Limbic thalamus atrophy is associated with visual hallucinations in Lewy body disorders.

Recent models of hallucinations in Lewy body disorders implicate dysfunction in 'higher order' thalamic regions involved in perceptual integration and cognitive processing. However, the degree of pathology and degeneration in these regions has not been assessed. We sought to assess atrophy, neuronal size, and neuronal numbers in the Mediodorsal (MDn) and Anterior Principal (APn) nuclei of the thalamus across Lewy body disorders comparing between patients with and without hallucinations. Postmortem tissue was acquired from 24 patients with Lewy body disease and 10 age-matched controls and analyzed using standard stereological and quantitative neuropathological techniques. Atrophy in MDn was significantly greater in patients with well-formed visual hallucinations and did not correlate significantly with neuronal size or number. Atrophy in APn was seen across all Lewy body disorders but was not significantly associated with hallucinations. α-synuclein immunoreactivity was found to be low in both the APn and MDn across all groups. These results suggest that MDn atrophy may be a marker of hallucinations and plays a role in their pathophysiology.

Extreme sleep pattern in Lewy body dementia: a hypothalamic matter?

Excessive sleep during the night and for >2 hours during the day is part of the fluctuating wakefulness criterion of dementia with Lewy bodies (DLB). The phenomenon 'sleep days' is not uncommon in nursing homes. Here, we describe a woman who, for months, slept for 3 days and nights in a row and thereafter was awake for 3 days and nights. Electroencephalogram (EEG) showed slow background activity and increased delta activity. No epileptiform activity was detected. Polysomnography showed a severely disturbed, markedly fragmented sleep pattern. On her death, neuropathology revealed degeneration and loss of neurons along with α-synuclein-containing Lewy body inclusions and neurites in the substantia nigra, locus coeruleus, hypothalamus, and neocortex, thus fulfilling the criteria of DLB, cortical type. We propose that the hypothalamic degeneration contributed significantly to the clinical profile in this case. We suggest that patients with sleep days should be investigated for other DLB signs.

Synergistic neuroprotection by coffee components eicosanoyl-5-hydroxytryptamide and caffeine in models of Parkinson's disease and DLB.

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.

Does attentional dysfunction and thalamic atrophy predict decline in dementia with Lewy bodies?

INTRODUCTION: To evaluate the clinical characteristics of DLB subjects who died within 1 year of assessment compared to those who survived and investigate their patterns of in vivo regional thalamic atrophy using structural MRI. METHODS: Seventy subjects (35 DLB, 35 aged controls) underwent 3 T T1-weighted MR scanning as well as clinical and cognitive assessments, including a computerised assessment of attention. All subjects were contacted after 12 months for reassessment. For both hemispheres, using FSL FIRST, the thalamus was automatically segmented followed by inter-subject vertex-wise analyses involving group comparisons and behavioural correlates. RESULTS: There was significant bilateral atrophy in the ventral-dorsal and pulvinar regions in DLB relative to controls (pcorrected < 0.05). The DLB group was then re-categorised based on 12-month mortality data: DLB-a (n = 26) and DLB-d (n = 9) (a = alive, d = death within 12 months of study assessment). Compared to controls, significant attentional dysfunction and bilateral atrophy of the pulvinar, ventral and dorsal nuclei were observed in DLB-d (pcorrected < 0.05), whereas in DLB-a, atrophy was far less extensive. CONCLUSIONS: Distinct patterns of thalamic atrophy occur in DLB that may relate to the attentional dysfunction and cognitive fluctuations that characterise this disorder. Relative to controls, the extent of attentional impairment and pattern of thalamic degeneration differ in those patients who died within 12 months of assessment, despite having an otherwise similar level of dementia severity. These findings may provide insight into the neurobiological changes underpinning important clinical characteristics and disease heterogeneity.

Dopamine transporter imaging for the diagnosis of dementia with Lewy bodies.

BACKGROUND: Dementia with Lewy bodies (DLB) is a common cause of neurodegenerative dementia of old age. Its accurate recognition can be important in clinical management and is essential for the development of disease-modifying treatments. The current clinical diagnostic criteria are limited particularly by relatively poor sensitivity. Dopamine transporter (DAT) imaging using single-photon emission computed tomography (SPECT) is the most highly developed supplementary test for DLB, and is now incorporated as a suggestive feature in the consensus diagnostic criteria. However, there is uncertainty about its accuracy and its place in clinical practice. It is most commonly used in people who are already suspected of having DLB. OBJECTIVES: We had two objectives in this review: (A) to estimate the accuracy of DAT imaging for the diagnosis of DLB in people with dementia in secondary care (specialist dementia services), and (B) to estimate the accuracy of DAT imaging for the diagnosis of DLB in people with dementia in secondary care who are already suspected of having DLB on the basis of a prior clinical work-up. SEARCH METHODS: We searched MEDLINE (1946 to February 2013), Embase (1980 to February 2013), BIOSIS Previews (1926 to February 2013), PsycINFO (1806 to February 2013), CINAHL (1982 to February 2013), LILACS (February 2013) and Web of Science and Conference Proceedings (ISI Web of Science) (1945 to February 2013). Several of these sources contain conference abstracts. We also searched four specialised databases containing diagnostic reviews: Meta-analyses van Diagnostisch Onderzoek (MEDION; February 2013), Database of Abstracts of Reviews of Effects (DARE; February 2013), Health Technology Assessment Database (HTA; February 2013), and Aggressive Research Intelligence Facility (ARIF; February 2013). We checked reference lists of relevant studies and reviews for potential additional studies. Terms for electronic database searching were devised in conjunction with the team at the Cochrane Dementia and Cognitive Improvement Group. STUDY DESIGN: We included test accuracy studies with delayed verification, diagnostic case-control studies, and two-gate studies with alternative diagnosis controls. PARTICIPANTS: (A) participants with dementia in secondary care, (B) participants in secondary care meeting consensus clinical criteria (other than the DAT imaging criterion) for possible or probable DLB, or both. INDEX TEST: SPECT or positron emission tomography (PET) imaging of brain dopamine transporters. Reference standard: Neuropathological diagnosis at autopsy. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion and extracted data. We extracted results into a 2x2 table, showing the binary test results cross-classified with the binary reference standard. We used this data to calculate sensitivities, specificities, and their 95% confidence intervals. We used the QUADAS-2 tool plus some additional items to assess methodological quality. MAIN RESULTS: We included one study that was applicable to our first objective (A). It reported data on 22 participants who met consensus clinical criteria for DLB or National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for Alzheimer's disease, or both (a two-gate design with alternative diagnosis controls). The index test was SPECT scanning using the ligand (123)I-FP-CIT. We considered the study to be at high risk of bias in the participant selection and index test domains (QUADAS-2). (123)I-FP-CIT SPECT analysed semiquantitatively had a sensitivity of 1.00 (95% confidence interval (CI) 0.66 to 1.00) and a specificity of 0.92 (95% CI 0.64 to 1.00) for the diagnosis of DLB (n = 22, 1 study). Analysed visually, the sensitivity was 0.86 (95% CI 0.42 to 1.00) and the specificity was 0.83 (95% CI 0.52 to 0.98) (n = 19, 1 study).We considered that the study also provided the best available data to address our second objective (B). At baseline, 15 participants were clinically suspected of having DLB. In this group, (123)I-FP-CIT SPECT scanning analysed semiquantitatively had a sensitivity of 1.00 (95% CI 0.63 to 1.00) and a specificity of 1.00 (95% CI 0.59 to 1.00) for the diagnosis of DLB (n = 15, 1 study). Analysed visually, accuracy in this group was lower with a sensitivity of 0.83 (95% CI 0.36 to 1.00) and a specificity of 0.71 (95% CI 0.29 to 0.96) (n = 13, 1 study). AUTHORS' CONCLUSIONS: Only one study has used a neuropathological reference standard to assess the accuracy of DAT imaging for the diagnosis of DLB. The small size of the included study means that sensitivity and specificity estimates are imprecise. However, data from this study suggest that DAT imaging is more accurate than clinical diagnosis. Clinical diagnosis is therefore unsuitable to use as a reference standard for assessing the accuracy of DAT imaging.No studies using a neuropathological reference standard have directly addressed the common clinical scenario where the use of DAT imaging is considered as a diagnostic test in a person with possible DLB, or assessed the accuracy of DAT imaging in people with mild dementia. However, the data from the included study suggest that, where there is moderately severe dementia and a strong pre-existing suspicion of DLB (probable DLB), then a normal (123)I-FP-CIT SPECT scan may be an accurate means of excluding the diagnosis.Semiquantitative ratings of (123)I-FP-CIT SPECT scans appeared to be more accurate than visual ratings in all analyses.

Thalamic Involvement in Fluctuating Cognition in Dementia with Lewy Bodies: Magnetic Resonance Evidences.

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.

Characterizing dementia with Lewy bodies by means of diffusion tensor imaging.

OBJECTIVE: To investigate patterns of in vivo white matter tract change using diffusion tensor imaging (DTI), we conducted a cross-sectional study of dementia with Lewy bodies (DLB) in comparison with Alzheimer disease (AD) and normal aging. METHODS: The study included 106 subjects (35 with DLB, 36 with AD, and 35 elderly controls) who underwent clinical and neuropsychological assessment and diffusion tensor MRI. We used tract-based spatial statistics to investigate patterns of reduced fractional anisotropy (FA) and increased mean diffusivity (MD) across the entire white matter tract skeleton and also investigated correlations with clinical features. RESULTS: Areas of reduced FA in subjects with DLB vs controls were found primarily in parieto-occipital white matter tracts; in AD, the changes were much more diffuse. DLB was also associated with reduced FA in the pons and left thalamus, in comparison with AD. The pattern of MD increase was diffuse in AD and DLB. We found an association between DTI parameters and impaired episodic memory, letter fluency, and severity of motor parkinsonism in DLB. CONCLUSIONS: Despite a similar level of dementia severity, patterns of DTI changes in AD and DLB differed significantly. The selective involvement of the visual association areas and subcortical structures and the significant clinical correlations highlight the potential importance of white matter tract change in the pathogenesis of DLB. DTI may be a useful technique to investigate early and possible preclinical changes in DLB and warrants further investigation.

The pedunculopontine nucleus is related to visual hallucinations in Parkinson's disease: preliminary results of a voxel-based morphometry study.

Visual hallucinations (VH) are common in Parkinson's disease (PD) and lead to a poor quality of life. For a long time, dopaminergic therapy was considered to be the most important risk factor for the development of VH in PD. Recently, the cholinergic system, including the pedunculopontine nucleus (PPN), has been implicated in the pathophysiology of VH. The aim of the present study was to investigate grey matter density of the PPN region and one of its projection areas, the thalamus. Thirteen non-demented PD patients with VH were compared to 16 non-demented PD patients without VH, 13 demented PD patients (PDD) with VH and 11 patients with dementia with Lewy bodies (DLB). Isotropic 3-D T1-weighted MRI images (3T) were analysed using voxel-based morphometry (VBM) with the PPN region and thalamus as ROIs. PD and PDD patients with VH showed grey matter reductions of the PPN region and the thalamus compared to PD patients without VH. VH in PD(D) patients are associated with atrophy of the PPN region and its thalamic target area, suggesting that a cholinergic deficit may be involved in the development of VH in PD(D).

[Magnetic resonance imaging with 21.1 T and pathological correlations--diffuse Lewy body disease].

We investigated fixed basal ganglia specimens, including globus pallidus and putamen, with 21.1-Tesla MRI allowing us to achieve a microscopic level resolution from a patient with pathologically confirmed dementia with Lewy bodies (DLB) and a neurologically normal control case. We acquired T2 and T2 * weighted images that demonstrated diffuse and patchy lower intensities in the basal ganglia compared to control. There are several paramagnetic substances in brain tissue that could potentially reduce both T2 and T2 * relaxation times, including ferritin, iron (Fe3+), manganese, copper and others. Because iron is most abundant, low intensities on T2 and T2 * weighted images most likely reflect iron deposition. Iron, especially Fe3+, deposition was visible in the pathological specimens stained with Prussian blue after images were obtained. Although radiological-pathological comparisons are not straightforward with respect to either the MRI signal or relaxation quantification, there appears to be a correlation between the relative increase in iron as assessed by Prussian blue staining and the decrease in T2 * value between the DLB and control specimens. As such, this exceptionally high field MRI technique may provide details about the role that iron deposition plays either directly or indirectly as a biomarker in neurodegenerative processes.

Nerve cells immunoreactive for p62 in select hypothalamic and brainstem nuclei of controls and Parkinson's disease cases.

The protein p62 plays an important role in the proteasomal and/or autophagic clearance of misfolded and aggregation-prone proteins. Immunoreactivity for p62, however, not only characterizes pathological proteinaceous inclusions but also occurs in the form of homogeneous nerve cell labeling in brains of both healthy and diseased individuals, e.g., in the vagal dorsal motor nucleus and other subcortical nuclei. In sporadic Parkinson's disease (PD), the pathological process initially involves preganglionic neurons of the parasympathetic and sympathetic system and probably advances caudo-rostrally from there along the neuroaxis. Since all subsequently affected nuclei (lower raphe nuclei, magnocellular reticular formation, locus coeruleus, and central subnucleus of the amygdala) generate descending projections that terminate in the vagal dorsal motor nucleus and intermediolateral column, it has been conjectured that retrograde axonal transport and transsynaptic transmission of a pathogen contribute to the pathogenesis of PD. The hypothalamic paraventricular nucleus also sends projections to the preganglionic nuclei under consideration and, thus, should belong to the nuclei endangered by the pathological process. However, it remains uninvolved for the duration of the disorder. For this reason, we performed a retrospective study of the relevant nuclei in a cohort of 36 individuals, including 17 with clinically documented PD, one case with incidental Lewy body disease (ILBD), and 18 controls using p62-immunocytochemistry. Remarkably, the neurosecretory cells of the paraventricular nucleus were among the sites showing homogeneous p62-immunolabeling with the greatest consistency. Its p62-immunoreactive profile may indicate that the hypothalamic paraventricular nucleus is somehow capable of effectively metabolizing misfolded proteins and/or preventing their aggregation.

Intralaminar nuclei of the thalamus in Lewy body diseases.

Although the intralaminar thalamus is a target of alpha-synuclein pathology in Parkinson's disease, the degree of neuronal loss in Lewy body diseases has not been assessed. We have used unbiased stereological techniques to quantify neuronal loss in intralaminar thalamic nuclei concentrating alpha-synuclein pathology (the anterodorsal, cucullar, parataenial, paraventricular, central medial, central lateral and centre-median/parafascicular complex) in different clinical forms of Lewy body disease (Parkinson's disease with and without dementia, and dementia with Lewy bodies, N=21) compared with controls (N=5). Associations were performed in the Lewy body cases between intralaminar cell loss and the main diagnostic clinical (parkinsonism, dementia, fluctuation in consciousness, and visual hallucinations) and pathological (Braak stage of Parkinson's disease) features of these diseases, as well as between cell loss and the scaled severity of the alpha-synuclein deposition within the intralaminar thalamus. As expected, significant alpha-synuclein accumulation occurred in the intralaminar thalamus in the cases with Lewy body disease. Pathology concentrated anteriorly and in the central lateral and paraventricular nuclei was related to the Braak stage of Parkinson's disease, ageing, and the presence of dementia. Across all types of Lewy body cases there was substantial atrophy and neuronal loss in the central lateral, cucullar and parataenial nuclei, and neuronal loss without atrophy in the centre-median/parafascicular complex. Cases with visual hallucinations showed a greater degree of atrophy of the cucullar nucleus, possibly due to amygdala denervation. The significant degeneration demonstrated in the intralaminar thalamus is likely to contribute to the movement and cognitive dysfunction observed in Lewy body disorders.

Abnormal levels of prohibitin and ATP synthase in the substantia nigra and frontal cortex in Parkinson's disease.

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.

Thalamic D2 receptors in dementia with Lewy bodies, Parkinson's disease, and Parkinson's disease dementia.

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.

Impaired metabotropic glutamate receptor/phospholipase C signaling pathway in the cerebral cortex in Alzheimer's disease and dementia with Lewy bodies correlates with stage of Alzheimer's-disease-related changes.

The aim of the present work was to analyze the status of metabotropic glutamate receptors (mGluRs) in the frontal cortex (area 8) from ten cases with common form DLB (cDLB) and eleven cases with pure AD in comparison with five age-matched controls. mGluRs, determined by radioligand binding assays, were significantly decreased in cerebral cortex in cDLB. This decrease was already present in cases with early AD changes not involving the frontal cortex, but dramatically correlated with AD neuropathological changes, at its greatest in isocortical stages, which was associated with a decrease in the expression levels of mGluR1 detected by Western blotting. Moreover, mGluRs analyzed in pure AD were lower than those obtained in cDLB and also correlated with progression of illness. On the other hand, the expression levels of phospholipase Cbeta1 (PLCbeta1) isoform, which is the effector of group I mGluRs, was decreased in parallel in cDLB cases. Finally, the PLCbeta1 decrease was associated with reduced GTP- and l-glutamate-stimulated PLC activity in both cDLB and AD cases. These results show that group I mGluRs/PLC signaling are down-regulated and desensitized in the frontal cortex in cDLB and AD cases and that these modifications worsen with progression of AD changes in the cerebral neocortex. Therefore, group I mGluR dysfunction may be implicated in the pathogenesis of cognitive impairment and dementia in common form of DLB and pure AD.

Cholinergic nicotinic receptor involvement in movement disorders associated with Lewy body diseases. An autoradiography study using [(125)I]alpha-conotoxinMII in the striatum and thalamus.

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.

Involvement of alpha6/alpha3 neuronal nicotinic acetylcholine receptors in neuropsychiatric features of Dementia with Lewy bodies: [(125)I]-alpha-conotoxin MII binding in the thalamus and striatum.

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.

Abeta1-42 promotes cholinergic sprouting in patients with AD and Lewy body variant of AD.

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.

Damage to nuclear DNA in Lewy body disease.

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.

Regional brain atrophy in progressive supranuclear palsy and Lewy body disease.

There have been no previous three-dimensional volumetric studies of regional brain atrophy in patients with pathologically confirmed progressive supranuclear palsy (PSP). Postmortem cortical and subcortical volumes were compared with neuropathology in 9 patients with PSP, 15 patients with Parkinson's disease, 10 patients with dementia with Lewy bodies, and 23 controls. Cases with the neuritic pathology of Alzheimer's disease were excluded. The topography of brain atrophy differed according to clinicopathological phenotype. Patients with Parkinson's disease had atrophy confined to the amygdala. Atrophy of the frontal lobe was found in both PSP and dementia with Lewy bodies and correlated with increasing neurofibrillary tangle or Lewy body densities, respectively. Patients with PSP could be differentiated by their marked atrophy of the internal globus pallidus. Further analysis of variance revealed that trends for greater frontal lobe atrophy correlated with clinical dementia in PSP, whereas both greater frontal and hippocampal atrophy and higher densities of Lewy bodies and Lewy neurites correlated with clinical dementia in cases with Lewy bodies. The present study provides evidence for selective regional atrophy that correlates with the underlying pathology of PSP and Lewy body disease.