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We evaluated the association between mini-mental status examination (MMSE) scores proximal to death and the values of 43 different clinical and pathological parameters. Studies were performed using data from 334 elderly, longitudinally evaluated research subjects who had undergone autopsy and satisfied inclusion criteria from an initial study group of 501. Interindividual variance in MMSE scores was used as a surrogate for the severity of cognitive impairment linked to aging (CILA). A statistical linear regression-based model provided a framework for assessing the parameters with significant, direct impact on CILA severity. Strong association between CILA and Alzheimer's disease (AD) pathology, especially isocortical neurofibrillary tangles, was evident. The pattern of association between AD lesion densities with cognitive impairment severity was biologically informative, with neuritic plaques having more impact in relatively high-functioning individuals. Abundant isocortical Lewy bodies tended to be an additive pathology correlating with final MMSE scores approximately 10 points lower. In a subset of cases we found evidence for association between TDP-43-related pathology and CILA severity, independent of AD or hippocampal sclerosis. There was no support for independent association between CILA severity and most evaluated indices including diffuse plaques, argyrophilic grains, heart disease, education level, apolipoprotein E alleles or diabetes.

Brains that have many neurofibrillary tangles (NFTs) in medial temporal lobe structures (Braak stage III or IV) but no cortical neuritic plaques (NPs) may be a diagnostic dilemma; they also raise questions about the amyloid cascade hypothesis of Alzheimer disease (AD) in which NFT development is thought to occur downstream of the development of amyloid plaques. To determine the clinical, demographic, and biological factors related to NFT+/NP- cases, we analyzed 26 NFT+/NP- patient brains identified from the University of Kentucky AD Center autopsy cohort (n=502); most of these patients were at least 85 years old and lacked profound antemortem cognitive impairment. A subset of the cases had NFTs in the medulla oblongata. Aberrant trans-activator regulatory DNA-binding protein 43 immunohistochemical staining was seen in 5 of the 26 cases with the clinical diagnoses of AD or mild cognitive impairment. We also queried cases in the National Alzheimer's Coordinating Center Registry (n=5,108) and found 219 NFT+/NP- cases. Those patients had a relatively high likelihood of belonging to a birth cohort with the highest incidence of influenza infection during the 1918 to 1919 pandemic. This observation may link the pathogenesis in NFT+/NP- cases to encephalitis during childhood. We conclude that NFT+/NP- cases comprise approximately 5% of aged individuals in multiple data sets; these cases are not necessarily within the spectrum of AD.

We studied Alzheimer's disease (AD) pathology in the precuneus and surrounding brain areas. Anatomically, the precuneus corresponds to the medial portion of human cerebral cortical Brodmann Area 7. This study utilized patients from the University of Kentucky Alzheimer's Disease Center autopsy cohort. Data from 47 brains were used comprising patients of differing antemortem cognitive impairment severities, each with longitudinal clinical data and extensive neuropathological data. We assessed whether the precuneus and surrounding areas are differentially vulnerable to AD-type pathological lesions (diffuse amyloid plaques, neuritic amyloid plaques, and neurofibrillary tangles). Eleven areas of brain were evaluated for each case: amygdala, hippocampal CA1, subiculum, entorhinal cortex, frontal cortex, superior and middle temporal gyri, inferior parietal lobule, occipital cortex, posterior cingulate gyrus, Brodmann Area 31, and the precuneus proper. Like other areas of neocortex, the precuneus demonstrated increased diffuse and neuritic amyloid plaques early in the evolution in AD, and increased neurofibrillary tangles late in AD. Correcting for the antemortem cognitive status of the patients, there was no evidence of an increase in the density of AD-type pathology in the precuneus or neighboring areas relative to other areas of cerebral neocortex. Our results are not consistent with the idea that the precuneus is involved in a special way with plaques or tangles relative to other areas of neocortex.

Amnestic mild cognitive impairment (MCI) appears to be a very early stage of Alzheimer's disease (AD). The amyloid-beta peptide (Abeta) is believed to be a possible substrate for AD, but little is currently known about Abeta alterations in MCI and how these changes compare to later stages of disease. In the present study Abeta was differentially extracted from the brains of age-matched control, MCI, and AD cases and compared with plaque counts. For comparison, APPxPS-1 knock-in mice were processed in parallel. We observed that Abeta42 was significantly elevated in MCI subjects, even though there was no significant alteration in the total amount of Abeta. Relative Abeta solubility within the different extractable pools was identical between AD and MCI subjects, with both significantly altered relative to controls. Temporal analysis of Abeta levels and solubility in a knock-in mouse model of Abeta pathogenesis recapitulated many of the salient features observed in AD. Characterization of the SDS fraction showed some similarities between aged knock-in mice and AD subjects. These data suggest that distinct changes in Abeta occur throughout the progression of AD, and that elevations in Abeta42 occur at an early, clinically defined stage.

Background: There is evidence that pain is under detected and undertreated for people with communication difficulties, including people with dementia (Scott et al, 2011 BMC Geriatrics, 11:61). Pain tools exist but there is evidence that they are not used in everyday practice (Manias, E. 2012 International Journal of Nursing Studies 49(10): 1243–1254).Innovation: A group of multidisciplinary clinicians identified a lack of a pain assessment tool for patients with communication difficulties.Observations were carried out on medical and surgical wards which showed that cognitively impaired patients were less likely to be asked about pain.Six existing pain tools were examined in workshops and evaluated for likely ease of use. Three were identified as the most suitable and were trialled on six wards.Each tool was used on two wards and evaluated by nursing and physiotherapy staff, with qualitative and quantitative results. A crossover evaluation was carried out with each ward using a second tool.This showed that pain assessment tools could be used successfully, but practical problems were identified.Evaluation: Using these results a Bolton Pain Assessment Tool (BPAT) was devised which combined elements from the other tools as well as prompts to ask carers' opinions. BPAT was well received and used across the hospital. BPAT was then trialled at another hospital in four clinical areas. All staff agreed that it was easy and quick to use. Family involvement was limited but relevant. Nurses administered analgesia in 76% of cases. Staff rated the scale as a median of 8/10 and the majority rated it as better than other pain assessment tools.Conclusions: A multidisciplinary collaborative approach enabled the development of a Pain Tool that was effective and easy to use. Using a pain tool leads to increased interventions from the nursing staff. [ABSTRACT FROM PUBLISHER]