ABSTRACT
The PD-DLB psychosis complex found in Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB) includes hallucinations, Somatic Symptom/Functional Disorders, and delusions. These disorders exhibit similar presentation patterns and progression. Mechanisms at the root of these symptoms also share similarities with processes promoting altered states of consciousness found in Rapid Eye Movement sleep, psychiatric disorders, or the intake of psychedelic compounds. We propose that these mechanisms find a crucial driver and trigger in the dysregulated activity of high-order thalamic nuclei set in motion by ThalamoCortical Dysrhythmia (TCD). TCD generates the loss of finely tuned cortico-cortical modulations promoted by the thalamus and unleashes the aberrant activity of the Default Mode Network (DMN). TCD moves in parallel with altered thalamic filtering of external and internal information. The process produces an input overload to the cortex, thereby exacerbating DMN decoupling from task-positive networks. These phenomena alter the brain metastability, creating dreamlike, dissociative, or altered states of consciousness. In support of this hypothesis, mind-altering psychedelic drugs also modulate thalamic-cortical pathways. Understanding the pathophysiological background of these conditions provides a conceptual bridge between neurology and psychiatry, thereby helping to generate a promising and converging area of investigation and therapeutic efforts.
Subject(s)
Hallucinogens , Lewy Body Disease , Neurodegenerative Diseases , Parkinson Disease , Psychotic Disorders , Humans , Hallucinogens/pharmacology , Lewy Body Disease/drug therapy , Lewy Body Disease/diagnosis , Lewy Body Disease/metabolism , Neurodegenerative Diseases/drug therapy , Thalamus , Parkinson Disease/drug therapyABSTRACT
INTRODUCTION: The impairment of nigrostriatal dopaminergic network is a core feature of dementia with Lewy bodies (DLB). The involvement and reconfiguration of extranigrostriatal dopaminergic circuitries in the DLB continuum is still theme of debate. We aim to investigate in vivo the dynamic changes of local and long-distance dopaminergic networks across DLB continuum. METHODS: Forty-nine patients (including 29 with dementia and 20 prodromal cases) and fifty-two controls entered the study. Each subject underwent a standardized clinical and neurological examination and performed Brain SPECT to measuring brain dopamine transporter (DAT) density. Spatially normalized images underwent the occipital-adjusted specific binding to obtain parametric data. The ANCOVA was applied to assess 123I-FP-CIT differences between pDLB, overt-DLB and CG, considering age, gender, and motor impairment as variables of no interest. Between-nodes correlation analysis measured molecular connectivity within the ventral and dorsal dopaminergic networks. RESULTS: Prodromal DLB and DLB patients showed comparable nigrostriatal deficits in basal ganglia regions compared with CG. Molecular connectivity analyses revealed extensive connectivity losses, more in ventral than in dorsal dopaminergic network in DLB dementia. Conversely, the prodromal group showed increased connectivity compared to CG, mostly putamen-thalamus-cortical and striatal-cortical connectivity. CONCLUSIONS: This study indicates a comparable basal ganglia deficit in nigrostriatal projections in DLB continuum and supports a different reorganization of extra-striatal dopaminergic connectivity in the prodromal phases of DLB. The shift from an increased to a decreased bilateral putamen-thalamus-cortex connectivity might be a hallmark of transition from prodromal to dementia DLB stages.
Subject(s)
Alzheimer Disease , Lewy Body Disease , Humans , Lewy Body Disease/metabolism , Basal Ganglia/metabolism , Corpus Striatum/metabolism , Brain/metabolism , Thalamus/metabolism , Tomography, Emission-Computed, Single-Photon/methods , Alzheimer Disease/metabolismABSTRACT
OBJECTIVES: The authors investigated the topography of cholinergic vulnerability in patients with dementia with Lewy bodies (DLB) using positron emission tomography (PET) imaging with the vesicular acetylcholine transporter (VAChT) [18F]-fluoroethoxybenzovesamicol ([18F]-FEOBV) radioligand. METHODS: Five elderly participants with DLB (mean age, 77.8 years [SD=4.2]) and 21 elderly healthy control subjects (mean age, 73.62 years [SD=8.37]) underwent clinical assessment and [18F]-FEOBV PET. RESULTS: Compared with the healthy control group, reduced VAChT binding in patients with DLB demonstrated nondiffuse regionally distinct and prominent reductions in bilateral opercula and anterior cingulate to mid-cingulate cortices, bilateral insula, right (more than left) lateral geniculate nuclei, pulvinar, right proximal optic radiation, bilateral anterior and superior thalami, and posterior hippocampal fimbria and fornices. CONCLUSIONS: The topography of cholinergic vulnerability in DLB comprises key neural hubs involved in tonic alertness (cingulo-opercular), saliency (insula), visual attention (visual thalamus), and spatial navigation (fimbria/fornix) networks. The distinct denervation pattern suggests an important cholinergic role in specific clinical disease-defining features, such as cognitive fluctuations, visuoperceptual abnormalities causing visual hallucinations, visuospatial changes, and loss of balance caused by DLB.
Subject(s)
Acetylcholine/metabolism , Cerebral Cortex , Lewy Body Disease , Nerve Net , Thalamus , Aged , Aged, 80 and over , Cerebral Cortex/diagnostic imaging , Cerebral Cortex/metabolism , Cerebral Cortex/physiopathology , Cross-Sectional Studies , Female , Fornix, Brain/diagnostic imaging , Fornix, Brain/metabolism , Fornix, Brain/physiopathology , Humans , Lewy Body Disease/diagnostic imaging , Lewy Body Disease/metabolism , Lewy Body Disease/physiopathology , Male , Nerve Net/diagnostic imaging , Nerve Net/metabolism , Nerve Net/physiopathology , Piperidines , Positron-Emission Tomography , Thalamus/diagnostic imaging , Thalamus/metabolism , Thalamus/physiopathologyABSTRACT
One of the core diagnostic criteria for Dementia with Lewy Bodies (DLB) is the presence of visual hallucinations. The presence of hallucinations, along with fluctuations in the level of arousal and sleep disturbance, point to potential pathological mechanisms at the level of the thalamus. However, the potential role of thalamic dysfunction in DLB, particularly as it relates to the presence of formed visual hallucinations is not known. Here, we review the literature on the pathophysiology of DLB with respect to modern theories of thalamocortical function and attempt to derive an understanding of how such hallucinations arise. Based on the available literature, we propose that combined thalamic-thalamic reticular nucleus and thalamocortical pathology may explain the phenomenology of visual hallucinations in DLB. In particular, diminished α7 cholinergic activity in the thalamic reticular nucleus may critically disinhibit thalamocortical activity. Further, concentrated pathological changes within the posterior regions of the thalamus may explain the predilection for the hallucinations to be visual in nature.
Subject(s)
Acetylcholine/metabolism , Cerebral Cortex/physiopathology , Hallucinations/physiopathology , Lewy Body Disease/physiopathology , Thalamus/physiopathology , Visual Perception/physiology , Cerebral Cortex/metabolism , Hallucinations/etiology , Hallucinations/metabolism , Humans , Lewy Body Disease/complications , Lewy Body Disease/metabolism , Thalamus/metabolismABSTRACT
Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are thought to be part of a spectrum: both have a clinical profile including symptoms associated with dopaminergic and serotonergic loss, yet few imaging studies have focused on serotonergic neurodegeneration in both disorders. We aimed to study degeneration of terminals with dopamine and serotonin transporter (DAT and SERT, respectively) in patients with early-stage PD and DLB relative to healthy controls, using 123I-N-ω-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)nortropane (123I-FP-CIT) single photon emission computed tomography (SPECT). We conducted region of interest (ROI) and voxel-based analyses on 123I-FP-CIT SPECT scans. Using the cerebellum as a reference region, we determined binding ratios (BRs) for bilateral ROIs in the DAT-rich striatum (head of the caudate nucleus and posterior putamen) and SERT-rich extrastriatal brain regions (thalamus, hypothalamus and hippocampus). We compared BRs in PD and DLB patients with BRs in healthy controls (all groups: nâ¯=â¯16). Both PD and DLB patients had lower striatal 123I-FP-CIT BRs than healthy controls for the bilateral caudate head (PD-left: F(1,29)â¯=â¯28.778, Pâ¯<â¯.001, ω2â¯=â¯0.35; right: F(1,29)â¯=â¯35.338, Pâ¯<â¯.001, ω2â¯=â¯0.42; DLB-left: F(1,29)â¯=â¯28.241, Pâ¯<â¯.001, ω2â¯=â¯0.31; right: F(1,29)â¯=â¯18.811, Pâ¯<â¯.001, ω2â¯=â¯0.26) and bilateral posterior putamen (PD-left: F(1,29)â¯=â¯107.531, Pâ¯<â¯.001, ω2â¯=â¯0.77; right: F(1,29)â¯=â¯87.525, Pâ¯<â¯.001, ω2â¯=â¯0.72; DLB-left: F(1,29)â¯=â¯39.910, Pâ¯<â¯.001, ω2â¯=â¯0.48; right: F(1,29)â¯=â¯26.882, Pâ¯<â¯.001, ω2â¯=â¯0.38). DLB patients had lower hypothalamic 123I-FP-CIT BRs than healthy controls (F(1,29)â¯=â¯6.059, Pâ¯=â¯.020, ω2â¯=â¯0.12). In the voxel-based analysis, PD and DLB patients had significantly lower striatal binding than healthy controls. Both PD patients in the early disease stages and DLB patients have reduced availability of striatal DAT, and DLB patients lower hypothalamic SERT compared with healthy controls. These observations add to the growing body of evidence that PD and DLB are not merely dopaminergic diseases, thereby providing additional clinicopathological insights.
Subject(s)
Dopamine Plasma Membrane Transport Proteins/metabolism , Hippocampus/metabolism , Hypothalamus/metabolism , Lewy Body Disease/metabolism , Neostriatum/metabolism , Parkinson Disease/metabolism , Serotonin Plasma Membrane Transport Proteins/metabolism , Thalamus/metabolism , Tomography, Emission-Computed, Single-Photon/methods , Tropanes , Aged , Cross-Sectional Studies , Female , Hippocampus/diagnostic imaging , Humans , Hypothalamus/diagnostic imaging , Lewy Body Disease/diagnostic imaging , Male , Middle Aged , Neostriatum/diagnostic imaging , Parkinson Disease/diagnostic imaging , Retrospective Studies , Thalamus/diagnostic imagingABSTRACT
BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the presence of inclusions known as Lewy bodies in some brain regions. Lewy bodies consist of α-synuclein and many other proteins including chaperones. OBJECTIVE: To learn more about the role of chaperone complexes in PD and a related disorder, i.e., dementia with Lewy bodies (DLB), in this work we analyzed the expression of HSP90 and its two quite recently identified co-chaperones, SGT1 and CHP-1, in selected brain regions from patients suffering from these diseases. METHODS: To fulfill the aim of our study we used human material and applied immunohistochemistry, Western blot analysis and real time/quantitative PCR (RT-qPCR). RESULTS: We have found that HSP90 mRNA level is higher in the temporal cortex of PD and in frontal cortex of DLB brains, even though level of protein does not change significantly. The mRNA level of SGT1 is higher in the frontal and temporal cortex of PD and in substantia nigra of DLB brains while no significant changes in the level of protein were noticed. Similarly, the mRNA level of CHP-1 was found to be higher in the frontal and temporal cortex of PD and in all examined regions i.e. substantia nigra, frontal and temporal cortex of DLB brains. In the case of CHP-1 the protein level was found to be higher in frontal cortex of PD and in all examined areas of DLB patients. CONCLUSIONS: Our data indicate that the level of HSP90, SGT1 and CHP-1 is upregulated in the majority of cases of PD and DLB, which suggests that the examined proteins might be involved in these pathologies.
Subject(s)
Calcium-Binding Proteins/metabolism , Cell Cycle Proteins/metabolism , Frontal Lobe/metabolism , HSP90 Heat-Shock Proteins/metabolism , Lewy Body Disease/metabolism , Molecular Chaperones/metabolism , Parkinson Disease/metabolism , Substantia Nigra/metabolism , Temporal Lobe/metabolism , Tissue Banks , Aged , Aged, 80 and over , Humans , Middle Aged , RNA, Messenger/metabolismABSTRACT
Hyperphosphorylated α-synuclein in Lewy bodies and Lewy neurites is a characteristic neuropathological feature of Parkinson's disease (PD) and Dementia with Lewy bodies (DLB). The catalytic subunit of the specific phosphatase, protein phosphatase 2A (PP2A) that dephosphorylates α-synuclein, is hypomethylated in these brains, thereby impeding the assembly of the active trimeric holoenzyme and reducing phosphatase activity. This phosphatase deficiency contributes to the accumulation of hyperphosphorylated α-synuclein, which tends to fibrillize more than unmodified α-synuclein. Eicosanoyl-5-hydroxytryptamide (EHT), a fatty acid derivative of serotonin found in coffee, inhibits the PP2A methylesterase so as to maintain PP2A in a highly active methylated state and mitigates the phenotype of α-synuclein transgenic (SynTg) mice. Considering epidemiologic and experimental evidence suggesting protective effects of caffeine in PD, we sought, in the present study, to test whether there is synergy between EHT and caffeine in models of α-synucleinopathy. Coadministration of these two compounds orally for 6 mo at doses that were individually ineffective in SynTg mice and in a striatal α-synuclein preformed fibril inoculation model resulted in reduced accumulation of phosphorylated α-synuclein, preserved neuronal integrity and function, diminished neuroinflammation, and improved behavioral performance. These indices were associated with increased levels of methylated PP2A in brain tissue. A similar profile of greater PP2A methylation and cytoprotection was found in SH-SY5Y cells cotreated with EHT and caffeine, but not with each compound alone. These findings suggest that these two components of coffee have synergistic effects in protecting the brain against α-synuclein-mediated toxicity through maintenance of PP2A in an active state.
Subject(s)
Caffeine/pharmacology , Coffee/chemistry , Lewy Body Disease/metabolism , Neuroprotection/drug effects , Parkinson Disease/metabolism , Serotonin/analogs & derivatives , Animals , Brain/drug effects , Brain/metabolism , Brain/pathology , Disease Models, Animal , Fatty Acids/metabolism , Lewy Body Disease/drug therapy , Lewy Body Disease/pathology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , Parkinson Disease/drug therapy , Parkinson Disease/pathology , Phosphorylation , Protein Phosphatase 2/metabolism , Serotonin/pharmacology , alpha-Synuclein/metabolismABSTRACT
Lipid rafts are highly dynamic membrane microdomains intimately associated with cell signaling. Compelling evidence has demonstrated that alterations in lipid rafts are associated with neurodegenerative diseases such Alzheimer's disease, but at present, whether alterations in lipid raft microdomains occur in other types of dementia such dementia with Lewy bodies (DLB) remains unknown. Our analyses reveal that lipid rafts from DLB exhibit aberrant lipid profiles including low levels of n-3 long-chain polyunsaturated fatty acids (mainly docosahexaenoic acid), plasmalogens and cholesterol, and reduced unsaturation and peroxidability indexes. As a consequence, lipid raft resident proteins holding principal factors of the ß-amyloidogenic pathway, including ß-amyloid precursor protein, presenilin 1, ß-secretase, and PrP, are redistributed between lipid rafts and nonraft domains in DLB frontal cortex. Meta-analysis discloses certain similarities in the altered composition of lipid rafts between DLB and Parkinson's disease which are in line with the spectrum of Lewy body diseases. In addition, redistribution of proteins linked to the ß-amyloidogenic pathway in DLB can facilitate generation of ß-amyloid, thus providing mechanistic clues to the intriguing convergence of Alzheimer's disease pathology, particularly ß-amyloid deposition, in DLB.
Subject(s)
Alzheimer Disease/metabolism , Frontal Lobe/cytology , Frontal Lobe/metabolism , Lewy Body Disease/metabolism , Lipid Metabolism , Membrane Microdomains/metabolism , Nerve Tissue Proteins/metabolism , Parkinson Disease/metabolism , Aged , Aged, 80 and over , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/metabolism , Cholesterol/metabolism , Docosahexaenoic Acids/metabolism , Female , Humans , Male , Plasmalogens/metabolismABSTRACT
OBJECTIVE: Depression is a common symptom in dementia with Lewy bodies (DLB), Parkinson disease dementia (PDD), and Alzheimer disease (AD), yet its molecular basis remains unclear and current antidepressants do not appear to be effective. Cerebral zinc has been implicated in depression and synaptic dysfunction. We investigated the relationship between synaptic zinc regulation (for which zinc transporter 3 [ZnT3] is responsible) and depression in a large clinicopathologic study. METHODS: We examined brains from people with PDD (N = 29), DLB (N = 27), and AD (N = 15) and comparison subjects without depression or dementia (N = 24). Individuals were categorized according to the presence and severity of depression (on a scale of 0-3) based on standardized assessments during life (principally Neuropsychiatric Inventory). Western blotting was used to determine ZnT3 levels in Brodmann area 9 (BA9), and regression analysis was used to determine the relationship between ZnT3 and depression. RESULTS: Reductions in ZnT3 in BA9 were significantly associated with elevated depression scores in the study cohort (ß = -0.351, df = 93, t = -3.318 p = 0.0004). This association remained when only individuals with DLB, PDD, and no dementia or depression were examined (ß = -0.347, df = 78, t = -3.271, p = 0.002) or only individuals with AD and no dementia or depression were examined (ß = -0.433, df = 37, t = -2.924, p = 0.006). CONCLUSION: Although decreased zinc levels have been implicated in the genesis of depression in animal models and in major depressive disorder in humans, this study provides the first evidence of a role for zinc in depression in people with dementia and highlights zinc metabolism as a therapeutic target.
Subject(s)
Alzheimer Disease/metabolism , Cation Transport Proteins/metabolism , Depression/metabolism , Lewy Body Disease/metabolism , Parkinson Disease/metabolism , Synapses/metabolism , Zinc/metabolism , Aged , Aged, 80 and over , Alzheimer Disease/complications , Case-Control Studies , Depression/complications , Female , Frontal Lobe/metabolism , Gyrus Cinguli/metabolism , Humans , Lewy Body Disease/complications , Male , Parietal Lobe/metabolism , Parkinson Disease/complicationsABSTRACT
Dementia with Lewy bodies (DLB) is characterized by fluctuation in cognition and attention. Thalamocortical connectivity and integrity of thalami are central to attentional function. We hypothesize that DLB patients with marked and frequent fluctuating cognition (flCog) have a loss of thalamocortical connectivity, an intrinsic disruption to thalamic structure and imbalances in thalamic neurotransmitter levels. To test this, magnetic resonance imaging (MRI), diffusion tensor imaging (DTI) and proton MR spectroscopy on thalami were performed on 16 DLB, 16 Alzheimer's disease (AD) and 13 healthy subjects. MRI and DTI were combined to subdivide thalami according to their cortical connectivity and to investigate microstructural changes in connectivity-defined thalamic regions. Compared with controls, lower N-acetyl-aspartate/total creatine (NAA/tCr) and higher total choline/total creatine (tCho/tCr) values were observed within thalami of DLB patients. tCho/tCr increase was found within right thalamus of DLB patients as compared with AD. This increase correlated with severity and frequency of flCog. As compared with controls, DLB patients showed bilateral damage within thalamic regions projecting to prefrontal and parieto-occipital cortices, whereas AD patients showed bilateral alteration within thalamic region projecting to temporal cortex. We posit that microstructural thalamic damage and cholinergic imbalance may be central to the etiology of flCog in DLB.
Subject(s)
Cognition , Lewy Body Disease/metabolism , Lewy Body Disease/pathology , Thalamus/pathology , Aged , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Alzheimer Disease/psychology , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Diffusion Magnetic Resonance Imaging , Diffusion Tensor Imaging , Female , Humans , Lewy Body Disease/psychology , Male , Neural Pathways/metabolism , Neural Pathways/pathology , Proton Magnetic Resonance SpectroscopyABSTRACT
Prohibitin and ATP synthase protein levels were examined in the substantia nigra and frontal cortex (area 8) in five cases of Parkinson's disease (PD), five cases of dementia with Lewy bodies pure form (pDLB), five cases of early Alzheimer's disease (AD stage IIA, B), nine cases with advanced AD (stages V/VIC), and nine controls. A significant reduction of prohibitin and ATP synthase was observed in the substantia nigra in PD cases. In contrast, increased prohibitin and ATP synthase levels were found in the frontal cortex in PD, and increased prohibitin but not ATP synthase in the frontal cortex in pDLB. Superoxide dismutase 2 (SOD2) expression levels were also increased in the frontal cortex in PD and pDLB. No modifications in prohibitin and ATP synthase levels were found in the frontal cortex in sporadic AD. These findings demonstrate disease-specific modifications in the expression of mitochondrial-related proteins in the frontal cortex at stages of PD in which there is no alpha-synuclein aggregation in the form of Lewy bodies and Lewy neurites in this area. These findings emphasize the presence of mitochondrial modifications before the appearance of histological hallmarks of PD, and point to the possibility of a more extended molecular pathology in PD than currently accepted.
Subject(s)
Frontal Lobe/metabolism , Mitochondrial Proton-Translocating ATPases/metabolism , Parkinson Disease/metabolism , Repressor Proteins/metabolism , Substantia Nigra/metabolism , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Alzheimer Disease/physiopathology , Biomarkers/analysis , Biomarkers/metabolism , Frontal Lobe/pathology , Frontal Lobe/physiopathology , Humans , Lewy Body Disease/metabolism , Lewy Body Disease/pathology , Lewy Body Disease/physiopathology , Mitochondria/metabolism , Mitochondrial Diseases/metabolism , Mitochondrial Diseases/pathology , Mitochondrial Diseases/physiopathology , Parkinson Disease/pathology , Parkinson Disease/physiopathology , Predictive Value of Tests , Prohibitins , Substantia Nigra/pathology , Substantia Nigra/physiopathology , Superoxide Dismutase/metabolism , Up-Regulation/physiologyABSTRACT
Dementia with Lewy bodies (DLB) is characterized by progressive dementia with two of three core symptoms; Parkinsonism, visual hallucinations or disturbances of consciousness/fluctuating attention. Dementia in Parkinson's disease (PDD) has similar neuropsychiatric characteristics. Reduced nigrothalamic dopamine and altered thalamic D2 receptors may mediate some of the non-motor symptoms of DLB and PDD. The study aims were to ascertain whether thalamic D2 density was altered in Parkinson's disease (PD), PDD and DLB, and whether D2 density was related to core symptoms. Thalamic D2 receptor binding was measured by post-mortem autoradiography in 18 cases of DLB, 13 PDD, 6 PD and 14 normal elderly controls. Highest D2 density in control cases was in the intralaminar, midline, anterior and mediodorsal nuclei. In PD without dementia D2 binding was elevated above controls in all thalamic regions, significantly in reticular, laterodorsal, centromedian, ventral centromedian, parafascicular, paraventricular, ventroposterior, ventrolateral posterior, and ventrointermedius nuclei. Compared to controls, DLB cases with Parkinsonism (DLB+EPS) had significantly elevated D2 receptor density in laterodorsal and ventrointermedius nuclei; PDD cases had significantly raised density in the ventrointermedius, and DLB cases without Parkinsonism (DLB-EPS) did not show increased D2 density in any areas. In DLB and PDD cases with disturbances of consciousness, cases treated with neuroleptics had higher D2 binding in all thalamic regions, significantly in the mediodorsal and ventrolateral posterior nuclei. D2 receptor binding did not vary with cognitive decline (MMSE) or visual hallucinations, but was significantly higher with increased extrapyramidal symptoms.
Subject(s)
Dementia/metabolism , Lewy Body Disease/metabolism , Parkinson Disease/metabolism , Receptors, Dopamine D2/metabolism , Thalamus/metabolism , Aged , Aged, 80 and over , Antipsychotic Agents/therapeutic use , Autopsy , Autoradiography , Basal Ganglia Diseases/metabolism , Basal Ganglia Diseases/psychology , Cerebral Cortex/pathology , Consciousness Disorders/metabolism , Consciousness Disorders/psychology , Dementia/etiology , Dementia/psychology , Female , Hallucinations/metabolism , Hallucinations/psychology , Humans , Lewy Bodies/pathology , Lewy Body Disease/pathology , Lewy Body Disease/psychology , Male , Movement Disorders/metabolism , Movement Disorders/psychology , Neuropsychological Tests , Parkinson Disease/complications , Parkinson Disease/psychology , Thalamic Nuclei/metabolism , Thalamic Nuclei/pathology , Thalamus/pathologyABSTRACT
Disturbances of consciousness (DOC) are common in dementia with Lewy bodies (DLB). Following previous findings of preserved temporal cortical high-affinity nicotinic binding relating to DOC, we investigated this receptor in thalamus, an area of high nicotinic receptor concentration, implicated in consciousness. 5-[125I]-A-85380 binding, primarily reflecting the alpha4beta2 subtype, was compared in 16 DLB patients with DOC and 6 without DOC, matched for duration and severity of dementia. Binding was higher in patients with DOC compared to patients without DOC in all thalamic nuclei examined, reaching significance in the reticular and ventral anterior thalamic nuclei. Comparing DLB patients with and without DOC to previously reported controls revealed similar binding levels in patients with DOC and lower binding in patients without DOC, reaching significance in the ventral anterior, indicating preserved nicotinic receptor density in DLB patients with DOC. These findings, together with previous neocortical data, implicate nicotinic modulation of thalamo-cortical circuitry as a key component in the control of conscious awareness in DLB.
Subject(s)
Consciousness Disorders/metabolism , Lewy Body Disease/metabolism , Receptors, Nicotinic/metabolism , Thalamus/metabolism , Aged , Aged, 80 and over , Azetidines/metabolism , Consciousness Disorders/physiopathology , Female , Humans , Iodine Radioisotopes , Lewy Body Disease/physiopathology , Male , Neocortex/cytology , Neural Pathways , Prospective Studies , Thalamus/cytology , Thalamus/physiopathologyABSTRACT
The presence of alpha6 subunit containing nicotinic acetylcholine receptors on nigrostriatal dopaminergic neurons has been demonstrated in rodents and monkeys. [(125)I]alpha-conotoxinMII is a radioligand that binds to alpha6, and also alpha3 subunits of nicotinic acetylcholine receptors (nAChRs). In the present study, we have compared the distribution of [(125)I]alpha-conotoxinMII binding in post mortem human tissue from four groups of patients: individuals with dementia with Lewy bodies displaying extra-pyramidal features (DLB + EPF), DLB without extra-pyramidal features (DLB - EPF) Parkinson's disease without dementia (PD) and age-matched controls. Reduced binding was observed in the putamen and caudate in PD and both DLB groups. In DLB patients, the decline was greater in DLB + EPF compared to DLB - EPF group. The declines in nicotinic receptor binding in the striatum were in part paralleled by reductions in the striatal dopamine transporter. In the thalamus, [(125)I]alpha-conotoxinMII binding was significantly reduced in the centromedian nucleus in both DLB groups, and also in the parafascicular nucleus in the DLB - EPF group. In DLB + EPF and PD patients, there was decreased binding in the ventral lateral nucleus. This study demonstrates alterations of alpha6 and/or alpha3 nAChRs binding in DLB and PD, which are likely to relate to extra-pyramidal symptoms.
Subject(s)
Conotoxins/metabolism , Lewy Body Disease/metabolism , Neostriatum/metabolism , Receptors, Nicotinic/metabolism , Thalamus/metabolism , Aged , Aged, 80 and over , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Autoradiography , Binding, Competitive , Conotoxins/pharmacokinetics , Dopamine Plasma Membrane Transport Proteins , Female , Humans , Iodine Radioisotopes , Lewy Body Disease/pathology , Male , Membrane Glycoproteins/analysis , Membrane Glycoproteins/metabolism , Membrane Transport Proteins/analysis , Membrane Transport Proteins/metabolism , Neostriatum/chemistry , Neostriatum/pathology , Nerve Tissue Proteins/analysis , Nerve Tissue Proteins/metabolism , Parkinson Disease/metabolism , Parkinson Disease/pathology , Receptors, Nicotinic/analysis , Thalamus/chemistry , Thalamus/pathologyABSTRACT
Dementia with Lewy bodies (DLB) is a neurodegenerative disease associated with a range of neuropsychiatric symptoms and reduced expression of neuronal nicotinic acetylcholine receptors (nAChRs) in neocortex, hippocampus, thalamus and basal ganglia. To determine whether there are selective associations between alterations in alpha6/alpha3 neuronal nicotinic acetylcholine receptors (nAChRs) and the two key neuropsychiatric features of DLB, impaired consciousness (IC) and visual hallucinations (VH), quantitative [(125)I]-alpha-conotoxin MII ([(125)I]-alpha-Ctx MII) autoradiography was undertaken on 28 people with DLB and 15 control cases from the Newcastle Brain Bank. There was a highly significant overall trend for reduced thalamic [(125)I]-alpha-Ctx MII binding in DLB (p < 0.001), with significant deficits in the centromedian, ventral lateral and ventroposterior medial thalamic nuclei (p < 0.05), together with caudate and putamen (p < 0.001). [(125)I]-alpha-Ctx MII binding was significantly lower in DLB cases with IC than without IC in the putamen (p < 0.05), however there was no significant association between [(125)I]-alpha-Ctx MII binding and VH. Reductions in [(125)I]-alpha-Ctx MII binding in caudate and putamen were paralleled by similar reductions in [(125)I]PE2I binding. [(125)I]PE2I binding was also significantly lower in DLB cases with IC than without IC in the caudate (p < 0.05) and putamen (p < 0.001). These results demonstrate that deficits in alpha6/alpha3 nAChRs occur in specific brain regions in DLB, may in part be related to the loss of dopaminergic neurons and may contribute to the development of impaired consciousness in the disorder.
Subject(s)
Conotoxins/metabolism , Corpus Striatum/metabolism , Lewy Body Disease/pathology , Lewy Body Disease/psychology , Nicotinic Antagonists/metabolism , Receptors, Nicotinic/physiology , Thalamus/metabolism , Aged , Aged, 80 and over , Autoradiography , Brain/pathology , Consciousness/physiology , Dopamine/metabolism , Dopamine Plasma Membrane Transport Proteins , Female , Hallucinations/metabolism , Hallucinations/psychology , Humans , Lewy Body Disease/metabolism , Male , Membrane Glycoproteins/metabolism , Membrane Transport Proteins/metabolism , Nerve Tissue Proteins/metabolism , Receptors, Nicotinic/metabolism , Sex CharacteristicsABSTRACT
BACKGROUND: The neurodegenerative process in Alzheimer's disease (AD) and in the Lewy body variant of AD (LBV) patients is characterized by cholinergic dysfunction and deposition of amyloid beta-peptide (Abeta) 1-40 and 1-42; however, the differential effects of Abeta species on the cholinergic system are not completely clear. OBJECTIVE: To better understand the relationship between levels of Abeta1-40 and 1-42 on cholinergic deficits in AD and LBV patients. METHODS: Levels of choline acetyltransferase (ChAT) activity and ChAT immunoreactivity in the plaques in the frontal cortex of patients with AD and LBV were correlated with Abeta1-42 and 1-40 levels determined by ELISA and with neuropathologic and neurologic markers. RESULTS: Although the overall levels of ChAT activity were reduced in AD and LBV cases, there was a direct correlation with Abeta1-42 levels. Furthermore, patients with high Abeta1-42 levels had more abundant cholinergic dystrophic neurites in the plaques than cases with lower Abeta1-42. CONCLUSION: Abeta1-42 may also trigger cholinergic dysfunction by promoting aberrant neuritic sprouting.
Subject(s)
Alzheimer Disease/pathology , Amyloid beta-Peptides/physiology , Cholinergic Fibers/pathology , Frontal Lobe/pathology , Lewy Body Disease/pathology , Peptide Fragments/physiology , Aged , Aged, 80 and over , Alzheimer Disease/metabolism , Amyloid beta-Peptides/analysis , Basal Nucleus of Meynert/pathology , Choline O-Acetyltransferase/analysis , Female , Frontal Lobe/chemistry , GAP-43 Protein/analysis , Humans , Lewy Body Disease/metabolism , Male , Nerve Tissue Proteins/analysis , Neurites/ultrastructure , Neurofibrillary Tangles , Neuropsychological Tests , Peptide Fragments/analysis , Plaque, Amyloid/chemistry , Single-Blind MethodABSTRACT
Patients with parkinsonism-dementia complex (PDC) of Guam showed moderate loss of choline acetyl transferase activity in the midfrontal and inferior parietal cortex, and severe loss in the superior temporal cortex. This deficit was similar to that seen in Alzheimer's disease and less severe than Lewy body disease. Thus, cholinergic deficits in the neocortex might contribute to some of the cognitive alterations in PDC of Guam.
Subject(s)
Choline O-Acetyltransferase/metabolism , Neocortex/enzymology , Parkinson Disease/metabolism , Acetylcholine/metabolism , Aged , Alzheimer Disease/metabolism , Basal Ganglia/enzymology , Female , Frontal Lobe/enzymology , Guam , Humans , Lewy Body Disease/metabolism , Male , Parietal Lobe/enzymology , Presynaptic Terminals/metabolism , Temporal Lobe/enzymologyABSTRACT
To assess the significance of damaged nuclear DNA in autopsy brain tissue in Lewy body disease (LBD), we examined the patterns of expression of two DNA repair enzymes (PARP and DNA-PKCS), TUNEL and caspase-3 activation, in sections of midbrain and frontal cortex from nine patients with LBD who had not received L-DOPA, and from five neurologically normal controls. In LBD but not controls, many neurons and glia in the midbrain had translocated DNA-PKCS and PARP from the cytoplasm into the nucleus, particularly in the substantia nigra. LBD midbrains contained sparse TUNEL-positive neurons. Caspase-3 activity was largely restricted to microglia but was detected in an occasional nigral neuron. Nuclear DNA damage occurs in vivo in LBD but only rarely indicates neuronal apoptosis.
Subject(s)
Cell Nucleus/pathology , DNA Damage , DNA-Binding Proteins , Frontal Lobe/pathology , Lewy Body Disease/pathology , Mesencephalon/pathology , Aged , Aged, 80 and over , Apoptosis , Caspase 3 , Caspases/analysis , Caspases/biosynthesis , Cell Count , Cell Nucleus/metabolism , DNA/metabolism , DNA-Activated Protein Kinase , Frontal Lobe/metabolism , Humans , Immunohistochemistry , In Situ Nick-End Labeling , Lewy Body Disease/metabolism , Mesencephalon/metabolism , Middle Aged , Neuroglia/metabolism , Neuroglia/pathology , Neurons/metabolism , Neurons/pathology , Nuclear Proteins , Poly(ADP-ribose) Polymerases/analysis , Poly(ADP-ribose) Polymerases/biosynthesis , Protein Serine-Threonine Kinases/analysis , Protein Serine-Threonine Kinases/biosynthesis , Protein Subunits , Substantia Nigra/metabolism , Substantia Nigra/pathologyABSTRACT
UNLABELLED: Memory and attention are cognitive functions that depend heavily on the cholinergic system. Local activity of acetylcholine esterase (AChE) is an indicator of its integrity. Using a recently developed tracer for positron emission tomography (PET), C-11-labeled N-methyl-4-piperidyl-acetate (C11-MP4A), we measured regional AChE activity in 4 non-demented subjects, 4 patients with dementia of Alzheimer type (DAT) and 1 patient with senile dementia of Lewy body type (SDLT), and compared the findings with measurements of blood flow (CBF) and glucose metabolism (CMRGlc). Initial tracer extraction was closely related to CBF. AChE activity was reduced significantly in all brain regions in demented subjects, whereas reduction of CMRGlc and CBF was more limited to temporo-parietal association areas. AChE activity in SDLT was in the lower range of values in DAT. Our results indicate that, compared to non-demented controls, there is a global reduction of cortical AChE activity in dementia. KEYWORDS: Dementia, cholinergic system, acetylcholine esterase, positron emission tomography, cerebral blood flow, cerebral glucose metabolism.