McKeith, IG. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the Consortium on DLB International Workshop. J Alzheimers Dis 9(3 Suppl): 417-423
Dementia with Lewy bodies (DLB) was considered to be an uncommon cause of dementia until improved neuropathological staining methods for ubiquitin were developed in the late 1980's. Subsequent recognition that 10-15% of dementia cases in older people were associated with Lewy body pathology led to the publication in 1996 of Consensus clinical and pathological diagnostic criteria for the disorder. These have greatly raised global awareness of DLB and helped to generate a body of knowledge which informs modern clinical management of this pharmacologically sensitive group of patients. They have also enabled important issues surrounding the relationships of DLB with Alzheimer's disease and Parkinson's disease to be addressed and partially resolved. A recent re-evaluation of the Consensus criteria has confirmed many aspects of the original recommendations, supplementing these with suggestions for improved pathological characterisation, clinical detection and management. Virtu-ally unrecognised 20 years ago, DLB could within this decade be one of the best characterised and potentially treatable neurodegenerative disorders of late life.
"In addition, magnetic resonance imaging or computed tomography scanning showing either a normal picture or atrophy, no more than one clinically silent infarction , and no more than mild white matter lesion were required for a diagnosis of pure AD. Vascular dementia was diagnosed according to the Alzheimer's Disease Diagnostic and Treatment Center (ADDTC) core criteria , frontotemporal dementia according to the McKhann criteria  and Lewy body dementia according to the McKeith criteria . A diagnosis of mixed dementia was made when both AD and cerebrovascular disease were considered to contribute to dementia. "
[Show abstract][Hide abstract] ABSTRACT: Objective:
To study the association between self-reported sleep disturbances and dementia risk.
Self-reported sleep disturbances and established risk factors for dementia were measured in men at ages 50 (n = 1574) and 70 (n = 1029) years. Dementia incidence was determined by reviewing their patient history between ages 50 and 90 years. In addition, plasma levels of β-amyloid (Aβ) peptides 1-40 and 1-42 were measured at ages 70, 77, and 82 years.
Cox regression demonstrated that men with self-reported sleep disturbances had a higher risk of developing dementia (+33%) and Alzheimer's disease (AD, +51%) than men without self-reported sleep disturbances (both P < .05). Binary logistic regression showed the increased risk for both dementia (+114%) and AD (+192%) were highest when sleep disturbance was reported at age 70 years (both P < .001). No group differences were found in Aβ levels.
Improving sleep quality may help reduce the neurodegenerative risk in older men.
Alzheimer's & dementia: the journal of the Alzheimer's Association 09/2015; 11(9):1090-7. DOI:10.1016/j.jalz.2014.08.104 · 12.41 Impact Factor
"SVD was diagnosed in accordance with National Institute of Neurological Disorders and Stroke- Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS- AIREN) criteria (Roman et al., 1993) and imaging criteria proposed by Erkinjuntti (2002). Other types of dementia were diagnosed using McKeith criteria for dementia with Lewy bodies (DLB) (McKeith et al., 1996) and the Lund and Manchester criteria for frontotemporal dementia (FTD) (The Lund and Manchester Groups, 1994). Onset of dementia was marked as the date on which the clinical symptoms and neuropsychological findings first allowed the diagnosis of dementia to be made. "
[Show abstract][Hide abstract] ABSTRACT: Cerebral white matter hyperintensities (WMH) are prevalent incident findings on brain MRI scans among elderly people and have been consistently implicated in cognitive dysfunction. However, differential roles of WMH by region in cognitive function are still unclear. The aim of this study was to ascertain the differential role of regional WMH in predicting progression from mild cognitive impairment (MCI) to different subtypes of dementia.
Participants were recruited from the Clinical Research Center for Dementia of South Korea (CREDOS) study. A total of 622 participants with MCI diagnoses at baseline and follow-up evaluations were included for the analysis. Initial MRI scans were rated for WMH on a visual rating scale developed for the CREDOS. Differential effects of regional WMH in predicting incident dementia were evaluated using the Cox proportional hazards model.
Of the 622 participants with MCI at baseline, 139 patients (22.3%) converted to all-cause dementia over a median of 14.3 (range 6.0-36.5) months. Severe periventricular WMH (PWMH) predicted incident all-cause dementia (Hazard ratio (HR) 2.22; 95% confidence interval (CI) 1.43-3.43) and Alzheimer's disease (AD) (HR 1.86; 95% CI 1.12-3.07). Subcortical vascular dementia (SVD) was predicted by both PWMH (HR 16.14; 95% CI 1.97-132.06) and DWMH (HR 8.77; 95% CI 1.77-43.49) in more severe form (≥ 10 mm).
WMH differentially predict dementia by region and severity. Our findings suggest that PWMH may play an independent role in the pathogenesis of dementia, especially in AD.
International Psychogeriatrics 07/2015; -1:1-9. DOI:10.1017/S1041610215001076 · 1.93 Impact Factor
"While in AD abnormal accumulation of misfolded amyloid-β protein (Aβ) in the neocortex and limbic system is responsible for the neurodegenerative pathology [2,3], in PD accumulation and propagation of α-synuclein (α-syn) has been centrally implicated in this condition [4-6]. The pathogenesis of AD and PD overlap in a heterogeneous group of conditions denominated jointly as Lewy body disease (LBD) [7,8], which includes dementia with Lewy bodies (DLB), Parkinson’s disease with dementia (PDD) and idiopathic PD (iPD). Direct and indirect interactions between α-syn and Aβ play a role in the pathogenesis of LBD [9-13]. "
[Show abstract][Hide abstract] ABSTRACT: Background
In dementia with Lewy bodies (DLB) abnormal interactions between α-synuclein (α-syn) and beta amyloid (Aβ) result in selective degeneration of neurons in the neocortex, limbic system and striatum. However, factors rendering these neurons selectively vulnerable have not been fully investigated. The metabotropic glutamate receptor 5 (mGluR5) has been shown to be up regulated in DLB and might play a role as a mediator of the neurotoxic effects of Aβ and α-syn in vulnerable neuronal populations. In this context, the main objective of the present study was to investigate the role of mGluR5 as a mediator of the neurotoxic effects of α-syn and Aβ in the hippocampus.
We generated double transgenic mice over-expressing amyloid precursor protein (APP) and α-syn under the mThy1 cassette and investigated the relationship between α-syn cleavage, Aβ, mGluR5 and neurodegeneration in the hippocampus. We found that compared to the single tg mice, the α-syn/APP tg mice displayed greater accumulation of α-syn and mGluR5 in the CA3 region of the hippocampus compared to the CA1 and other regions. This was accompanied by loss of CA3 (but not CA1) neurons in the single and α-syn/APP tg mice and greater loss of MAP 2 and synaptophysin in the CA3 in the α-syn/APP tg. mGluR5 gene transfer using a lentiviral vector into the hippocampus CA1 region resulted in greater α-syn accumulation and neurodegeneration in the single and α-syn/APP tg mice. In contrast, silencing mGluR5 with a lenti-shRNA protected neurons in the CA3 region of tg mice. In vitro, greater toxicity was observed in primary hippocampal neuronal cultures treated with Aβ oligomers and over-expressing α-syn; this effect was attenuated by down-regulating mGluR5 with an shRNA lentiviral vector. In α-syn-expressing neuronal cells lines, Aβ oligomers promoted increased intracellular calcium levels, calpain activation and α-syn cleavage resulting in caspase-3-dependent cell death. Treatment with pharmacological mGluR5 inhibitors such as 2-Methyl-6-(phenylethynyl)pyridine (MPEP) and 3-((2-Methyl-4-thiazolyl)ethynyl)pyridine (MTEP) attenuated the toxic effects of Aβ in α-syn-expressing neuronal cells.
Together, these results support the possibility that vulnerability of hippocampal neurons to α-syn and Aβ might be mediated via mGluR5. Moreover, therapeutical interventions targeting mGluR5 might have a role in DLB.
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