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1.  Alpha-synucleinopathy and neuropsychological symptoms in a population-based cohort of the elderly 
Introduction
Studies with strong selection biases propose that alpha-synucleinopathy (AS) spreads upwards and downwards in the neuraxis from the medulla, that amygdala-dominant AS is strongly associated with Alzheimer’s disease (AD), and that a more severe involvement of the cerebral cortex is correlated with increasing risk of dementia. This study examines the association of AS patterns and observed neuropsychological symptoms in brains of a population-representative donor cohort.
Methods
Brains donated in 2 out of 6 cognitive function and ageing study cohorts (Cambridgeshire and Nottingham) were examined. Over 80% were >80 years old at death. The respondents were evaluated prospectively in life for cognitive decline and dementia. Immunocytochemistry for tau and alpha-synuclein (using LB509 by Zymed Laboratories) was carried out in 208 brains to establish Braak stage and the pattern and severity of AS following the dementia with Lewy bodies (DLB) consensus recommendations. Dementia, specific neuropsychological measures as measured using the Cambridge cognitive examination, the presence of hallucinations and Parkinson’s disease were investigated.
Results
Four patterns of AS were observed: no AS pathology (n = 92), AS pathology following the DLB consensus guidelines (n = 33, of which five were ‘neocortical’), amygdala-predominant AS (n = 18), and other AS patterns (n = 33). Each group was subdivided according to high/low neurofibrillary tangles (NFT) Braak stage. Results showed no association between dementia and these patterns of AS, adjusting for the presence of NFT or not. The risk of visual hallucinations shows a weak association with AS in the substantia nigra (odds ratio (OR) = 3.2; 95% confidence interval (CI) 0.5 to 15.5; P = 0.09) and amygdala (OR = 3.0; 95% CI 0.7 to 12.3; P = 0.07). The analysis is similar for auditory hallucinations in subcortical regions.
Conclusions
Among the whole population of older people, AS does not increase the risks for dementia, irrespective of Braak stage of NFT pathology. There was no evidence that the pattern of AS pathology in cortical areas was relevant to the risk of hallucination. In general, the hypothesis that AS as measured using these methods per se is a key determinant of cognitive clinical phenotypes is not supported.
doi:10.1186/s13195-015-0101-x
PMCID: PMC4394405  PMID: 25870655
2.  Vascular health, diabetes, APOE and dementia: the Aging, Demographics, and Memory Study 
Introduction
Evidence from clinical samples and geographically limited population studies suggests that vascular health, diabetes and apolipoprotein ε4 (APOE) are associated with dementia.
Methods
A population-based sample of 856 individuals aged 71 years or older from all contiguous regions of the United States received an extensive in-home clinical and neuropsychological assessment in 2001-2003. The relation of hypertension, diabetes, heart disease, stroke, medication usage, and APOE ε4 to dementia was modelled using adjusted multivariable logistic regression.
Results
Treated stroke (odds ratio [OR] 3.8, 95% confidence interval [CI] 2.0, 7.2), untreated stroke (OR 3.5, 95% CI 1.7, 7.3), and APOE ε4 (OR 2.8, 95% CI 1.7, 4.5) all increased the odds of dementia. Treated hypertension was associated with lower odds of dementia (OR 0.5, 95% CI 0.3, 1.0). Diabetes and heart disease were not significantly associated with dementia. A significant interaction was observed between APOE ε4 and stroke (P = 0.001).
Conclusions
Data from the first dementia study that is representative of the United States population suggest that stroke, the APOE ε4 allele and their interaction are strongly associated with dementia.
doi:10.1186/alzrt43
PMCID: PMC2919699  PMID: 20576093
3.  Beyond mild cognitive impairment: vascular cognitive impairment, no dementia (VCIND) 
Identifying the causes of dementia is important in the search for effective preventative and treatment strategies. The concept of mild cognitive impairment (MCI), as prodromal dementia, has been useful but remains controversial since in population-based studies it appears to be a limited predictor of progression to dementia. Recognising the relative contribution of neurodegenerative and vascular causes, as well as their interrelationship, may enhance predictive accuracy. The concept of vascular cognitive impairment (VCI) has been introduced to describe the spectrum of cognitive change related to vascular causes from early cognitive decline to dementia. A recent review of this concept highlighted the need for diagnostic criteria that encompass the full range of the VCI construct. However, very little is known regarding the mildest stage of VCI, generally termed 'vascular cognitive impairment, no dementia' (VCIND). Whether mild cognitive change in the context of neurodegenerative pathologies is distinct from that in the context of cerebrovascular diseases is not known. This is key to the definition of VCIND and whether it is possible to identify this state. Distinguishing between vascular (that is, VCIND) and non-vascular (that is, MCI) cognitive disorders and determining how well each might predict dementia may not be possible due to the overlap in pathologies observed in the older population. Here, we review the concept of VCIND in an effort to identify recent developments and areas of controversy in nosology and the application of VCIND for screening individuals at increased risk of dementia secondary to vascular disease and its risk factors.
doi:10.1186/alzrt4
PMCID: PMC2719105  PMID: 19674437

Results 1-3 (3)