Lewy Body Disease Dementia Research Articles

Association of β-Amyloid and Basal Forebrain With Cortical Thickness and Cognition in Alzheimer and Lewy Body Disease Spectra.

Cholinergic degeneration and β-amyloid contribute to brain atrophy and cognitive dysfunction in Alzheimer disease (AD) and Lewy body disease (LBD), but their relationship has not been comparatively evaluated. In this cross-sectional study, we recruited 28 normal controls (NC), 55 patients with AD mild cognitive impairment (MCI), 34 patients with AD dementia, 28 patients with LBD MCI, and 51 patients with LBD dementia. Participants underwent cognitive evaluation, brain MRI to measure the basal forebrain (BF) volume and global cortical thickness (CTh), and 18F-florbetaben (FBB) PET to measure the standardized uptake value ratio (SUVR). Using general linear models and path analyses, we evaluated the association of FBB-SUVR and BF volume with CTh or cognitive dysfunction in the AD spectrum (AD and NC) and LBD spectrum (LBD and NC), respectively. Covariates included age, sex, education, deep and periventricular white matter hyperintensities, intracranial volume, hypertension, diabetes, and hyperlipidemia. BF volume mediated the association between FBB-SUVR and CTh in both the AD and LBD spectra, while FBB-SUVR was associated with CTh independently of BF volume only in the LBD spectrum. Significant correlation between voxel-wise FBB-SUVR and CTh was observed only in the LBD group. FBB-SUVR was independently associated with widespread cognitive dysfunction in both the AD and LBD spectra, especially in the memory domain (standardized beta [B] for AD spectrum = -0.60, B for LBD spectrum = -0.33). In the AD spectrum, BF volume was associated with memory dysfunction (B = 0.18), and CTh was associated with language (B = 0.21) and executive (B = 0.23) dysfunction. In the LBD spectrum, however, BF volume and CTh were independently associated with widespread cognitive dysfunction. There is a common β-amyloid-related degenerative mechanism with or without the mediation of BF in the AD and LBD spectra, while the association of BF atrophy with cognitive dysfunction is more profound and there is localized β-amyloid-cortical atrophy interaction in the LBD spectrum.

A soluble tau fragment generated by caspase-2 is associated with dementia in Lewy body disease

Lewy body diseases are neurodegenerative disorders characterized by Lewy bodies in the brain. Lewy body dementia (LBD) refers to two forms of Lewy body disease: Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB). Tau is a cytoskeletal protein found in neurofibrillary tangles, but not Lewy bodies. The gene encoding tau, MAPT, is a well-established genetic risk factor for LBD; odds ratios of the H1:H2 MAPT haplotypes have been reported in the range of 2 to 4. Despite this genetic association, the mechanism by which tau contributes to dementia is unclear. Recently, a soluble form of tau, Δtau314, which is generated when caspase-2 (Casp2) cleaves tau at Asp314, was reported to be associated with impaired cognition in mice modeling frontotemporal dementia, and with mild cognitive impairment and Alzheimer’s disease (AD) in humans. To investigate whether Δtau314 is associated with dementia in Lewy body disease, we compared Δtau314 levels in aqueous extracts from the superior temporal gyrus of pathologically confirmed LBD (n = 21) and non-dementia Parkinson’s disease (PD) (n = 12). We excluded subjects with AD or microvascular pathology, which could mask potential associations of Δtau314 with LBD.Using a Δtau314-specific ELISA, we found ~ 2-fold higher levels of Δtau314 in LBD relative to PD (p = 0.009). Additionally, we found ~40% lower levels of soluble total tau and the neuronal marker β-III-tubulin in LBD. These results suggest that in LBD, there is substantial neuron loss or axonal degeneration in the neocortex but disproportionately high levels of Δtau314 in the surviving neurons.Our results indicate an association between Δtau314 and dementia in Lewy body disease. Cleavage of tau by Casp2 promotes the mislocalization of tau to dendritic spines leading to a reduction in postsynaptic AMPA receptors and excitatory neurotransmission, which suggests a mechanism of the synaptic dysfunction underlying cognitive impairment in LBD. These findings support the potential of Casp2 as a novel drug target for treating LBD.

Cortical Lewy bodies and Aβ burden are associated with prevalence and timing of dementia in Lewy body diseases.

Our main objective was to determine the neuropathological correlates of dementia in patients with Lewy body disease (LBD). Furthermore, we used data derived from clinical, neuropathological and genetic studies to investigate boundary issues between Dementia with Lewy bodies (DLB) and Parkinson's disease with (PDD) and without (PDND) dementia. One hundred and twenty-one cases with a neuropathological diagnosis of LBD and clinical information on dementia status were included in the analysis (55 PDD, 17 DLB and 49 PDND). We carried out topographical and semi-quantitative assessment of Lewy bodies (LB), Aβ plaques and tau-positive neuropil threads (NT). The APOE genotype and MAPT haplotype status were also determined. The cortical LB (CLB) burden was the only independent predictor of dementia (OR: 4.12, P < 0.001). The total cortical Aβ plaque burden was an independent predictor of a shorter latency to dementia from onset of motor signs (P = 0.001). DLB cases had a higher LB burden in the parietal and temporal cortex, compared to PDD. Carrying at least one APOE ϵ4 allele was associated with a higher cortical LB burden (P = 0.02), particularly in the neocortical frontal, parietal and temporal regions. High CLB burden is a key neuropathological substrate of dementia in LBD. Elevated cortical LB pathology and Aβ plaque deposition are both correlated with a faster progression to dementia. The higher CLB load in the temporal and parietal regions, which seems to be a distinguishing feature of DLB, may account for the shorter latency to dementia and could be mediated by the APOE ϵ4 allele.

Visuo-cognitive skill deficits in Alzheimer's disease and Lewy body disease: A comparative analysis.

Dementia is a chronic neurodegenerative disorder characterized by progressive cognitive loss. Alzheimer's disease (AD) and the Lewy body disease are the two most common causes of age-related degenerative dementia. Visuo-cognitive skills are a combination of very different cognitive functions being performed by the visual system. These skills are impaired in both AD and dementia with Lewy bodies (DLB). The aim of this review is to evaluate various studies for these visuo-cognitive skills. An exhaustive internet search of all relevant medical databases was carried out using a series of key-word applications, including The Cochrane Library, MEDLINE, PSYCHINFO, EMBASE, CINAHL, AMED, SportDiscus, Science Citation Index, Index to Theses, ZETOC, PEDro and occupational therapy (OT) seeker and OT search. We reviewed all the articles until March 2013 with key words of: Visual skills visual cognition dementia AD, but the direct neurobiological etiology is difficult to establish., Dementia of Lewy body disease. Although most studies have used different tests for studying these abilities, in general, these tests evaluated the individual's ability of (1) visual recognition, (2) visual discrimination, (3) visual attention and (4) visuo-perceptive integration. Performance on various tests has been evaluated for assessing these skills. Most studies assessing such skills show that these skills are impaired in DLB as compared with AD. Visuo-cognitive skills are impaired more in DLB as compared with AD. These impairments have evident neuropathological correlations, but the direct neurobiological etiology is difficult to establish.

EPA-0409 – Depression, incidental lewy body disease and pure psychiatric presentation of the lewy body disease

Introduction Parkinson's disease (PD), PD dementia (PDD) and dementia with Lewy body (DLB), collectively termed Lewy body disease (LBD), characterize an array of emotional, neurobehavioral and cognitive symptoms. Pure psychiatric presentation (PPP) of LBD is the fourth subtype of LBD in which psychiatric symptoms lasted for many years in the absence of neurological disturbance. Aims The aim of this study is to localize the PPP and its clinical characteristics in subjects with low uptake of myocardial metaiodobenzylguanidine (MIBG) study. Methods Sixty MIBG-verified patients (28 women and 32 men) were grouped into three psychiatric pictures; depression (group D: 27 patients), isolated visual hallucinations (group V: 16 patients) and psychotic picture (group P: 17 patients). Fifty six cases were examined with cerebral single photon emission tomography study. Thirty-seven cases had hypoperfusion regions and 19 cases showed no abnormality. Final diagnoses of PD, PDD, DLB and PPP were evaluated with an aid of DSM-IV-TR, UPDRS part III, the Hoehn and Yahr Scale, MMSE and the movement disorder society task force diagnostic criteria. Results Three clusters, PDD and Group P, DLB and Group V, and Group D and PPP-PD were found significantly with correspondence analysis. UPDRS average score showed negative correlation with average MMSE scores. All patients with PPP and majority of patients with PD featured depression. Conclusions PPP subjects are considered to be incidental LBD or depression of pre-motor PD. Psychotic parkinsonian features contributed highly to dementia of LBD, and visual hallucination was closely associated with DLB.

Neprilysin Activity in Cerebrospinal Fluid is Associated with Dementia and Amyloid-β42 Levels in Lewy Body Disease

Lewy body disease, defined by the occurrence of α-synuclein aggregates as fibrils in Lewy bodies and Lewy neurites, is associated with increased probabilities for both co-occurrence of dementia, and co-occurrence of Alzheimer's disease (AD)-like pathology, in particular amyloid-β (Aβ) plaques and lowered cerebrospinal fluid (CSF) Aβ42 levels. Not surprisingly, in patients with Lewy body disease patients, there is a strong association between dementia and Aβ pathology. Neprilysin (NEP) is an Aβ-degrading protein found at presynaptic terminals and in body fluids. Reduced CSF NEP activity levels have been shown to occur in early AD, suggesting that altered CSF NEP activity levels may also be associated with dementia and lowered CSF Aβ42 levels in Lewy body disease. Hypothesizing a relation between CSF NEP activity and dementia in Lewy body disease, we determined CSF and serum NEP activity, and Aβ42 levels of 41 demented Lewy body disease patients, 38 non-demented Lewy body disease patients, and of 23 elderly controls. Demented Lewy body disease patients had lowered CSF NEP activity levels (0.3 pmol/min*ml, 0.2-81.5), compared to both non-demented Lewy body disease subjects (8.5 pmol/min*ml, 0.2-87.2; p=0.004) and controls (21.5 pmol/ml*min, 0.15-413.4; p=0.02). In addition, CSF NEP activity levels correlated positively with CSF Aβ42 levels (Rho=0.28, p=0.008) which was not explained by the presence or absence of ApoE4. Serum NEP activity levels were not significantly different between the groups. We conclude that, in Lewy body disease, CSF NEP activity levels are associated with dementia, probably via the Aβ pathway.

Cognition, language, and clinical pathological features of non-Alzheimer's dementias: An overview

There are many distinct forms of dementia whose pharmacological and behavioral management differ. Differential diagnosis among the dementia variants currently relies upon a weighted combination of genetic and protein biomarkers, neuroanatomical integrity, and behavior. Diagnostic specificity is complicated by a high degree of overlap in the initial presenting symptoms across dementia subtypes. For this reason, reliable markers are of considerable diagnostic value. Communication disorders have proven to be among the strongest predictors for discriminating among dementia subtypes. As such, speech-language pathologists may be poised to make an increasingly visible contribution to dementia diagnosis and its ongoing management. The value and durability of this potential contribution, however, demands an improved discipline-wide knowledge base about the unique features associated with different dementia variants. To this end we provide an overview of cognition, language, and clinical pathological features of four of the most common non-Alzheimer's dementias: frontotemporal dementia, vascular dementia, Lewy body disease dementia, and Parkinson's disease dementia. Learning outcomes: Readers will learn characteristics and distinguishing features of several non-Alzheimer's dementias, including Parkinson's disease dementia, frontotemporal dementia, vascular dementia, and Lewy body dementia. Readers will also learn to distinguish between several variants of frontotemporal dementia. Finally, readers will gain knowledge of the term primary progressive aphasia as it relates to the aforementioned dementia etiologies.

The CST3 BB Genotype and Low Cystatin C Cerebrospinal Fluid Levels are Associated with Dementia in Lewy Body Disease

A large proportion of demented Lewy body disease patients have Alzheimer's disease (AD)- like pathology, in particular amyloid-beta (Abeta) plaques. Cystatin C (CysC) is a carrier of soluble Abeta (42) in the cerebrospinal fluid (CSF) and reduces Abeta plaque formation. The CST3 BB genotype leads to a reduced secretion of the protein in vitro and increases the risk for AD, suggesting that variability in the CST3 gene and CysC protein concentration may be associated with dementia in Lewy body disease. We therefore determined the CST3 genotype in 51 demented and 71 nondemented Lewy body disease patients, and in 52 controls, as well as CSF CysC and Abeta (42) levels from 132 of these subjects. The CST3 BB genotype was associated with lowered CSF CysC levels and with dementia. Demented Lewy body disease patients had decreased CSF CysC levels. The correlation between CSF CysC and Abeta (42) levels was high in non-demented subjects, but poor in demented patients. We conclude that, in Lewy body disease, the CST3 BB genotype and low CSF CysC levels are associated with dementia, possibly through a disturbed elimination of soluble Abeta(42).

The role of peroxiredoxins in ischemia-reperfusion-induced cardiac damage

myocardial ischemia related to infarction is a disease of multiple pathways with variable outcomes. Both ischemia and reperfusion contribute to cell and tissue damage after cardiac infarction. Myocardial ischemia-reperfusion initiates maldistribution of ions and various signaling mechanisms, leading

Frontal cortical synaptophysin in Lewy body diseases: relation to Alzheimer’s disease and dementia

OBJECTIVESDementia in Alzheimer’s disease correlates closely with loss of neocortical synapses. Similar synaptic loss has been shown in patients whose Alzheimer’s disease is also associated with neocortical and brain stem...

Amyloid beta-peptide and its relationship with dementia in Lewy body disease.

Cerebral cortical Lewy bodies occur in a spectrum of clinical syndromes including Parkinson's disease (PD) with and without dementia, and dementing conditions clinically resembling Alzheimer's disease with few or without parkinsonian features. It is unclear whether these conditions are variants of one disease process or represent pathogenetically distinct entities. Here we compared the cortical pathology in post mortem brains of three groups representing the predominant clinical phenotypes of Lewy body disease, including 27 non-demented cases of PD, 23 demented PD cases, and 11 cases of Lewy body disease who initially presented with dementia and showed only limited features of parkinsonism during the course of their illness. In addition to neuropathology, computer-assisted histoblot analysis was used to assess cortical amyloid beta-peptide deposition. There was wide overlap of the pathomorphometric features between the two groups of demented cases. It appears that substantial cortical Alzheimer-type pathology present in most demented cases contributes significantly to the development of dementia in Lewy body disease.