pattern in DLB vs. PDD [69]. ...
Lewy body dementias (LBDs) consist of dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), which are clinically similar syndromes that share neuropathological findings with widespread cortical Lewy body deposition, often with a variable degree of concomitant Alzheimer pathology. The objective of this article is to provide an overview of the neuropathological and clinical features, current diagnostic criteria, biomarkers, and management of LBD. Literature research was performed using the PubMed database, and the most pertinent articles were read and are discussed in this paper. The diagnostic criteria for DLB have recently been updated, with the addition of indicative and supportive biomarker information. The time interval of dementia onset relative to parkinsonism remains the major distinction between DLB and PDD, underpinning controversy about whether they are the same illness in a different spectrum of the disease or two separate neurodegenerative disorders. The treatment for LBD is only symptomatic, but the expected progression and prognosis differ between the two entities. Diagnosis in prodromal stages should be of the utmost importance, because implementing early treatment might change the course of the illness if disease-modifying therapies are developed in the future. Thus, the identification of novel biomarkers constitutes an area of active research, with a special focus on α-synuclein markers.
... Similarly, in humans, one report described complete arrest of volitional behavior, unresponsiveness, and amnesia upon stimulation of the left claustrum (Koubeissi et al., 2014). Furthermore, brain lesions circumscribed to the claustrum have shown impairments of memory (Kozlowski et al., 1997;Yamamoto et al., 2007;Smith et al., 2008;Kalaitzakis et al., 2009), cognition (Sperner et al., 1996), and consciousness (Chau et al., 2015), and increased claustral signal intensity in MRI has been associated with status epilepticus by a number of investigators (Silva et al., 2017;Meletti et al., 2015). ...
Objective:
The claustrum has been implicated in consciousness, and MRIs of patients with status epilepticus have shown increased claustral signal intensity. In an attempt to investigate the role of claustrum in cognition and seizures, we (1) assessed the effect of high-frequency stimulation (HFS) of the claustrum on performance in the operant chamber; (2) studied interclaustral and claustrohippocampal connectivity through cerebro-cerebral evoked potentials (CCEPs); and (3) investigated the role of claustrum in kainate-induced (KA) seizures.
Methods:
Adult male Sprague-Dawley rats were trained in operant conditioning and implanted with electrodes in bilateral claustra and hippocampi. Claustrum HFS (50 Hz) was delivered bilaterally and unilaterally with increasing intensities from 50 to 1000 μA, and performance scores were assessed. CCEPs were studied by averaging the responses to bipolar stimulations, 1-ms wide pulses at 0.1 Hz to the claustrum. KA seizures were analyzed on video-EEG recordings.
Results:
Generalized Estimating Equations analysis revealed that claustral stimulation reduced task performance scores relative to rest sessions (bilateral: -15.8 percentage points, p < 0.0001; unilateral: -15.2, p < 0.0001). With some stimulations, the rats showed a stimulus-locked decrease in attentiveness and, occasionally, an inability to complete the operant task. CCEPs demonstrated interclaustral and claustrohippocampal connectivity. Some KA seizures appeared to originate from the claustrum.
Conclusions:
Findings from the operant conditioning task suggest stimulation of the claustrum can alter attention or awareness. CCEPs demonstrated connectivity between the two claustra and between the claustrum and the hippocampi. Such connectivity may be part of the circuitry that underlies the alteration of awareness in limbic seizures. Lastly, KA seizures showed early involvement of the claustrum, a finding that also supports a possible role of the claustrum in the alteration of consciousness that accompanies dyscognitive seizures.
... Through numerous neuroanatomical studies, the claustrum and many neocortical areas including the frontal cortex [33], visual cortical fields including the striate cortex [8], temporal cortex [56], entorhinal cortex [26], parieto-occipital cortex [51], and the parietal cortex [48] have been reported to be interconnected. Limbic structures such as the hippocampus [3] and the amygdala [4] as well as the caudate nucleus and putamen [6] regions have been shown to relate to dementia in Parkinson's disease [28,29] are mutually connected to the claustrum [30]. ...
The purpose of this study was to reveal the computer-aided three-dimensional (3D) appearance, the dimensions, and neighbourly relations of the claustrum and make a stereotactic approach to it by using serial sections taken from the brain of a human cadaver. The Snake technique was used to carry out 3D reconstructions of the claustra and surrounding structures. The photorealistic imaging and stereotactic approach were rendered by using the Advanced Render Module in Cinema 4D software. The claustrum takes the form of the concavity of the insular cortex and the convexity of the putamen. The inferior border of the claustrum is at about the same level as the bottom edge of the insular cortex and the putamen, but the superior border of the claustrum is at a lower level than the upper edge of the insular cortex and the putamen. The volume of the right claustrum, in the dimensions of 35.5710 mm x 1.0912 mm x 16.0000 mm, was 828.8346 mm(3), and the volume of the left claustrum, in the dimensions of 32.9558 mm x 0.8321 mm x x 19.0000 mm, was 705.8160 mm(3). The surface areas of the right and left claustra were calculated to be 1551.149697 mm2 and 1439.156450 mm(2) by using Surfdriver software. This is the first study reporting the 3D reconstruction and photorealistic imaging of the claustrum of the human brain. This technique enables us to determine the spatial coordinates of the target tissues and to rehearse the surgical procedures for preoperative trajectory planning by using virtual surgery. We believe that this study will be a really useful anatomic guide for neuroscientists and neurosurgeons interested in the claustrum.
... With regard to the clinical implications of our research, it is of interest to note that CaBP functions as a neuroprotectant in severe neurodegenerative disorders such as Parkinson's disease (Lavoie and Parent 1991; German et al. 1992; Iacopino et al. 1992; Mouatt-Prigent et al. 1994; Damier et al. 1999), Huntington's chorea (Cicchetti and Parent 1996), and Alzheimer's disease (Hof et al. 1993; Sampson et al. 1997). Moreover, the claustrum has been implicated in the etiology and sequelae of these devastating maladies (Bruen et al. 2008; Kalaitzakis et al. 2009; Beal et al. 1988), as well as in those of autism and schizophrenia Brain Struct Funct 123 ...
The morphology and distribution of parvalbumin-immunoreactive neurons (PV-ir) were studied in the human claustrum. PV-ir neurons were observed throughout the claustrum, with the highest numbers noted in the central (broadest) portion as compared with the dorsal and ventral aspects. Reaction product was evident in the neuronal perikarya, dendritic processes, and spines. In the majority of these labeled neurons, the cytoplasm was devoid of lipofuscin pigment. Cell bodies varied widely in both shape and size, ranging from oval and small, to multipolar and large. PV-ir neurons were classified into two groups, primarily based on dendritic morphology: spiny neurons with long and straight dendrites, and aspiny neurons with thin and curving dendritic processes. PV-ir fibers were seen throughout the neuropil, with many immuno-positive puncta noted.
... expression (ranked 88th of 105). Overall, this pattern agrees with past studies of SNCA expression and PD pathology [17,18]. ...
Expression patterns of the alpha-synuclein gene (SNCA) were studied across anatomy, development, and disease to better characterize its role in the brain. In this postmortem study, negative spatial co-expression between SNCA and 73 interferon-γ (IFN-γ) signaling genes was observed across many brain regions. Recent animal studies have demonstrated that IFN-γ induces loss of dopamine neurons and nigrostriatal degeneration. This opposing pattern between SNCA and IFN-γ signaling genes increases with age (rho = -0.78). In contrast, a meta-analysis of four microarray experiments representing 126 substantia nigra samples reveals a switch to positive co-expression in Parkinson's disease (p<0.005). Use of genome-wide testing demonstrates this relationship is specific to SNCA (p<0.002). This change in co-expression suggests an immunomodulatory role of SNCA that may provide insight into neurodegeneration. Genes showing similar co-expression patterns have been previously linked to Alzheimer's (ANK1) and Parkinson's disease (UBE2E2, PCMT1, HPRT1 and RIT2).
... This may be a testament to the redundancy of neural connectivity. Other apparently contravening but difficult to interpret threads of clinical observation have also been described (Yamamoto et al., 2007;Kalaitzakis et al., 2009). Whatever the claustrum and its dense interneural connectivity conjures in the human brain, it, in itself, is not the seat of the human soul. ...
A model of human consciousness and perceived agency is described, in which the distributed elements underlying unified phenomenological consciousness and its emotional valence, as well as triggered recollections, are recruited, bound, and reinforced by reciprocal connections with the heavily networked claustrum. Preliminary evidence for this theory, which builds on the work of Crick and Koch, Ramachandran, Smythies, and others, is briefly reviewed, followed by a discussion of the implications this model may have for our understanding of the basis for the potency of poetic devices wielded in the practice of that art.
Key Words: selfhood, consciousness, neuroscience, poetics.
... Regarding Parkinson's Disease (PD), it is worth noting that claustral alterations might have important implications for the onset of motor symptoms and cognitive ones. Indeed, it was demonstrated that claustral αSynuclein depositions showed increased severity if considering PD or PD with dementia; the worst alterations were found in dementia with Lewy bodies [33]. These findings might suggest that the claustral role is more associated with high-order brain functions allowing cognitive skills since its damage is able to affect these ones. ...
Purpose:
Complex claustral connection network was widely demonstrated both in humans and animals. Moreover, several studies have suggested that claustral connections directly involve also the contralateral hemisphere. Detection of contralateral cortico-claustral and inter-claustral connections was reported mainly in animals and only partially in humans. The main purpose of this study was to provide more robust tractography-driven support of the existence of inter-hemispheric claustral connections in humans, by means of a dedicated optimized tractographic protocol.
Methods:
Fifteen healthy subjects were examined by means of an advanced magnetic resonance imaging-based probabilistic constrained spherical deconvolution tractographic protocol. Moreover, quantitative diffusion parameters were extracted by each reconstructed pathway.
Results:
In this study, further imaging-based support on the possible existence in humans of contralateral cortico-claustral and inter-claustral connections was provided. These connections were found to involve almost all the superior portion of each claustrum, showing a topographical organization. Moreover, the detection of inter-claustral connections passing through the anterior commissure was reported, for the first time, in humans.
Conclusions:
The possible existence of inter-claustral and cortico-claustral contralateral pathways might provide the morphological basis for the complex functional phenomena observed in previous studies. Furthermore, these connections might have several important clinical implications, since they might explain how the inter-hemispheric coordination governed by the claustrum, as well as the functional recovery subsequent to damages involving one claustrum, takes place.
... Although AD and PD are clinically distinct entities, the two diseases appear in a close association in pathological evidence. Aβ, one important hallmark of AD pathology, has been reported present in patients with PD [6][7][8][9]. Similarly, PD pathologies have also been reported in some AD cases, for example, pathological evidence indicated Lewy body deposition also exited in AD cases [9,10]. ...
Alzheimer's disease (AD) and Parkinson's disease (PD) have overlapping pathological mechanisms and genetic background, suggesting it would be meaningful to replicate PD-related genetic variants in AD population to identify new loci of AD. Here, in order to discover potential AD-related loci, we investigated the association between late-onset AD (LOAD) susceptibility and nine single-nucleotide polymorphisms (SNPs) (rs11724635 of BST1, rs12637471 of MCCC1, rs15553999 of TMEM229, rs17649553 of MAPT, rs34311866 of TMEM175-GAK-DGKQ, rs356182 of SNCA, rs6430538 of ACMSD-TMEM163, rs76904798 of LRRK2 and rs823118 of RAB7L1-NUCKS1) which were reported to have genome-wide significant associations with PD risk in a recent Genome Wide Association Study performed among white population. We included 2350 samples comprising with 992 sporadic LOAD patients and 1358 gender- and age-matched control subjects who were unrelated northern Han Chinese residents. Finally, among these included genetic variants, only rs76904798 of LRRK2 was proved to significantly reduce LOAD risk in a multivariate analysis in a dominant model after adjusting for age, sex, and apolipoprotein E (APOE) ε4 status (OR = 0.616; 95 % CI 0.446-0.849; Bonferroni corrected P = 0.027). In addition, when these data were stratified by APOE ε4 status, rs76904798 was still evident among subjects without APOE ε4 allele. Our results first time indicated rs76904798 of LRRK2 is also a common risk genetic variant for LOAD susceptibility in a northern Han Chinese people.
... In addition to the information on the functional neuroanatomy of the claustrum and its neurophysiology (Segundo & Machne, 1956;Spector et al., 1974;Olson & Graybiel, 1980;Salerno et al., 1981;Cortimiglia et al., 1982;Shima et al., 1996;Shibuya & Yamamoto, 1998;Chachich & Powell, 2004;Sherk, 2014), post-mortem studies indicate that the typical brain pathology of several neurodegenerative disorders also affects the claustrum-amyloid plaques in Alzheimers's disease claustrum, possibly related to the degree of dementia and cognitive dysfunction (Morys et al., 1996); Lewy bodies in dementia with Lewy bodies, possibly related to visual hallucinations (Kosaka, 1978;Yamamoto et al., 2007); and a-synuclein burden in idiopathic Parkinson's disease (PD) cases with dementia (Kalaitzakis et al., 2009). Similarly, a recent morphometric study in post-mortem brain found reduced claustrum volumes in cases with schizophrenia and major depression (Bernstein et al., 2016). ...
In the human brain, the claustrum is a small subcortical telencephalic nucleus, situated between the insular cortex and the putamen. A plethora of neuroanatomical studies have shown the existence of dense, widespread, bidirectional and bilateral monosynaptic interconnections between the claustrum and most cortical areas. A rapidly growing body of experimental evidence points to the integrative role of claustrum in complex brain functions, from motor to cognitive. Here, we examined for the first time, the behaviour of the classical monoamine neurotransmitters dopamine, noradrenaline and serotonin in the claustrum of the normal autopsied human brain and of patients who died with idiopathic Parkinson's disease (PD). We found in the normal claustrum substantial amounts of all three monoamine neurotransmitters, substantiating the existence of the respective brain stem afferents to the claustrum. In PD, the levels of dopamine and noradrenaline were greatly reduced by 93% and 81%, respectively. Serotonin levels remained unchanged. We propose that by virtue of their projections to the claustrum, the brain stem dopamine, noradrenaline and serotonin systems interact directly with the cortico-claustro-cortical information processing mechanisms, by-passing their (parallel) routes via the basal ganglia-thalamo-cortical circuits. We propose that loss of dopamine and noradrenaline in the PD claustrum is critical in the aetiology of both the motor and the non-motor symptoms of PD. This article is protected by copyright. All rights reserved.
... The presence of Aβ in DLB and less in PDD, and its great sensitivity to differentiate DLB from PDD are evident (Ballard et al. 2006;Halliday et al. 2011b;Ruffmann et al. 2016;Walker et al. 2015a). DLB shows greater αSyn burden in the claustrum compared to PDD, while a hierarchy PD < PDD < DLB was seen in both Aβ and tau burden Kalaitzakis et al. 2009). The globus pallidus is free of amyloid plaques, while few αSyn deposits were seen in 76% of DLB and in around 30% of PDD brains, but only in 10% of nondemented PD cases. ...
Dementia with Lewy bodies (DLB) and Parkinson’s disease-dementia (PDD), although sharing many clinical, neurochemical and morphological features, according to DSM-5, are two entities of major neurocognitive disorders with Lewy bodies of unknown etiology. Despite considerable clinical overlap, their diagnosis is based on an arbitrary distinction between the time of onset of motor and cognitive symptoms: dementia often preceding parkinsonism in DLB and onset of cognitive impairment after onset of motor symptoms in PDD. Both are characterized morphologically by widespread cortical and subcortical α-synuclein/Lewy body plus β-amyloid and tau pathologies. Based on recent publications, including the fourth consensus report of the DLB Consortium, a critical overview is given. The clinical features of DLB and PDD include cognitive impairment, parkinsonism, visual hallucinations, and fluctuating attention. Intravitam PET and post-mortem studies revealed more pronounced cortical atrophy, elevated cortical and limbic Lewy pathologies (with APOE ε4), apart from higher prevalence of Alzheimer pathology in DLB than PDD. These changes may account for earlier onset and greater severity of cognitive defects in DLB, while multitracer PET studies showed no differences in cholinergic and dopaminergic deficits. DLB and PDD sharing genetic, neurochemical, and morphologic factors are likely to represent two subtypes of an α-synuclein-associated disease spectrum (Lewy body diseases), beginning with incidental Lewy body disease—PD-nondemented—PDD—DLB (no parkinsonism)—DLB with Alzheimer’s disease (DLB-AD) at the most severe end, although DLB does not begin with PD/PDD and does not always progress to DLB-AD, while others consider them as the same disease. Both DLB and PDD show heterogeneous pathology and neurochemistry, suggesting that they share important common underlying molecular pathogenesis with AD and other proteinopathies. Cognitive impairment is not only induced by α-synuclein-caused neurodegeneration but by multiple regional pathological scores. Recent animal models and human post-mortem studies have provided important insights into the pathophysiology of DLB/PDD showing some differences, e.g., different spreading patterns of α-synuclein pathology, but the basic pathogenic mechanisms leading to the heterogeneity between both disorders deserve further elucidation. In view of the controversies about the nosology and pathogenesis of both syndromes, there remains a pressing need to differentiate them more clearly and to understand the processes leading these synucleinopathies to cause one disorder or the other. Clinical management of both disorders includes cholinesterase inhibitors, other pharmacologic and nonpharmacologic strategies, but these have only a mild symptomatic effect. Currently, no disease-modifying therapies are available.
... 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]. ...
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.
... On the [79,81]. Deposition of Aβ in the claustrum has been shown by one study to be correlated with the occurrence of dementia in PD and DLB [82]. Claustrum is a subcortical structure with multiple connections with neocortical areas and limbic structure. ...
Parkinson’s disease (PD) is the second commonest neurodegenerative disorder in the world with a rising prevalence. The pathophysiology is multifactorial but aggregation of misfolded α-synuclein is considered to be a key underpinning mechanism. Amyloid-β (Aβ) and tau deposition are also comorbid associations and especially Aβ deposition is associated with cognitive decline in PD. Some existing evidence suggests that low cerebrospinal fluid (CSF) Aβ42 is predictive of future cognitive impairment in PD. Recent studies also show that CSF Aβ is associated with the postural instability and gait difficulties (PIGD) or the newly proposed cholinergic subtype of PD, a possible risk factor for cognitive decline in PD. The glial-lymphatic system, responsible for convective solute clearance driven by active fluid transport through aquaporin-4 water channels, may be implicated in brain amyloid deposition. A better understanding of the role of this system and more specifically the role of Aβ in PD symptomatology, could introduce new treatment and repurposing drug-based strategies. For instance, apomorphine infusion has been shown to promote the degradation of Aβ in rodent models. This is further supported in a post-mortem study in PD patients although clinical implications are unclear. In this review, we address the clinical implication of cerebral Aβ deposition in PD and elaborate on its metabolism, its role in cognition and motor function/gait, and finally assess the potential effect of apomorphine on Aβ deposition in PD.
... Severe pathology also involves the noradrenergic locus ceruleus (LC) [100] and the serotonergic dorsal raphe nucleus [101] as well as the ventral tegmental area not always associated with coincidental AD lesions [102]. LC neuronal loss and the accompanying norepinephrinergic deficiency are an important cause and pharmacological target for the (symptomatic) treatment of PD/PDD/DLB [103,104]. ...
... All the abnormalities mentioned above occur both in PDD and in DLB, however there are differences in their distribution and intensity within the central nervous system (CNS). The location where the most α-synuclein accumulates in course of PDD is cingulate cortex [27], while in DLB it is hippocampus and amygdala [28,29]. Abnormalities typical of AD are more severe in other locations such as: striatum, neocortex, claustrum, and entorhinal cortex in utratę neuronów cholinergicznych w jądrach przodomózgowia brzusznego. ...
Introduction: Introduction: Both dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD) are important dementia syndromes that overlap in their clinical features and clinical course, neuropathological abnormalities, and also therapeutic approach. Nevertheless it is still unclear whether DLB and PDD are two different disorders that require differentiation or are one clinical entity within a spectrum of Lewy body disease. Currently these disorders are mainly distinguished on the basis of the relative timing of the onset of symptoms of dementia and parkinsonism. The present paper presents current concepts on the pathogenesis of both disorders and their possible overlap.
Material and methods: Online databases in the field of DLB and PDD were searched for to find potentially eligible articles. Only most recent articles published after the year 2000 were chosen.
Results: The clinical features of DLB and PDD are similar and include dementia with hallucinations and cognitive fluctuations, as well as parkinsonian signs. Also cognitive deficits are similar in PDD and in DLB, with predominance of executive dysfunction, visual-spatial deficits and memory impairment. Neuropathological changes in both disorders involve the presence of Lewy bodies and Lewy neurites within brainstem, limbic and neocortex, as well as loss of midbrain dopamine cells, and loss of cholinergic neurons in the nuclei of ventral forebrain.
Conclusions: Similarities in clinical manifestation, neuropsychological deficits and neuropathological abnormalities may suggest that both DLB and PDD are two different phenotypes of the same disorder. This review article presents current knowledge on similarities and differences between these two clinical entities and raises the question whether they require differentiation or not.
... Based on our recent studies, we propose that the CLA plays a role in SN-related neuropsychiatric disorders (Kalaitzakis et al., 2009;Cascella et al., 2011;Smith and Alloway, 2014;Wegiel et al., 2014;Patru and Reser, 2015;Bernstein et al., 2016;Smith et al., 2017). A recent fMRI study of Parkinson's disease patients has found significant decreases in the functional connectivity of the CLA compared to age-matched control patients, especially ''with areas mainly involved in visuomotor and attentional systems'' (Arrigo et al., 2018). ...
The claustrum (CLA) is a subcortical structure, present only in mammals, whose function remains uncertain. Previously, using resting-state functional magnetic resonance imaging (rs-fMRI) in awake head-fixed rats, we found evidence that the CLA is part of the rodent homolog of the default mode network (DMN; Smith et al., 2017). This network emerged as strong functional connections between the medial prefrontal cortex (mPFC), mediodorsal (MD) thalamus, and CLA in the awake state, which was not present following administration of isoflurane anesthesia. In the present report, we review evidence indicating that the rodent CLA also has connections with structures identified in the rodent homolog of the salience network (SN), a circuit that directs attention towards the most relevant stimuli among a multitude of sensory inputs (Seeley et al., 2007; Menon and Uddin, 2010). In humans, this circuit consists of functional connections between the anterior cingulate cortex (ACC) and a region that encompasses both the CLA and insular cortex. We further go on to review the similarities and differences between the functional and anatomical connections of the CLA and insula in rodents using both rs-fMRI and neuroanatomical tracing, respectively. We analyze in detail the connectivity of the CLA with the cingulate cortex, which is a major node in the SN and has been shown to modulate attention. When considered with other recent behavior and physiology studies, the data reveal a role for the CLA in salience-guided orienting. More specifically, we hypothesize that limbic information from mPFC, MD thalamus, and the basolateral amygdala (BLA) are integrated by the CLA to guide modality-related regions of motor and sensory cortex in directing attention towards relevant (i.e., salient) sensory events.
... The claustrum has emerged as a focus of intense research interest (Baizer and Reser, 2017), for both its putative role in normal brain functions (Atlan et al., 2018;Bray, 2018;Jackson et al., 2018;White and Mathur, 2018a,b) and for its association with a number of devastating neurological and psychiatric diseases (Smythies et al., 2014;Patru and Reser, 2015;Marek, 2018), including epilepsy (Bayat et al., 2018;Silva et al., 2018;Zhang et al., 2018); frontotemporal dementia and amyotrophic lateral sclerosis (De Reuck et al., 2014, 2017; major depressive disorder (Su et al., 2018); schizophrenia (Cascella et al., 2011;Mallikarjun et al., 2018), Wilson's disease (King et al., 1996), and Parkinson's disease (Sener, 1998;Braak et al., 2001Braak et al., , 2007Kalaitzakis et al., 2009;Shao et al., 2015;Sitte et al., 2017;Arrigo et al., 2018). The molecular basis of claustrum function is starting to become clear (Kivell et al., 2014;Tantra et al., 2018), and both structural and functional connectomic studies have highlighted the importance of the claustrum complex for understanding connectivity in both normal and pathological brain states (Fernández-Miranda et al., 2008;Reser et al., 2014Reser et al., , 2017Bruni et al., 2018;Fillinger et al., 2018;Rabellino et al., 2018;Randerath et al., 2018;Ribas et al., 2018;Stepniewska et al., 2018). ...
There has been a surge of interest in the structure and function of the mammalian claustrum in recent years. However, most anatomical and physiological studies treat the claustrum as a relatively homogenous structure. Relatively little attention has been directed toward possible compartmentalization of the claustrum complex into anatomical subdivisions, and how this compartmentalization is reflected in claustrum connections with other brain structures. In this study, we examined the cyto- and myelo-architecture of the claustrum of the common marmoset (Callithrix jacchus), to determine whether the claustrum contains internal anatomical structures or compartments, which could facilitate studies focused on understanding its role in brain function. NeuN, Nissl, calbindin, parvalbumin, and myelin-stained sections from eight adult marmosets were studied using light microscopy and serial reconstruction to identify potential internal compartments. Ultra high resolution (9.4T) post-mortem magnetic resonance imaging was employed to identify tractographic differences between identified claustrum subcompartments by diffusion-weighted tractography. Our results indicate that the classically defined marmoset claustrum includes at least two major subdivisions, which correspond to the dorsal endopiriform and insular claustrum nuclei, as described in other species, and that the dorsal endopiriform nucleus (DEnD) contains architecturally distinct compartments. Furthermore, the dorsal subdivision of the DEnD is tractographically distinguishable from the insular claustrum with respect to cortical connections.
... This is in line with the enrichments we found regarding addiction and depression (bipolar) gene sets in the IC and claustrum, as well as dopamine activity in the IC. Although we did not observe any gene sets indicating an association with Parkinson's disease and schizophrenia, studies have implicated the IC and claustrum in these diseases (Kalaitzakis et al., 2009;Cascella et al., 2011;Chen et al., 2016;Criaud et al., 2016;Arrigo et al., 2018;Joutsa et al., 2018). ...
The insular cortex has been linked to a multitude of functions. In contrast, the nearby claustrum is a densely connected subcortical region with unclear function. To view the insula-claustrum region from the molecular perspective we analyzed the transcriptomic profile of these areas in six adult and four fetal human brains. We identified marker genes with specific expression and performed transcriptome-wide tests for enrichment of biological processes, molecular functions, and cellular components. In addition, specific insular and claustral expression of genes pertaining to diseases, addiction, and depression was tested. At the anatomical level, we used brain-wide analyses to determine the specificity of our results and to determine the transcriptomic similarity of the insula-claustrum region. We found UCMA to be the most significantly enriched gene in the insular cortex and confirmed specific expression of NR4A2, NTNG2, and LXN in the claustrum. Furthermore, the insula was found to have enriched expression of genes associated with mood disorders, learning, cardiac muscle contraction, oxygen transport, glutamate and dopamine signaling. Specific expression in the claustrum was enriched for genes pertaining to human immunodeficiency virus (HIV), severe intellectual disability, epileptic encephalopathy, intracellular transport, spine development, and macroautophagy. We tested for enrichment of genes related to addiction and depression, but they were generally not highly specific to the insula-claustrum region. Exceptions include high insular expression of genes linked to cocaine abuse and genes associated with ever smoking in the claustrum. Brain-wide, we find that markers of the adult claustrum are most specifically expressed in the fetal and adult insula. Altogether, our results provide a novel molecular perspective on the unique properties of the insula and claustrum.
Dementia associated with α-synucleinopathy predominantly arises in two clinical contexts. Firstly, the clinical presentation of a dementia disorder, especially in the elderly, may involve features consistent with the clinical diagnostic guidelines for the syndrome of dementia with Lewy bodies, including fluctuating cognitive performance, visual hallucination and mild features of parkinsonism. Secondly, patients with an established neurological diagnosis of Parkinson's disease have an increased risk of developing dementia during their illness. At these extremes the clinical diagnoses are distinct, but many patients are encountered who are less easy to classify clinically. Throughout this spectrum the pathological features of brain and peripheral nerve disease are overlapping and do not provide the basis for clear-cut syndromic diagnoses. Cognitive impairment in dementia with Lewy bodies and Parkinson's disease dementia is associated with more extensive anatomical spread of α-synucleinopathy in the brain and variable, often extensive, Alzheimer type pathology. Both dementia with Lewy bodies and Parkinson's disease dementia present challenges for clinicopathological correlation and diagnosis.
Dementia is a common feature in Parkinson disease (PD), the time of onset determining how patients are classified. Those patients where dementia develops prior to parkinsonism or during the first year of disease are designated as having dementia with Lewy bodies (DLB). In those where dementia develops over a year after the onset of motor signs, the condition is known as Parkinson's disease with dementia (PDD). While this seems at first sight to be a definitive way to distinguish these conditions, reality is rather different. The overlap between them is considerable, and there is much uncertainty associated with patients who have both motor symptoms and early cognitive impairment. The diagnosis is still based on medical history and clinical evaluation. It is not even certain that they can be accurately distinguished at autopsy. For this reason, the data concerning these entities have been reviewed, to examine various markers employed or measured in clinical, neuropathological, neuroimaging, and biochemical investigations. The concept of PDD and DLB being separate conditions is comparatively new, and the most promising tools with which to separate them at present are cerebrospinal fluid (CSF) markers and positron emission tomography (PET) scanning that indicate increased amyloid-beta burden in DLB compared to PDD. However as yet there are no markers that unequivocally distinguish between PDD and DLB.
Although amyloid beta (Aβ) peptide can promote tau pathology and its toxicity is concurrently tau-dependent, the underlying mechanisms of the in vivo interplay of these proteins remain unsolved. Structural and functional mitochondrial alterations play an early, precipitating role in synaptic failure of Alzheimer's disease (AD) pathogenesis and an aggravated mitochondrial impairment has been described in triple APP/PS/tau transgenic mice carrying both plaques and tangles, if compared with mice overexpressing tau or amyloid precursor protein (APP) alone. Here, we show that a neurotoxic aminoterminal (NH(2))-derived tau fragment mapping between 26 and 230 amino acids of the human tau40 isoform (441 amino acids)-but not the physiological full-length protein-preferentially interacts with Aβ peptide(s) in human AD synapses in association with mitochondrial adenine nucleotide translocator-1 (ANT-1) and cyclophilin D. The two peptides-Aβ 1-42 and the smaller and more potent NH(2)-26-44 peptide of the longest 20-22 kDa NH(2)-tau fragment-inhibit the ANT-1-dependent adenosine diphosphate-adenosine triphosphate (ADP/ATP) exchange in a noncompetitive and competitive manner, respectively, and together further aggravate the mitochondrial dysfunction by exacerbating the ANT-1 impairment. Taken together, these data establish a common, direct and synergistic toxicity of pathological APP and tau products on synaptic mitochondria and suggest potential, new pathway(s) and target(s) for a combined, more efficient therapeutic intervention of early synaptic dysfunction in AD.
Background
Cognitive dysfunction is one of the most disabling non-motor symptoms of Parkinson's disease (PD), though its pathological correlates still remain elusive. Hippocampal Lewy pathology has recently been correlated by compelling evidence from post-mortem and imaging studies. Animal models recapitulating cognitive impairment in PD are essential to better understand the underlying pathophysiology. To investigate the hippocampal involvement in cognitive dysfunction of PD, we generated an experimental model by inducing midbrain and hippocampal α-synuclein pathology simultaneously.
Methods
Rats were injected either with human α-synuclein or green fluorescent protein (GFP) expressing adeno-associated viral vectors (AAV), or saline bilaterally into substantia nigra (SN) and dentate gyrus (DG). A group of untreated animals were used as naïve controls. Cognitive and behavioral changes were evaluated with tests probing for spatial learning, short-term memory, anxiety and hedonistic behavior. Immunohistochemical staining, immunoblotting and stereological analysis were performed for pathological characterization.
Results
Bilateral α-synuclein overexpression in SN and DG led to mild but significant motor impairment as well as dysfunctions in short-term memory and spatial learning. There was no hedonistic deficit, whereas a hypo-anxious state was induced. While stereological analysis revealed no significant neuronal loss in any sectors of cornu ammonis, there was considerable decrease (43%) in TH⁺-neurons in SN pars compacta supporting the well-known vulnerability of nigral dopaminergic neurons to α-synuclein mediated neurodegeneration. On the other hand, synaptophysin levels decreased in similar amounts both in striatum and hippocampus, suggesting comparable synaptic loss in target areas. Interestingly, phosphorylated-S129-α-synuclein staining revealed significant expression in CA2 characterized by more mature and dense cellular accumulations compared to CA1-CA3 sub-regions displaying more diffuse grain-like aggregates, suggesting preferential susceptibility of CA2 to produce α-synuclein induced pathology.
Conclusion
Bilateral α-synuclein overexpression in DG and SN reproduced partial motor and hippocampus related cognitive deficits. Using this model, we showed a predisposition of CA2 for pathological α-synuclein accumulation, which may provide further insights for future experimental and clinical studies.
The aim of our study was to examine the relationship between corticostriatal Aβ-amyloid deposition and cognitive dysfunction in a cohort of patients with Parkinson disease (PD) at risk for dementia.
This was a cross-sectional study of 40 patients with PD with mild cognitive impairment (MCI) or other known dementia risk factors. Subjects underwent dynamic Aβ-amyloid and vesicular monoamine transporter 2 PET imaging using [(11)C] Pittsburgh compound B (PiB) and [(11)C]dihydrotetrabenazine (DTBZ), respectively, and neuropsychological assessment. PiB and DTBZ PET data were analyzed using the Logan graphical method to determine cerebral PiB deposition relative to the cerebellar hemispheres and striatal DTBZ binding relative to occipital neocortex. Component z scores were calculated for individual cognitive domains (memory, visuospatial processing, working memory/attention, and executive function) and combined linearly for global estimation of cognition. Correlation of cognitive function and cortical PiB binding was investigated.
Elevated cerebral PiB binding at levels seen in patients with AD was infrequent (6 of 40 subjects). Mean cortical PiB binding in the entire cohort was 1.16 ± 0.16 (distribution volume ratio; range 0.96-1.78). A significant correlation was noted between cortical PiB binding and global composite cognitive function (r = -0.55, p < 0.005) as well as the Wechsler Adult Intelligence Scale score (r = -0.54, p = 0.0004).
Elevated cerebral Aβ-amyloid deposition at levels seen in Alzheimer disease is uncommon in subjects with PD at risk for dementia. In our sample, the prevalence of markedly elevated PiB binding was significantly lower than that found in prior studies of cognitively normal elderly individuals. Neocortical PiB binding correlated robustly with measures of cognitive impairment in our cohort.
Abnormal sleep is a common feature of Parkinson's disease (PD) and prodromal disorders of sleep are frequent (e.g. restless legs syndrome and rapid eye movement sleep behaviour disorder). However, the exact pathological basis of disturbed sleep remains as yet undefined.
To investigate this further, 32 PD cases were stratified into three groups: (1) PD with disturbed sleep, PD(S); (2) PD with dementia (PDD) and disturbed sleep, PDD(S); and (3) PD without disturbed sleep, PD(nS). The extent of α-synuclein (αSyn) and Alzheimer disease (AD)-type pathology [amyloid β peptide (Aβ) and tau] was assessed in 15 regions of the PD brain.
The results demonstrate a significant association between disturbed sleep in PD and αSyn pathology in specific brainstem [locus coeruleus (P = 0.006) and raphe nuclei (P = 0.02)], hypothalamic [paramammillary nuclei (P = 0.04) and posterior nucleus (P = 0.02)], subcortical/limbic [amygdala (P = 0.03), thalamus (P = 0.01)] and cortical [entorhinal cortex (P = 0.01)] regions. A statistically significant increase of tau pathology was observed in the amygdala (P = 0.03), CA2 sector of the hippocampus (P = 0.01) and entorhinal cortex (P = 0.04) in PD cases with disturbed sleep.
Pathological changes in these structures, residing in the brain circuitry relating to sleep physiology, strongly predict the presence of sleep disturbances in PD.
The hippocampus has a critical role in cognition and human memory and is one of the most studied structures in the brain. Despite more than 400 years of research, little is known about the Ammon’s horn region cornu ammonis 2 (CA2) subfield in comparison to other subfield regions (CA1, CA3, and CA4). Recent findings have shown that CA2 plays a bigger role than previously thought. Here, we review understanding of hippocampus and CA2 ontogenesis, together with basic and clinical findings about the potential role of this region in neurodegenerative disease. The CA2 has widespread anatomical connectivity, unique signaling molecules, and intrinsic electrophysiological properties. Experimental studies using in vivo models found that the CA2 region has a role in cognition, especially in social memory and object recognition. In models of epilepsy and hypoxia, the CA2 exhibits higher resilience to cell death and hypoxia in comparison with neighboring regions, and while hippocampal atrophy remains poorly understood in Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), findings from postmortem PD brain demonstrates clear accumulation of α-synuclein pathology in CA2, and the CA2-CA3 region shows relatively more atrophy compared with other hippocampal subfields. Taken together, there is a growing body of evidence suggesting that the CA2 can be an ideal hallmark with which to differentiate different neurodegenerative stages of PD. Here, we summarize these recent data and provide new perspectives/ideas for future investigations to unravel the contribution of the CA2 to neurodegenerative diseases.
Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by a variety of non-motor complications, such as neuropsychiatric and autonomic and vegetative features, in addition to the core motor syndrome. While the classical motor signs in PD are ascribed in the main to dopaminergic cell loss in the substantia nigra pars compacta, brain (and extracerebral) pathology is multi-focal, affecting many extranigral structures, which explains the complex clinical picture of the disease. The claustrum is a telencephalic subcortical structure of largely unknown physiological function. Recent studies indicate that the claustrum can receive, assimilate, integrate and channel sensory information in the brain through its connections with cortical and subcortical nuclei. Therefore, pathology in the claustrum may contribute to the development of some of the clinical signs seen in PD patients. However, only a handful of studies have been reported in the literature with regard to claustral pathology in PD. The majority of these publications are primarily concerned with other brain regions and not the claustrum itself. In this chapter the possible clinical relevance of claustral pathology in PD is discussed.
Extrapyramidal movement disorders include hypokinetic rigid and hyperkinetic or mixed forms, most of them originating from dysfunction of the basal ganglia (BG) and their information circuits. The functional anatomy of the BG, the cortico-BG–thalamocortical, and BG–cerebellar circuit connections are briefly reviewed. Pathophysiologic classification of extrapyramidal movement disorder mechanisms distinguish (1) parkinsonian syndromes, (2) chorea and related syndromes, (3) dystonias, (4) myoclonic syndromes, (5) ballism, (6) tics, and (7) tremor syndromes. Recent genetic and molecular–biologic classifications distinguish (1) synucleinopathies (Parkinson’s disease, dementia with Lewy bodies, Parkinson’s disease–dementia, and multiple system atrophy); (2) tauopathies (progressive supranuclear palsy, corticobasal degeneration, FTLD-17; Guamian Parkinson–dementia; Pick’s disease, and others); (3) polyglutamine disorders (Huntington’s disease and related disorders); (4) pantothenate kinase-associated neurodegeneration; (5) Wilson’s disease; and (6) other hereditary neurodegenerations without hitherto detected genetic or specific markers. The diversity of phenotypes is related to the deposition of pathologic proteins in distinct cell populations, causing neurodegeneration due to genetic and environmental factors, but there is frequent overlap between various disorders. Their etiopathogenesis is still poorly understood, but is suggested to result from an interaction between genetic and environmental factors. Multiple etiologies and noxious factors (protein mishandling, mitochondrial dysfunction, oxidative stress, excitotoxicity, energy failure, and chronic neuroinflammation) are more likely than a single factor. Current clinical consensus criteria have increased the diagnostic accuracy of most neurodegenerative movement disorders, but for their definite diagnosis, histopathological confirmation is required. We present a timely overview of the neuropathology and pathogenesis of the major extrapyramidal movement disorders in two parts, the first one dedicated to hypokinetic-rigid forms and the second to hyperkinetic disorders.
Dementia in Parkinson's disease (PD/PDD) is a common complication with a prevalence of up to 50%, but the specific changes underlying the cognitive decline remain undefined. Neuronal degeneration resulting in the dysfunction of multiple subcortical neurochemical projection systems has been described along with Lewy body-type pathology in cortical and limbic regions. Advanced alpha-synuclein (alphaSyn) pathology is not necessarily sufficient for producing dementia and concomitant Alzheimer's disease (AD) change has also been proposed as a possible substrate of PDD. A lack of consensus in the extant literature likely stems from clinical heterogeneity and variable reliability in clinical characterisation as well as other historical and methodological issues. The concurrent presence of abnormally deposited alphaSyn, amyloid-beta and tau proteins in the PDD brain and the interaction of these molecules in a linked pathological cascade of AD and PD-related mechanisms may prove important in determining the underlying pathological process for the development of dementia in PD and this concept of combined pathologies awaits further investigation.
The distribution of neurons in the basal telencephalon, the diencephalon, and the brainstem that project to the hippocampal formation has been analyzed in mature cynomolgus monkeys (Macaca fascicularis) by the injection of horseradish peroxidase into different rostro-caudal levels of the hippocampal formation. After injections which involve Ammon's horn, the dentate gyrus, and the subicular complex, retrogradely labeled neurons are found in the following regions: in the amygdala (specifically in the anterior amygdaloid area, the basolateral nucleus, and the periamygdaloid cortex); in the medial septal nucleus and the nucleus of the diagonal band; in the ventral part of the claustrum; in the substantia innominata and the basal nucleus of Meynert; in the rostral thalamus (specifically in the anterior nuclear complex, the laterodorsal nucleus, the paraventricular and parataenial nuclei, the nucleus reuniens, and the nucleus centralis medialis); in the lateral preoptic and lateral hypothalamic areas, and especially in the supramammillary and retromammillary regions; in the ventral tegmental area, the tegmental reticular fields, the raphé nuclei (specifically in nucleus centralis superior and the dorsal raphé nucleus), in the nucleus reticularis tegmenti pontis, the central gray, the dorsal tegmental nucleus, and in the locus coeruleus.
To clarify the distribution, morphology, and density of amyloid deposits in patients with Alzheimer's disease (AD), tissue sections from various areas of the central nervous system of 14 patients with AD and from 20 nondemented aged controls were investigated immunohistochemically using anti-beta protein antiserum. beta-protein amyloid deposits were present not only in the cores of the senile plaques and in the vascular wall (amyloid angiopathy), but also in various sized plaque-shaped fibrillary, perivascular, subpial, and subependymal deposits. Amyloid deposits were found mainly in the cerebral cortex in nondemented controls, while in AD they were distributed widely in the regions that were not affected in nondemented controls. The positivity of amyloid deposits in AD was 100% in the cerebral cortex, hippocampus, amygdala, thalamus, caudate nucleus, claustrum, hypothalamus, nucleus basalis of Meynert, and cerebellar cortex. Putamen and brain-stem nuclei were affected frequently, and the spinal cord, dentate nucleus, and globus pallidus were sometimes (less than 50%) affected. This result provides an evidence that Alzheimer's disease is a beta-protein amyloidosis of the central nervous system. An assessment of the distribution of amyloid deposits should prove to be useful for the histopathologic diagnosis of AD.
Pathological changes in the claustrum and its main parts (dorsal, temporal, orbital and paramygdalar) were studied on ten brains of patients with Alzheimer's disease and five control brains. The brains after fixation in formalin were embedded in paraffin, coronal-8-micron-thick serial sections were cut and stained either with cresyl violet or with immunocytochemical methods for amyloid and tangles. Morphometrical studies were performed in all parts of the claustrum along its whole extension. The claustrum in control brains was free of neurofibrillary and amyloid pathology except for one case with few senile plaques in the paramygdalar part. In AD affected brains the most severe changes were found in the paramygdalar part connected with the entorhinal cortex (neuronal loss -46%; 698 +/- 244.6 neurofibrillary tangles per mm3, tangle/neuron ratio -6.8 +/- 2.4%). In other parts of the claustrum related mainly with the neocortex pathological changes were significantly less expressed. As pathological AD type alteration affects severely practically the whole hippocampal formation, including the entorhinal cortex, the extensive neuronal pathology of the paramygdalar part of the claustrum is probably related to this process and may deeper memory dysfunction.
Consensus opinion characterizes dementia with Lewy bodies (DLB) as a progressive dementing illness, with significant fluctuations in cognition, visual hallucinations and/or parkinsonism. When parkinsonism is an early dominant feature, consensus opinion recommends that dementia within the first year is necessary for a diagnosis of DLB. If dementia occurs later, a diagnosis of Parkinson's disease with dementia (PDD) is recommended. While many previous studies have correlated the neuropathology in DLB with dementia and parkinsonism, few have analysed the relationship between fluctuating cognition and/or well-formed visual hallucinations and the underlying neuropathology in DLB and PDD. The aim of the present study was to determine any relationship between these less-studied core clinical features of DLB, and the distribution and density of cortical Lewy bodies (LB). The brains of 63 cases with LB were obtained over 6 years following population-based studies of dementia and parkinsonian syndromes. Annual, internationally standardized, clinical assessment batteries were reviewed to determine the presence and onset of the core clinical features of DLB. The maximal density of LB, plaques and tangles in the amygdala, parahippocampal, anterior cingulate, superior frontal, inferior temporal, inferior parietal and visual cortices were determined. Current clinicopathological diagnostic criteria were used to classify cases into DLB (n = 29), PDD (n = 18) or parkinsonism without dementia (n = 16) groups. Predictive statistics were used to ascertain whether fluctuating cognition or visual hallucinations predicted the clinicopathological group. Analysis of variance and regressions were used to identify any significant relationship(s) between the presence and severity of neuropathological and clinical features. Cognitive fluctuations and/or visual hallucinations were not good predictors of DLB in pathologically proven patients, although the absence of these features early in the disease course was highly predictive of PDD. Cases with DLB had higher LB densities in the inferior temporal cortex than cases with PDD. There was no association across groups between any neuropathological variable and the presence or absence of fluctuating cognition. However, there was a striking association between the distribution of temporal lobe LB and well-formed visual hallucinations. Cases with well-formed visual hallucinations had high densities of LB in the amygdala and parahippocampus, with early hallucinations relating to higher densities in parahippocampal and inferior temporal cortices. These temporal regions have previously been associated with visual hallucinations in other disorders. Thus, our results suggest that the distribution of temporal lobe LB is more related to the presence and duration of visual hallucinations in cases with LB than to the presence, severity or duration of dementia.
Few longitudinal studies of dementia in Parkinson disease (PD) have been reported, and the proportion of patients with PD who eventually develop dementia is unknown.
To examine the 8-year prevalence, characteristics, and risk factors of dementia in patients with PD.
Patients were recruited from an epidemiological study of PD in the county of Rogaland, Norway, using explicit criteria for PD. Subjects with cognitive impairment at disease onset were excluded. A semistructured caregiver-based interview, cognitive rating scales, and neuropsychological tests were used to diagnose dementia according to criteria from the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition at baseline and 4 and 8 years later. A population-based sample of 3295 subjects in the municipality of Odense, Denmark, was used as a comparison group and examined at baseline and after 2 and 5 years.
We included 224 patients with PD (116 women). At baseline, 51 patients (26%) had dementia. Fifty-five patients died, and 10 refused follow-up without their dementia status known. Forty-three and 28 new cases of dementia were identified at the 4- and 8-year evaluations, respectively. The 4-year prevalence of dementia in PD was nearly 3 times higher than in the non-PD group. The 8-year prevalence in PD was 78.2% (95% confidence interval [CI], 71.1-84.0). Risk factors for dementia were hallucinations before baseline (odds ratio [OR] = 3.1; 95% CI, 1.6-6.2) and akinetic-dominant or mixed tremor/akinetic PD (OR = 3.3; 95% CI, 1.2-8.5).
More than three quarters of this representative PD cohort developed dementia during the 8-year study period. Early hallucinations and akinetic-dominant PD were associated with an increased risk of dementia.
This investigation was undertaken to clarify the neuropathological substrates of key psychiatric symptoms in dementia with Lewy bodies.
The authors studied 112 autopsy-confirmed cases of dementia with Lewy bodies in patients who had had annual standardized clinical evaluations until their death. The relationships of persistent psychiatric symptoms (visual hallucinations, delusions, depression) to plaques (Consortium to Establish a Registry for Alzheimer's Disease protocol), tangles (Braak staging), and Lewy bodies (consensus Lewy body staging) were evaluated. In addition, symptom frequency and persistent symptoms were compared in the patients with Lewy body dementia and 90 patients with autopsy-confirmed Alzheimer's disease studied prospectively during life.
The main neuropathological correlate of persistent visual hallucinations was the presence of less severe tangle pathology, but there was no significant association between tangle pathology and persistent delusions. Lewy body staging was associated with the presence of persistent visual hallucinations and persistent delusions. All baseline psychiatric features were significantly more frequent in dementia with Lewy bodies than in Alzheimer's disease, as were persistent visual hallucinations, but patients who had dementia with Lewy bodies and severe tangle pathology had a clinical symptom profile more similar to that of Alzheimer's disease patients and were less likely to have neocortical Lewy bodies.
The modest proportion of patients with Lewy body dementia and more severe tangle pathology resembled Alzheimer's disease patients clinically. Unlike Alzheimer's disease, dementia with Lewy bodies showed a significant inverse association between tangle burden and psychosis.
Intracytoplasmic aggregation of alpha-synuclein protein as Lewy bodies in the brainstem neurons is diagnostic for Parkinson's disease, whereas if this process also occurs in the cortical neurons, it is considered pathognomonic for dementia with Lewy bodies. However, the link between alpha-synuclein incorporation into inclusions, neuronal dysfunction, and clinical symptoms needs to be clarified. Another important issue of the pathogenetic puzzle is to understand where alpha-synuclein pathology begins and how it progresses in the brain. To study this, we collected all cases from autopsy material (N = 904) that had alpha-synuclein pathology in the dorsal motor nucleus of vagus, substantia nigra, and/or basal forebrain nuclei. In this way, our study has a unique design because the selection of material is entirely based on the presence of alpha-synuclein pathology regardless of clinical phenotype. Retrospective clinical assessment then showed that only 32 (30%) of 106 alpha-synuclein-positive cases were diagnosed with a neurodegenerative disorder. The distribution or load of alpha-synuclein pathology did not permit a dependable postmortem diagnosis of extrapyramidal symptoms or cognitive impairment. Some neurologically unimpaired cases had a reasonable burden of alpha-synuclein pathology in both brainstem and cortical areas, suggesting that alpha-synuclein-positive structures are not definite markers of neuronal dysfunction.
The claustrum (Cl) is a subcortical structure located in the basolateral telencephalon of the mammalian brain. It has been a subject of inquiry since the mid-nineteenth century. The Cl can be identified in a number of species, and appears as a phylogenetically related nucleus in Insectivores, Prosimians and Marsupials. Ontogenetic investigations have been the subject of much debate over the years. There are three hypotheses for claustral development. To date, the "hybrid theory" has garnered the most support. Pathological conditions specifically associated with the Cl, while few in number, are of interest from a functional perspective. Several cases of claustral agenesis have been reported. The implications of these clinical reports are discussed. Claustral neuroanatomy at the light-microscopic and electron-microscopic level is reviewed. The morphology of the claustral neuron consists of several types, which roughly corresponds to the neuron's location within distinct claustral subdivisions. The interconnectivity of the Cl with the cerebral cortex is rather complex and reflective of complex functional interrelationships. Several researchers have investigated the angioarchitecture of the Cl. It appears that vessels permeating the insula also vascularize the Cl. Literature investigating the neurotransmitters and overall chemical neuroanatomy of the Cl is extensive. These studies clearly demonstrate that the Cl is richly innervated with a wide and diverse array of neurotransmitters and neuromodulators. Lesion, stimulation and recording experiments demonstrate that the functional and physiologic capacity of the Cl is quite robust. A recurring theme of claustral function appears to be its involvement in sensorimotor integration. This may be expected of the Cl, given the degree ofheterotopic, heterosensory convergence and its interconnectivity with the key subcortical nuclei and sensory cortical areas. The Cl remains a poorly understood and under investigated nucleus. Therefore, a review of the world literature through 1986 prior to the advent of the "molecular revolution" is presented. This diverse and extensive body of knowledge is reviewed in the areas ofphylogeny, ontogeny, pathology, angioarchitecture, cytochemistry, anatomy and physiology. Theories of possible claustral function are also noted. It is hoped that this work will stimulate research scientists to further investigate the functional interrelationships of the Cl as well as to aim with far greater precision and accuracy towards a deeper understanding of its raison d'etre. The recent efforts in neurosciences by Sir Francis Crick and Christof Koch implicating the Cl in visual consciousness, is an important step in understanding just what its functions could encompass. Efforts in molecular neurosciences will be indispensable for a mechanistic understanding of these functions. Currently research efforts are underway from many perspectives. In considering the past scientific literature on the Cl, it is interesting to regard that this once obscure brain structure, may serve as a model system for the study of one of the most interesting and complex brain functions-consciousness.
Assessment of Alzheimer's disease (AD)-related neurofibrillary pathology requires a procedure that permits a sufficient differentiation between initial, intermediate, and late stages. The gradual deposition of a hyperphosphorylated tau protein within select neuronal types in specific nuclei or areas is central to the disease process. The staging of AD-related neurofibrillary pathology originally described in 1991 was performed on unconventionally thick sections (100 mum) using a modern silver technique and reflected the progress of the disease process based chiefly on the topographic expansion of the lesions. To better meet the demands of routine laboratories this procedure is revised here by adapting tissue selection and processing to the needs of paraffin-embedded sections (5-15 mum) and by introducing a robust immunoreaction (AT8) for hyperphosphorylated tau protein that can be processed on an automated basis. It is anticipated that this revised methodological protocol will enable a more uniform application of the staging procedure.
Summary of findings Introduction Dementia with Lewy bodies (DLB) probably accounts for 15–25% of all irreversible dementia cases and is the second most common form of dementia after Alzheimer's disease (AD) (McKeith et al., 1996). The disorder is named after Lewy bodies, the pathological finding in the central nervous system, first described by F. H. Lewy in 1913 (Lewy, 1913) and later described in conjunction with clinical dementia by Okazaki and colleagues in 1961 (Okazaki et al., 1961). DLB shares many clinical and pathological features with other diseases of the elderly, including AD, Parkinson's disease (PD) and Parkinson's disease with dementia (PDD) (Aarsland et al., 2004a; Cummings, 2004). For instance, patients with DLB suffer from an irreversible dementia and progressive cognitive decline as in AD, but may also have motor symptoms such as muscle rigidity, bradykinesia, and masked facies, which are typical of PD. As with most dementias, clinical diagnosis can be challenging, and diagnosis can only be confirmed by neuropathological studies. In 1996, the First International Workshop of the Consortium on Dementia with Lewy Bodies published consensus guidelines to aid clinical and pathological diagnosis of DLB (Table 24.1). These guidelines state that DLB requires first and foremost a progressive cognitive decline that causes functional impairment in social and/or occupational spheres. Additional “core features” include spontaneous parkinsonism, recurrent visual hallucinations, and fluctuating cognition or alertness; patients who have one of these core features are clinically diagnosed with “possible” DLB, while patients who have two core features receive a diagnosis of “probable” DLB (McKeith et al., 1996; 1999). © Cambridge University Press 2007 and Cambridge University Press, 2009.
The amygdala exhibits significant pathological changes in Parkinson’s disease, including atrophy and Lewy body (LB) formation. Amygdala pathology has been suggested to contribute to some clinical features of Parkinson’s disease, including deficits of olfaction and facial expression. The degree of neuronal loss in amygdala subnuclei and the relationship with LB formation in non‐demented Parkinson’s disease cases have not been examined previously. Using stereological methods, the volume of neurones and the number of neurones in amygdala subdivisions were estimated in 18 prospectively studied, non‐demented patients with Parkinson’s disease and 16 age‐ and sex‐matched controls. Careful exclusion (all cortical disease) and inclusion (non‐demented, levodopa‐responsive, idiopathic Parkinson’s disease or controls) criteria were applied. Seven Parkinson’s disease cases experienced well‐formed visual hallucinations many years after disease onset, while nine Parkinson’s disease cases and three controls were treated for depression. Anatomically, the amygdala was subdivided into the lateral nucleus, the basal (basolateral and basomedial) nuclei and the corticomedial (central, medial and cortical nuclei) complex. LB and Lewy neurites were identified by immunohistochemistry for α‐synuclein and ubiquitin and were assessed semiquantitatively. LB were found throughout the amygdala in Parkinson’s disease, being present in ∼4% of neurones. Total amygdala volume was reduced by 20% in Parkinson’s disease ( P = 0.02) and LB concentrated in the cortical and basolateral nuclei. Lewy neurites were present in most cases but did not correlate with any structural or functional variable. Amygdala volume loss was largely due to a 30% reduction in volume ( P = 0.01) and the total estimated number of neurones ( P = 0.007) in the corticomedial complex. The degree of neurone loss and the proportion of LB‐containing neurones in the cortical nucleus within this complex were constant across Parkinson’s disease cases and neither variable was related to disease duration ( R 2 0.5). The cortical nucleus has major olfactory connections and its degeneration is likely to contribute to the early selective anosmia common in Parkinson’s disease. There was a small reduction in neuronal density in the basolateral nucleus in all Parkinson’s disease cases, but no consistent volume or cell loss within this region. However, the proportion of LB‐containing neurones in the basolateral nucleus was nearly doubled in cases that exhibited visual hallucinations, suggesting that neuronal dysfunction in this nucleus contributes to this late clinical feature. Detailed quantitation of the other amygdala subdivisions failed to reveal any other substantial anomalies or any associations with depression. Thus, the impact of Parkinson’s disease on the amygdala is highly selective and correlates with both early and late clinical features.
Although still considered a paradigmatic movement disorder, Parkinson's disease (PD) is associated with a broad spectrum of non-motor symptoms. These include disorders of mood and affect with apathy, anhedonia and depression, cognitive dysfunction and hallucinosis, as well as complex behavioural disorders. Sensory dysfunction with hyposmia or pain is almost universal, as are disturbances of sleep-wake cycle regulation. Autonomic dysfunction including orthostatic hypotension, urogenital dysfunction and constipation is also present to some degree in a majority of patients. Whilst overall non-motor symptoms become increasingly prevalent with advancing disease, many of them can also antedate the first occurrence of motor signs - most notably depression, hyposmia or rapid eye movement sleep behaviour disorder (RBD). Although exact clinicopathological correlations for most of these non-motor features are still poorly understood, the occurrence of constipation, RBD or hyposmia prior to the onset of clinically overt motor dysfunction would appear consistent with the ascending hypothesis of PD pathology proposed by Braak and colleagues. Screening these early non-motor features might, therefore, be one approach towards early 'preclinical' diagnosis of PD. This review article provides an overview of the clinical spectrum of non-motor symptoms in PD together with a brief review of treatment options.
Dementia with Lewy bodies (DLB) and Parkinson's disease (PD) are distinguishable clinically but often not neuropathologically. This study aims to test whether the distribution of cortical Lewy bodies differs in these clinicopathological groups and to develop diagnostic protocols for their differentiation. Brains were obtained at autopsy from cases recruited from prospective clinical studies of dementia or movement disorders. All cases with significant pathologies other than Lewy bodies or plaques were excluded. Cases were categorised into either PD without dementia, DLB (dementia first or within 2 years of disease onset), or PD with a later onset of dementia (PDD). The distribution and density of Lewy bodies and Lewy neurites was determined using antibodies to ubiquitin and !-synuclein. Cortical Lewy body densities could not separate cases of DLB from those with PDD. However, semiquantitative thresholds in the parahippocampus could separate demented from non-demented cases with high sensitivity and specificity. Interactions between multiple pathologies were determined using factor analysis. Although many cases had CA2 Lewy neurites, this was not associated with severity or duration of either dementia or parkinsonism. Most DLB cases had significant plaque pathology, and severity and duration of dementia was related to both increasing parahippocampal Lewy body densities and neuritic plaque grade. Weighted kappa statistics revealed that the combination of these pathologies indicated a more severe dementia. These results suggest that dual pathologies cause DLB, and high densities of parahippocampal Lewy bodies indicate dementia regardless of additional pathologies.
A single dose of horseradish peroxidase polyacrylamide gel (10%, 1.0 μl) was injected, after callosotomy, into the head of the caudate nucleus in six macaque monkeys. In addition to the previously reported structures sending fibers to the caudate nucleus, such as the cerebral cortex, substantia innominata, thalamus, hypothalamus, substantia nigra and brainstem, labeled cells were found abundantly in the rostral portion of the ipsilateral claustrum, and fewer labeled cells were dispersed in the ipsilateral external and extreme capsules. Many labeled cells were also present in the ipsilateral insular cortex throughout its rostrocaudal extent. Moreover, labeled cells were seen ipsilaterally in the basolateral, basomedial, accessory basal, and cortical nuclei of the amygdaloid complex.
Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. Traditionally, attention has focused on the motor symptomatology of PD, but it is now appreciated that the nonmotor symptoms affecting neuropsychiatric, sleep, autonomic, and sensory domains occur in up to 88% of PD patients and can be an important source of disability. Nonmotor manifestations of PD play a significant role in the impairment of disease-related quality of life. The cause of nonmotor manifestations of PD is multifactorial, but to a large extent, these manifestations are related to the nature of the neurodegenerative process and the widespread nondopaminergic neuropathological changes associated with the disease. Recognition of nonmotor disability is essential not only for ascertaining the functional status of patients but also for better appreciating the nature of the neurodegenerative process in PD. In addition, a number of nonmotor manifestations can precede the onset of motor symptoms in PD and can be used as screening tools allowing for early disease identification and for trials of possible disease-modifying interventions. This article reviews depression, sleep, and autonomic dysfunction in PD.
The histochemical and structural properties and the topographical distribution pattern of Lewy bodies in the cerebral cortex as well as in the brain stem and diencephalon were studied in three cases.
The Lewy bodies in the cerebral cortex were found in the small or medium-sized neurons of the fifth and sixth layers, particularly in the anterior frontal, temporal, insular, and cingulate cortex, and showed minor differences in their histochemical and structural properties from typical Lewy bodies in the brain stem and diencephalon. By light microscopy they were more irregular in shape, less eosinophilic, less sharply demarcated, and did not have clear halos and central cores. From the ultrastructural aspect, the filaments in them did not radiate, but were arranged at random, and circular profiles were not associated in the central zone. This type of Lewy body was also distributed in the basal ganglia. A close relationship between Lewy bodies and monoamines in the cerebral cortex of our cases was not recognized. These three cases showed also concomitant senile changes, i.e., senile plaques and neurofibrillary tangles.
The possibility that certain of the afferents of the primate amygdaloid complex use an excitatory amino acid transmitter was evaluated by injecting D-[3H]-aspartate into the amygdala of two Macaca fascicularis monkeys. The distribution of D-[3H]-aspartate labeled neurons was compared with those labeled with the nonselective retrograde tracer WGA-HRP injected at the same location as the isotope. Retrogradely labeled cells of both types were observed in a variety of cortical and subcortical structures observed in a variety of cortical and subcortical structures and in discrete regions within the amygdala. D-[3H]-aspartate labeled neurons were observed in layers III and V of the frontal, cingulate, insular and temporal cortices. In the hippocampal formation, heavily labeled cells were observed in the CA1 region and in the deep layers of the entorhinal cortex. Of the subcortical afferents, the claustrum and the midbrain peripeduncular nucleus contained the greatest number of D-[3H]-aspartate labeled cells. Subcortical afferents that are not thought to use excitatory amino acids, such as the cholinergic neurons of the basal nucleus of Meynert, did not retrogradely transport the isotope. Within the amygdala, the most conspicuous labeling was in the paralaminar nucleus which forms the rostral and ventral limits of the amygdala. When the D-[3H]-aspartate injection involved the basal nucleus, many labeled cells were also observed in the lateral nucleus. Retrograde transport of D-[3H]-aspartate injected into the amygdala, therefore, appears to demonstrate a subpopulation of inputs that may use an excitatory amino acid transmitter.
The subcortical afferent connections of the entorhinal cortex of the Macaca fascicularis monkey were investigated by the placement of small injections of the retrograde tracer wheat germ agglutinin conjugated to horseradish peroxidase into each of its subdivisions. Retrogradely labeled cells were observed in several subcortical regions including the amygdaloid complex, claustrum, basal forebrain, thalamus, hypothalamus, and brainstem. In the amygdala, labeled cells were observed principally in the lateral nucleus, the accessory basal nucleus, the deep or paralaminar portion of the basal nucleus, and the periamygdaloid cortex. Additional retrogradely labeled cells were found in the endopiriform nucleus, the anterior amygdaloid area, and the cortical nuclei. Retrogradely labeled cells were observed throughout much of the rostrocaudal extent of the claustrum and tended to be located in its ventral half. In the basal forebrain, retrogradely labeled cells were observed in the medial septal nucleus, the nucleus of the diagonal band, and to lesser extent within the substantia innominata. Several of the cells in the latter region were large and located within the densely packed neuronal clusters of the basal nucleus of Meynert. Most of the labeled cells in the thalamus were located in the midline nuclei. Many were found in nucleus reuniens, but even greater numbers were located in the centralis complex. Additional labeled cells were located in the paraventricular and parataenial nuclei. In all cases, numerous retrogradely labeled cells were observed in the medial pulvinar. In the hypothalamus, most of the retrogradely labeled cells were located in the supramamillary area, though scattered cells were also observed in the perifornical region and in the lateral hypothalamic area. Caudal to the mamillary nuclei there were labeled cells in the ventral tegmental area. There were relatively few labeled cells in the brainstem and these were invariably located either in the raphe nuclei or locus coeruleus.
Lesions were placed in the brains of nine cats; three in the putamen, three in the caudate nucleus, and three in the substantia nigra. Preterminal degeneration from these lesions was found in the ipsilateral claustrum and, in some instances, in the contralateral claustrum also. It was concluded that the claustrum is part of the corpus striatum and may be concerned with its function.
The distribution of labelled cells and of extracellular granules in the claustrum has been studied after injections of horseradish peroxidase in several areas of the neocortex. The frontal and parietal lobes are related to the anterior and posterior halves respectively of the claustrum, and the occipital and temporal cortex to the posterior and inferior margins. Parts of the claustrum related to areas of the cortex in the frontal lobe overlap considerably in the antero-posterior dimension with parts related to widely separated but interconnected areas of the parieto-temporal cortex. Areas of cortex within one lobe which are interconnected are related to parts of the claustrum which overlap in the dorsoventral dimension.
The afferent connections of the insula in the rhesus monkey were studied with axonal transport methods. Injections of horseradish peroxidase (HRP) in the insula revealed labeled neurons in the prefrontal cortex, the lateral orbital region, the frontoparietal operculum, the cingulate gyrus and adjacent medial cortex, the prepiriform olfactory cortex, the temporal pole, the cortex of the superior temporal sulcus, the rhinal cortex, the supratemporal plane, and the posterior parietal lobe. Tritiated amino acid (TAA) injections in some of the cortical regions which contained retrogradely labeled neurons confirmed projections to the insula from prefrontal granular cortex, orbital frontal cortex, prepiriform cortex, temporal pole, rhinal cortex, cingulate gyrus, frontal operculum, and parietal cortex. In these studies, cortical areas that projected to the insula also projected to the claustrum. However, the topographic and quantitative relationships between the projections into the insula and those into the claustrum were inconsistent. Moreover, the claustrum has additional connections which it does not share with the insula. A selected review of the literature suggests that the claustrum and insula differ widely also with respect to ontogenesis and functional specialization.
We describe two protocols for preparing human brains collected for research and diagnosis. In both protocols, one half brain is processed for research and the other for neuropathological evaluation. Clinical, neuropathological and tissue mRNA retention data are used for sample categorization. In protocol 1, coronal, whole hemisphere slices cut at standardized landmarks are frozen with a cooling device at -90 degrees C, which yields discrete anatomical structures. In selected instances, small blocks of brain are frozen at -160 degrees C in liquid nitrogen vapor. Cooling device or liquid nitrogen vapor frozen samples are suitable for in situ hybridization, protein blotting or immunohistochemistry. Morphological freezing artifacts are minimal. In protocol 2, one half brain is frozen en bloc on dry ice; this tissue is suitable for regional evaluation of gene expression or neurochemistry. Morphological freezing artifacts are severe. In both protocols, the other half brain is fixed in formalin prior to sectioning and diagnostic evaluation. The standardized selection of paraffin blocks from each brain allows precise diagnoses to be established, including identification of dangerous infectious processes; moreover, it makes it possible to produce a set of uniformly selected blocks and slides for comparative studies. These protocols lead to standardized tissue preparation for research and reduce variables impairing interpretation and comparison of data.
The UK Parkinson's Disease Society Brain Bank receives tissue from patients with Parkinson's disease and a variety of different movement disorders. Half of the brain is used for full neuropathological examination prior to allocation for specific research projects. Clinical misdiagnosis occurs in a significant proportion of cases and clinico-pathological correlation provides valuable information for disease recognition. With the expanding number of other specialist brain banks there is a need for agreement on diagnostic criteria. Furthermore, awareness of different methods of tissue handling is essential.
To investigate the subcortical connections of inferior temporal cortex, we injected its anterior and posterior portions (Bonin and Bailey's cytoarchitectonic areas TE and TEO, respectively) in 6 rhesus monkeys with retrograde and anterograde tracers. The results indicate that both areas TE and TEO receive nonreciprocal inputs from several thalamic nuclei, including paracentralis, ventralis anterior, centralis, and limitans, and that TE also receives input from reuniens. Additional nonreciprocal inputs to both areas arise from the hypothalamus, basal nucleus of Meynert, dorsal and median raphe, locus coeruleus, and reticular formation. TE and TEO are reciprocally connected with the lateral, medial, and inferior nuclei of the pulvinar and with the ventral portion of the claustrum. The main subcortical nonreciprocal output from TE and TEO is to the striatum and from TEO to the superior colliculus. TE also sends a very limited projection to nucleus medialis dorsalis magnocellularis of the thalamus. Although the connections of areas TE and TEO are overlapping in most subcortical structures, they are partially segregated in the pulvinar, the reticular nucleus of the thalamus, and the striatum. Specifically, relative to those of TE, the projections of TEO are located more laterally in the medial, lateral, and inferior nuclei of the pulvinar, more ventrally in the reticular nucleus, and more caudally in both the ventral putamen and tail and head of the caudate nucleus.
In order to determine whether the cells in the monkey claustrum which project to visual area V4 are found in the same territory as cells projecting to other visual areas, we made injections of the retrograde fluorescent tracer diamidino yellow into area V4 in two monkeys. Injections of a second tracer, fast blue, were also made in area PM, an area just medial to area V4 on the prelunate gyrus, in one animal. Area V4 injections labeled cells in ventral claustrum over about 5-6 mm of its anterior-posterior extent. The more medial prelunate injection labeled cells in adjacent dorsal and more lateral claustrum. These results, together with data from other studies, suggest that in the monkey, as in the cat, there is a "visual" region of claustrum that is interconnected with multiple visual areas including V1, V2, V4, MT, FST, MST, TEO and TE. The data also suggest that dorsal and lateral to this region is another zone which is connected with different visual areas, including several in posterior parietal cortex.
Severe dementia affects 10 to 20% of all patients with Parkinson's disease (PD) and is particularly common in those aged 65 years and over. In a clinicopathologic study, we correlated Mini-Mental State Examination scores and DSM-III dementia ratings with the density of Lewy bodies, Lewy neurites, neurofibrillary tangles, neuritic plaques, gliosis, and neurons in the hippocampus and amygdala of 27 PD patients without Alzheimer's disease changes. Cortical Lewy body densities were examined in the anterior cingulate gyrus. The degree of cognitive impairment was correlated with the density of Lewy neurites in the CA2 hippocampal field, raising the possibility that disruption of the connection between the dentate gyrus, entorhinal cortex, septal nuclei, and hypothalamus and the CA1 field contributes to dementia in PD.
This report addresses the connectivity of the cortex occupying middle to dorsal levels of the anterior bank of the parieto-occipital sulcus in the macaque monkey. We have previously referred to this territory, whose perimeter is roughly circumscribed by the distribution of interhemispheric callosal fibres, as area V6, or the ‘V6 complex'. Following injections of wheatgerm agglutinin conjugated to horseradish peroxidase (WGA-HRP) into this region, we examined the laminar organization of labelled cells and axonal terminals to attain indications of relative hierarchical status among the network of connected areas. A notable transition in the laminar patterns of the local, intrinsic connections prompted a sub-designation of the V6 complex itself into two separate areas, V6 and V6A, with area V6A lying dorsal, or dorsomedial to V6 proper. V6 receives ascending input from V2 and V3, ranks equal to V3A and V5, and provides an ascending input to V6A at the level above. V6A is not connected to area V2 and in general is less heavily linked to the earliest visual areas; in other respects, the two parts of the V6 complex share similar spheres of connectivity. These include regions of peripheral representation in prestriate areas V3, V3A and V5, parietal visual areas V5A/MST and 7a, other regions of visuo-somatosensory association cortex within the intraparietal sulcus and on the medial surface of the hemisphere, and the premotor cortex. Subcortical connections include the medial and lateral pulvinar, caudate nucleus, claustrum, middle and deep layers of the superior colliculus and pontine nuclei.
Dementia is a frequent complication of idiopathic parkinsonism or PD, usually occurring later in the protracted course of the illness. The primary site of neuropathologic change in PD is the substantia nigra, but the neuropathologic and molecular basis of dementia in PD is less clear. Although Alzheimer's pathology has been a frequent finding, recent advances in immunostaining of alpha-synuclein have suggested the possible importance of cortical Lewy bodies (CLBs) in the brains of demented patients with PD.
The brains of 22 demented and 20 nondemented patients with a clinical and neuropathologic diagnosis of PD were evaluated with standard neuropathologic techniques. In addition, CLBs and dystrophic neurites were identified immunohistochemically with antibodies specific for alpha-synuclein and ubiquitin; plaques and tangles were identified by staining with thioflavine S. Associations between dementia status and pathologic markers were tested with logistic regression.
CLBs positive for alpha-synuclein are highly sensitive (91%) and specific (90%) neuropathologic markers of dementia in PD and slightly more sensitive than ubiquitin-positive CLBs. They are better indicators of dementia than neurofibrillary tangles, amyloid plaques, or dystrophic neurites.
CLBs detected by alpha-synuclein antibodies in patients with PD are a more sensitive and specific correlate of dementia than the presence of Alzheimer's pathology, which was present in a minority of the cases in this series.
We neuropathologically and immunohistochemically investigated characteristics of the central amygdaloid nucleus lesion and its relationship with the substantia nigra lesion in dementia with Lewy bodies (DLB) brains. Nine DLB, four Parkinson's disease (PD) and four Alzheimer-type dementia (ATD) cases were examined. The degree of neuronal loss in the substantia nigra was (+)-(+++) in DLB cases, (+++) in PD cases and (+) in ATD cases. All DLB cases showed spongy change and ubiquitin-positive spheroids in the central nucleus. The degree of spongy change was (+)-(+++) in DLB cases, (+) in PD cases and (-)-(+) in ATD cases, which was correlated with the degree of neuronal loss in the substantia nigra in DLB cases. The number of ubiquitin-positive spheroids was parallel to the degree of spongy change. The central nucleus receives dense dopaminergic fibers from the substantia nigra. Many ubiquitin-positive spheroids were also positive to alpha-synuclein and tyrosine-hydroxylase, suggesting that they derive from the degeneration of terminal or distal axons of Lewy body-bearing dopaminergic neurons in the substantia nigra. The disturbance of the dopaminergic connections from the substantia nigra to the central nucleus may be responsible for psychotic symptoms in DLB patients.
To assess the impact of coexisting Alzheimer (AD) pathology on the natural history of Parkinson's disease (PD).
AD changes are frequently present in brains of demented PD patients. Assessing the relative contribution of AD pathology to the natural history of PD is difficult and the impact of both AD and cortical Lewy body (LB) pathologies on cognitive dysfunction is still under discussion. From clinical experience, dementia in PD patients, mainly related to AD pathology, is associated with a poor outcome, but the impact of AD pathology on the natural history of PD has not been studied systematically.
In 200 consecutive autopsy cases of PD (sex (m/f) ratio 1:1.1), age at death 58-98 (mean 77.0 +/- 9.5) years, from a specialized Austrian brain bank, retrospectively assessed major initial clinical symptoms (tremor, akinesia), moderate/severe dementia, and duration of illness were correlated with associated AD pathologies using CERAD, Braak and NIA-Reagan criteria. Mann-Whitney U-test, Cox-regression were used for statistical analysis.
While gender had no influence on the clinical motor symptoms and outcome, tremor dominant type had a significantly better outcome than akinetic forms (p = 0.022), even after adjustment with age at onset and associated AD pathology (CERAD and Braak criteria). Patients with late onset showed significantly shorter duration of illness irrespective of dementia. Moderate to severe dementia, reported in 33% of the sample, was significantly correlated with AD pathology (all 3 criteria) that showed significantly negative correlation with survival: between CERAD 0-A vs. B and C there was a significant difference of odd ratios (p < 0.001), as was between Braak stages 0-2, 3-4.5, and 5, but not between Braak stages 3-4 and 5.
The present data confirm previous studies suggesting better outcome of tremor-dominant than akinetic-rigid type of PD, significantly worse outcome in PD with late onset and dementia that is significantly correlated with coexistent neuritic Alzheimer pathology, particularly when using the CERAD and NIA-R criteria for the diagnosis of AD. Further studies are needed to elucidate the relative impact of cortical LB and AD pathologies on the natural history of PD.
The amygdala exhibits significant pathological changes in Parkinson's disease, including atrophy and Lewy body (LB) formation. Amygdala pathology has been suggested to contribute to some clinical features of Parkinson's disease, including deficits of olfaction and facial expression. The degree of neuronal loss in amygdala subnuclei and the relationship with LB formation in non-demented Parkinson's disease cases have not been examined previously. Using stereological methods, the volume of neurones and the number of neurones in amygdala subdivisions were estimated in 18 prospectively studied, non-demented patients with Parkinson's disease and 16 age- and sex-matched controls. Careful exclusion (all cortical disease) and inclusion (non-demented, levodopa-responsive, idiopathic Parkinson's disease or controls) criteria were applied. Seven Parkinson's disease cases experienced well-formed visual hallucinations many years after disease onset, while nine Parkinson's disease cases and three controls were treated for depression. Anatomically, the amygdala was subdivided into the lateral nucleus, the basal (basolateral and basomedial) nuclei and the corticomedial (central, medial and cortical nuclei) complex. LB and Lewy neurites were identified by immunohistochemistry for alpha-synuclein and ubiquitin and were assessed semiquantitatively. LB were found throughout the amygdala in Parkinson's disease, being present in approximately 4% of neurones. Total amygdala volume was reduced by 20% in Parkinson's disease (P = 0.02) and LB concentrated in the cortical and basolateral nuclei. Lewy neurites were present in most cases but did not correlate with any structural or functional variable. Amygdala volume loss was largely due to a 30% reduction in volume (P = 0.01) and the total estimated number of neurones (P = 0.007) in the corticomedial complex. The degree of neurone loss and the proportion of LB-containing neurones in the cortical nucleus within this complex were constant across Parkinson's disease cases and neither variable was related to disease duration (R(2 )< 0.03; P > 0.5). The cortical nucleus has major olfactory connections and its degeneration is likely to contribute to the early selective anosmia common in Parkinson's disease. There was a small reduction in neuronal density in the basolateral nucleus in all Parkinson's disease cases, but no consistent volume or cell loss within this region. However, the proportion of LB-containing neurones in the basolateral nucleus was nearly doubled in cases that exhibited visual hallucinations, suggesting that neuronal dysfunction in this nucleus contributes to this late clinical feature. Detailed quantitation of the other amygdala subdivisions failed to reveal any other substantial anomalies or any associations with depression. Thus, the impact of Parkinson's disease on the amygdala is highly selective and correlates with both early and late clinical features.
Previous studies reported an association between cortical Lewy body (LB) formation and dementia in Parkinson's disease (PD). However, it is unclear whether cognitive decline in this disorder is related to specific patterns of LB distribution within the cerebral cortex. Moreover, the prediction of cognitive status based on concomitant assessment of LB and Alzheimer's disease lesions has led to conflicting results. We performed a clinicopathological study in 22 elderly PD patients in whom parkinsonism preceded cognitive decline by at least 3 years. Cognitive status was assessed prospectively using the clinical dementia rating scale (CDR); quantitative assessment of LB, neurofibrillary tangles (NFT), and senile plaques (SP) was performed in Brodmann areas 9, 21, 24, 40 and the entorhinal cortex. Statistical analysis was performed using both correlation coefficients and logistic regression models. There was a highly significant correlation between CDR scores and regional LB scores in the entorhinal cortex and area 24. LB and SP densities in the entorhinal cortex accounted for 36.2% and 19.3% of the variability in CDR scores. LB densities in area 24 could explain 25.2% of this variability. NFT densities did not predict cognitive status. In multivariate models only LB densities in the entorhinal cortex and anterior cingulate cortex were significantly associated with CDR scores. These results imply that an assessment of LB pathology limited to the entorhinal cortex and area 24 may be sufficient to predict cognition in PD. They also suggest that LB formation in limbic areas may be crucial for the development of PD dementia.
Dementia with Lewy bodies (DLB) is the second commonest cause of neurodegenerative dementia in older people. It is part of the range of clinical presentations that share a neuritic pathology based on abnormal aggregation of the synaptic protein alpha-synuclein. DLB has many of the clinical and pathological characteristics of the dementia that occurs during the course of Parkinson's disease. Here we review the current state of scientific knowledge on DLB. Accurate identification of patients is important because they have specific symptoms, impairments, and functional disabilities that differ from those of other common types of dementia. Severe neuroleptic sensitivity reactions are associated with significantly increased morbidity and mortality. Treatment with cholinesterase inhibitors is well tolerated by most patients and substantially improves cognitive and neuropsychiatric symptoms. Clear guidance on the management of DLB is urgently needed. Virtually unrecognised 20 years ago, DLB could within this decade be one of the most treatable neurodegenerative disorders of late life.
Visual hallucinations (VH) in Parkinson's disease (PD) are a chronic complication in 30 to 60% of treated patients and have a multifaceted phenomenology. Flickering, faultive impressions, and illusionary misperceptions precede the core syndrome of stereotyped, colorful images. The patient variably recognizes these images as hallucinations, being rarely irritated or frightened and more often amused as a bystander. Although studies on VH in PD focus on several research domains, no comprehensive, unified theory has been developed to study their pathophysiology. We have adapted Hobson's work on the states of consciousness and propose a model integrating seemingly disparate data on VH. We suggest that VH should be considered as a dysregulation of the gating and filtering of external perception and internal image production. Contributive elements and anatomical links for the model include poor primary vision, reduced activation of primary visual cortex, aberrant activation of associative visual and frontal cortex, lack of suppression or spontaneous emergence of internally generated imagery through the ponto-geniculo-occipital system, intrusion of rapid eye movement dreaming imagery into wakefulness, errative changes of the brainstem filtering capacities through fluctuating vigilance, and medication-related overactivation of mesolimbic systems. Different etiologies likely produce different phenomenologies and the prognosis may not be uniform. This new conceptual framework permits an anatomical view of VH and suggests new, testable hypotheses regarding their pathophysiology and therapy.
One-third of the 149 people recruited 15 to 18 years ago in the Sydney Multicenter Study of Parkinson's disease have survived. The original study compared low-dose levodopa with low-dose bromocriptine. We now report the problems experienced by people who survive 15 years from diagnosis. The standardized mortality ratio is significantly elevated at 1.86 and is not significantly different between treatment arms. Falls occur in 81% of patients, and 23% sustained fractures. Cognitive decline is present in 84%, and 48% fulfill the criteria for dementia. Hallucinations and depression are experienced by 50%. Choking has occurred in 50%, symptomatic postural hypotension in 35%, and urinary incontinence in 41%. No patient is still employed, and 40% of patients live in aged care facilities. Although approximately 95% have experienced L-dopa-induced dyskinesia/dystonia and end of dose failure of medication, in the majority, these symptoms are not disabling. Dyskinesia and dystonia were delayed by early use of bromocriptine, but end-of-dose failure appeared at a similar time once L-dopa was added. The rate of disease progression is similar in both arms of the study. We conclude that the most disabling long-term problems of Parkinson's disease relate to the emergence of symptoms that are not improved by L-dopa. Neuroprotective interventions in Parkinson's disease should be judged by their ability to improve non-L-dopa-responsive aspects of the disease, rather than just by their capacity to delay the introduction of L-dopa or reduce its associated side effects.
To identify factors associated with dementia in a cohort of Parkinson's disease (PD) brain donors and determine whether its presence may influence the clinical phenotype of the disease.
We included 67 consecutive patients with a clinical and pathological diagnosis of PD, who while alive, consented to donate their brains to the University of Miami Brain Endowment Bank(TM). Dementia and psychiatric complications of PD were diagnosed according to established criteria. Case histories were abstracted and reviewed and comparisons between PD patients with (PD-D, n = 34) and without (PD, n = 33) dementia were made.
Age at death, age at disease onset and disease duration did not differ significantly between PD-D and PD patients. Other symptoms were similar in both groups. Visual hallucinations and bilateral symptoms at diagnosis were significantly higher in PD-D patients. No association between dementia and overall survival duration was found. Although the frequency of depression and psychosis was higher in the PD patients with dementia no statistical significance was reached. The overall lifetime prevalence of dementia in our group was 50.7%.
Visual hallucinations and bilateral symptoms were associated with dementia in our cohort of PD brain donors. No association between dementia and survival duration was found. Understanding the influence of dementia on the clinical phenotype of the disease and predicting its development is essential for the successful management of PD.
The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.
We examined 19 autopsied cases of dementia with Lewy bodies (DLB) using pathological and alpha-synuclein-immunohistochemical methods, and investigated Lewy pathology in the primary visual pathway (lateral geniculate body and Brodmann's area 17), secondary visual pathway (pulvinar, Brodmann's areas 18 and 19, and inferior temporal cortex), amygdala and substantia nigra, to clarify the relationship between visual misidentification and Lewy pathology in the visual pathway. Consequently, the secondary visual pathway revealed significantly severer Lewy pathology than the primary visual pathway, suggesting that the degeneration of the secondary visual pathway induces dysfunction in the recognition of objects shape and color. In addition, the amygdala revealed significantly severer Lewy pathology and neuronal loss than the primary and secondary visual pathways, suggesting that the degeneration of the amygdala, which receives the afferent connections from the substantia nigra, fails to modulate the visual processing according to cognition and emotion. These findings suggest that Lewy pathologies in the secondary visual pathway and amygdala may cause the dysfunction of the visuo-amygdaloid pathway and participate in visual misidentification in DLB patients. In addition, we compared Lewy pathology between cases with and without visual hallucinations, and showed no significant differences between the two groups.
We investigated Lewy pathologies in the claustrum and the related cerebral cortices and subcortical nuclei of dementia with Lewy bodies (DLB) brains using alpha-synuclein-immunohistochemistry to clarify the relationship between Lewy pathology in the claustrum and visual misidentification of DLB patients. The claustrum is known to have strong reciprocal connections with the visual areas. Consequently, the claustrum demonstrated many Lewy bodies (LB) and LB-related neurites. The insular and inferior temporal cortices, amygdala, BA 18, 19, transentohrinal and cingulate cortices showed stronger or similar Lewy pathology as compared with the claustrum, while BA 17, precentral, postcentral and transverse temporal cortices showed weaker Lewy pathology. Comparing the correlation coefficient of Lewy pathology between the clausturm and other regions, BA 18 and 19 as well as the insular and transentorhinal cortices demonstrated a higher correlation coefficient. These findings suggest that Lewy pathology in the claustrum is more closely associated with that in visual areas than in auditory, somatosensory or motor areas, and that dysfunction of the visuo-claustral pathway participates in visual misidentification in addition to the visuo-amygdaloid pathway. The paralimbic cortices including the insular and transentorhinal cortices may connect visual areas with limbic areas by relay of the visuo-claustral or visuo-amygdaloid pathway.
Dementia is common in Parkinson disease (PD), although its anatomic and pathologic substrates remain undefined. Recently, striatal abnormalities in Lewy body diseases have been described, but their clinical relevance is not clear. Thirty PD cases from the United Kingdom Parkinson's Disease Society Tissue Bank were grouped as demented (PDD; n = 16) and nondemented (PD; n = 14) based on a review of clinical records. The extent of alpha-synuclein, tau, and amyloid beta peptide (Abeta) deposition in the caudate nucleus, putamen, and nucleus accumbens was assessed. All cases showed severe dopaminergic striatal terminal denervation based on tyrosine hydroxylase immunohistochemistry. Alpha-synuclein and tau deposition in the striatum were rare in both groups, but the Abeta burden was significantly greater in the striatum of PD cases with dementia than present in the nondemented PD group. Striatal Abeta deposition was type-independent of Alzheimer disease changes in the cortex and was minimal in nondemented PD cases. We conclude that Abeta deposition in the striatum strongly correlates with dementia in PD.
The pathological basis of dementia and visual hallucinations in Parkinson's disease (PD) is not yet fully understood. To investigate this further we have conducted a clinico-pathological study based on 30 post-mortem PD brains. PD cases were stratified into groups according to clinical characteristics as follows: (1) cognitively intact (n=9); (2) cases with severe dementia and visual hallucinations (n=12); (3) cases with severe dementia and no visual hallucinations (n=4); and (4) cases with severe visual hallucinations and no dementia (n=5). The extent of alpha-synuclein (alphaSyn), tau and amyloid beta peptide (Abeta) deposition was then examined in the CA2 sector of the hippocampus and in neocortical and subcortical areas known to subserve cognitive function. We find that dementia in PD is significantly associated with alphaSyn in the anterior cingulate gyrus, superior frontal gyrus, temporal cortex, entorhinal cortex, amygdaloid complex and CA2 sector of the hippocampus. Abeta in the anterior cingulate gyrus, entorhinal cortex, amygdaloid complex and nucleus basalis of Meynert is also associated with dementia as is tau in the CA2 sector of the hippocampus. alphaSyn burden in the amygdala is strongly related to the presence of visual hallucinations but only in those PD cases with concomitant dementia. Statistical analysis revealed that alphaSyn burden in the anterior cingulate gyrus could differentiate demented from non-demented PD cases with high sensitivity and specificity. We conclude that alphaSyn in limbic regions is related to dementia in PD as well as to visual hallucinations when there is an underlying dementia.
- G Gomez-Tortosa
- L A Halliday
- J Hansen
- T Hardy
- R N Iwatsubo
- D Kalaria
- R A Kaufer
- A Kenny
- K Korczyn
- V M Kosaka
- A Lee
- I Lees
- E Litvan
- O L Londos
- S Lopez
- Y Minoshima
- J A Mizuno
- E B Molina
- F Mukaetova-Ladinska
- R H Pasquier
- J B Perry
- J Q Schulz
- M Trojanowski
- Yamada
Gomez-Tortosa, G. Halliday, L.A. Hansen, J. Hardy, T. Iwatsubo, R.N. Kalaria, D.
Kaufer, R.A. Kenny, A. Korczyn, K. Kosaka, V.M. Lee, A. Lees, I. Litvan, E. Londos, O.L. Lopez, S. Minoshima, Y. Mizuno, J.A. Molina, E.B. Mukaetova-Ladinska,
F. Pasquier, R.H. Perry, J.B. Schulz, J.Q. Trojanowski, M. Yamada, Diagnosis and
management of dementia with Lewy bodies: third report of the DLB Consortium, Neurology 65 (2005) 1863-1872.
- I Mckeith
- J Mintzer
- D Aarsland
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- H Chiu
- J Cohen-Mansfield
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- B Dubois
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- S Gauthier
- G Halliday
- B Lawlor
- C Lippa
- O L Lopez
- J Carlos Machado
- J O 'brien
- J Playfer
- W Reid
I. McKeith, J. Mintzer, D. Aarsland, D. Burn, H. Chiu, J. Cohen-Mansfield, D. Dickson, B. Dubois, J.E. Duda, H. Feldman, S. Gauthier, G. Halliday, B. Lawlor, C. Lippa,
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Neuropathological substrates of psychiatric symptoms in prospectively studied patients with autopsy-confirmed dementia with lewy bodies
- C Perry
- E Joachim
- J T Jaros
- R H O 'brien
- I G Perry
- Mckeith
Perry, C. Joachim, E. Jaros, J.T. O'Brien, R.H. Perry, I.G. McKeith, Neuropathological substrates of psychiatric symptoms in prospectively studied patients with
autopsy-confirmed dementia with lewy bodies, Am. J. Psychiatry 161 (2004)
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- I G Mckeith
- D W Dickson
- J Lowe
- M Emre
- J T O'brien
- H Feldman
- J Cummings
- J E Duda
- C Lippa
- E K Perry
- D Aarsland
- H Arai
- C G Ballard
- B Boeve
- D J Burn
- D Costa
- T Ser
- B Dubois
- D Galasko
- S Gauthier
- C G Goetz
- E Gomez-Tortosa
- G Halliday
- L A Hansen
- J Hardy
- T Iwatsubo
- R N Kalaria
- D Kaufer
- R A Kenny
- A Korczyn
- K Kosaka
- V M Lee
- A Lees
- I Litvan
- E Londos
- O L Lopez
- S Minoshima
- Y Mizuno
- J A Molina
- E B Mukaetova-Ladinska
- F Pasquier
- R H Perry
- J B Schulz
- J Q Trojanowski
- M Yamada
I.G. McKeith, D.W. Dickson, J. Lowe, M. Emre, J.T. O'Brien, H. Feldman, J. Cummings, J.E. Duda, C. Lippa, E.K. Perry, D. Aarsland, H. Arai, C.G. Ballard, B. Boeve,
D.J. Burn, D. Costa, T. Del Ser, B. Dubois, D. Galasko, S. Gauthier, C.G. Goetz, E.
Gomez-Tortosa, G. Halliday, L.A. Hansen, J. Hardy, T. Iwatsubo, R.N. Kalaria, D.
Kaufer, R.A. Kenny, A. Korczyn, K. Kosaka, V.M. Lee, A. Lees, I. Litvan, E. Londos, O.L. Lopez, S. Minoshima, Y. Mizuno, J.A. Molina, E.B. Mukaetova-Ladinska,
F. Pasquier, R.H. Perry, J.B. Schulz, J.Q. Trojanowski, M. Yamada, Diagnosis and
management of dementia with Lewy bodies: third report of the DLB Consortium, Neurology 65 (2005) 1863-1872.