Development and validation of a frailty index for use in the osteoarthritis initiative.

BACKGROUND: The Osteoarthritis Initiative (OAI) evaluates the development and progression of osteoarthritis. Frailty captures the heterogeneity in aging. Use of this resource-intensive dataset to answer aging-related research questions could be enhanced by a frailty measure. OBJECTIVE: To: (i) develop a deficit accumulation frailty index (FI) for the OAI; (ii) examine its relationship with age and compare between sexes, (iii) validate the FI versus all-cause mortality and (iv) compare this association with mortality with a modified frailty phenotype. DESIGN: OAI cohort study. SETTING: North America. SUBJECTS: An FI was determined for 4,755/4,796 and 4,149/4,796 who had a valid FI and frailty phenotype. METHODS: Fifty-nine-variables were screened for inclusion. Multivariate Cox regression evaluated the impact of FI or phenotype on all-cause mortality at follow-up (up to 146 months), controlling for age and sex. RESULTS: Thirty-one items were included. FI scores (0.16 ± 0.09) were higher in older adults and among females (both, P < 0.001). By follow-up, 264 people had died (6.4%). Older age, being male, and greater FI were associated with a higher risk of all-cause mortality (all, P < 0.001). The model including FI was a better fit than the model including the phenotype (AIC: 4,167 vs. 4,178) and was a better predictor of all-cause mortality than the phenotype with an area under receiver operating characteristic curve: 0.652 vs. 0.581. CONCLUSION: We developed an FI using the OAI and validated it in relation to all-cause mortality. The FI may be used to study aging on clinical, functional and structural aspects of osteoarthritis included in the OAI.

Neuropathology and cholinesterase expression in the brains of octogenarians and older.

A subset of octogenarians and older maintain normal cognitive function (CNOO) despite high prevalence and incidence of cognitive decline attributed to neurodegeneration or aging in the population. The rostral prefrontal cortex (rPFC) and hippocampal formation are brain regions integral to cognition, namely attention and memory, facilitated in part by cholinergic innervation. We hypothesized that preserved cholinergic neurotransmission in these regions contributes to intact cognition in the CNOO. To test this, we evaluated the burden of neuropathological and cholinesterase-associated protein aggregates in the rPFC and hippocampal formation. Tissues from age- and sex-matched CNOO and Alzheimer's disease (AD) rPFC and hippocampal formation were stained for ß-amyloid (Aß), tau, α-synuclein, phosphorylated TAR DNA-binding protein 43 (pTDP-43), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). The relative abundance of neuropathological aggregates was semi-quantitatively scored. Deposition of Aß plaques, tau neurofibrillary tangles (NFT) and pTDP-43 inclusions were comparable between CNOO and AD cases. Intraneuronal Aß and tau-positive thorny astrocytes consistent with aging-related tau astrogliopathy, were also noted in the rPFC. Abundance of BChE-positive plaque pathology was significantly higher in AD than in CNOO cases in most regions of interest, followed closely by abundance of AChE-positive plaque pathology. BChE and AChE activities were also associated with varied NFT morphologies. CNOO cases maintained cognition despite a high neuropathological burden in the rPFC and hippocampal formation. BChE-positive and, to a lesser extent, AChE-positive pathologies were significantly lower in most regions in the CNOO compared to AD. This suggests a specificity of cholinesterase-associated neuropathology with AD. We conclude that while CNOO have cholinesterase-associated neuropathology in the rPFC and hippocampal formation, abundance in this population is significantly lower compared to AD which may contribute to their intact cognition.

Clinical and neuropathological variability in the rare IVS10 + 14 tau mutation.

Mutations in the microtubule-associated protein tau gene are known to cause progressive neurodegenerative disorders with variable clinical and neuropathological phenotypes, including the intronic 10 + 14 (IVS10 + 14) splice site mutation. Three families have been reported with the IVS10 + 14 microtubule-associated protein tau mutation. Here, we describe the clinical and neuropathological data from an additional family. Neuropathological data were available for 2 of the 3 cases, III-4, and III-5. While III-5 had widespread tau deposition and atrophy, III-4 exhibited more mild neuropathological changes except for the substantia nigra. The previously reported families that express the IVS10 + 14 mutation exhibited significant interfamilial heterogeneity, with symptoms including amyotrophy, dementia, disinhibition, parkinsonism, and breathing problems. In addition to expressing many of these symptoms, members of this fourth family experienced profound sensory abnormalities and sleep disturbance. Although there were probable clinicopathological correlates for the symptoms expressed by the earlier families and III-5 from our cohort, pathology in III-4 did not appear sufficient to explain symptom severity. This indicates the need to explore alternate mechanisms of tau-induced brain dysfunction.

Quantification of Butyrylcholinesterase Activity as a Sensitive and Specific Biomarker of Alzheimer's Disease.

Amyloid-ß (Aß) plaques are a neuropathological hallmark of Alzheimer's disease (AD); however, a significant number of cognitively normal older adults can also have Aß plaques. Thus, distinguishing AD from cognitively normal individuals with Aß plaques (NwAß) based on Aß plaque detection is challenging. It has been observed that butyrylcholinesterase (BChE) accumulates in plaques preferentially in AD. Thus, detecting BChE-associated plaques has the potential as an improved AD biomarker. We present Aß, thioflavin-S, and BChE quantification of 26 postmortem brain tissues; AD (n = 8), NwAß (n = 6), cognitively normal without plaques (n = 8), and other common dementias including corticobasal degeneration, frontotemporal dementia with tau, dementia with Lewy bodies, and vascular dementia. Pathology burden in the orbitofrontal cortex, entorhinal cortex, amygdala, and hippocampal formation was determined and compared. The predictive value of Aß and BChE quantification was determined, via receiver-operating characteristic plots, to evaluate their AD diagnostic performance using sensitivity, specificity, and area under curve (AUC) metrics. In general, Aß and BChE-associated pathology were greater in AD, particularly in the orbitofrontal cortex. In this region, the largest increase (9.3-fold) was in BChE-associated pathology, observed between NwAß and AD, due to the virtual absence of BChE-associated plaques in NwAß brains. Furthermore, BChE did not associate with pathology of the other dementias. In this sample, BChE-associated pathology provided better diagnostic performance (AUC = 1.0, sensitivity/specificity = 100% /100%) when compared to Aß (AUC = 0.98, 100% /85.7%). These findings highlight the predictive value of BChE as a biomarker for AD that could facilitate timely disease diagnosis and management.