Synergism between fornix microstructure and beta amyloid accelerates memory decline in clinically normal older adults.

The fornix is the primary efferent white matter tract of the hippocampus and is implicated in episodic memory. In this study, we investigated whether baseline measures of altered fornix microstructure and elevated beta amyloid (Aß) burden influence prospective cognitive decline. A secondary goal examined whether Aß burden is negatively associated with fornix microstructure. 253 clinically normal older adults underwent diffusion-weighted imaging and Pittsburgh Compound B positron emission tomography at baseline. We applied a novel streamline tractography protocol to reconstruct a fornix bundle in native space. Cognition was measured annually in domains of episodic memory, executive function, and processing speed (median follow-up = 4.0 ± 1.4 years). After controlling for covariates, linear mixed-effects models demonstrated an interaction of fornix microstructure with Aß burden on episodic memory, such that combined lower fornix microstructure and higher Aß burden was associated with accelerated decline. By contrast, associations with executive function and processing speed were not significant. There was no cross-sectional association between Aß burden and fornix microstructure. In conclusion, altered fornix microstructure may accelerate memory decline in preclinical Alzheimer's disease.

Global White Matter Diffusion Characteristics Predict Longitudinal Cognitive Change Independently of Amyloid Status in Clinically Normal Older Adults.

White matter degradation has been proposed as one possible explanation for age-related cognitive decline. In the present study, we examined 2 main questions: 1) Do diffusion characteristics predict longitudinal change in cognition independently or synergistically with amyloid status? 2) Are the effects of diffusion characteristics on longitudinal cognitive change tract-specific or global in nature? Cognitive domains of executive function, episodic memory, and processing speed were measured annually (mean follow-up = 3.93 ± 1.25 years). Diffusion tensor imaging and Pittsburgh Compound-B positron emission tomography were performed at baseline in 265 clinically normal older adults (aged 63-90). Tract-specific diffusion was measured as the mean fractional anisotropy (FA) for 9 major white matter tracts. Global diffusion was measured as the mean FA across the 9 white matter tracts. Linear mixed models demonstrated independent, rather than synergistic, effects of global FA and amyloid status on cognitive decline. After controlling for amyloid status, lower global FA was associated with worse longitudinal performance in episodic memory and processing speed, but not executive function. After accounting for global FA, none of the individual tracts predicted a significant change in cognitive performance. These findings suggest that global, rather than tract-specific, diffusion characteristics predict longitudinal cognitive decline independently of amyloid status.

Connectome-derived diffusion characteristics of the fornix in Alzheimer's disease.

The fornix bundle is a major white matter pathway of the hippocampus. While volume of the hippocampus has been a primary imaging biomarker of Alzheimer's disease progression, recent research has suggested that the volume and microstructural characteristics of the fornix bundle connecting the hippocampus could add relevant information for diagnosing and staging Alzheimer's disease. Using a robust fornix bundle isolation technique in native diffusion space, this study investigated whether diffusion measurements of the fornix differed between normal older adults and Alzheimer's disease patients when controlling for volume measurements. Data were collected using high gradient multi-shell diffusion-weighted MRI from a Siemens CONNECTOM scanner in 23 Alzheimer's disease and 23 age- and sex-matched control older adults (age range = 53-92). These data were used to reconstruct a continuous fornix bundle in every participant's native diffusion space, from which tract-derived volumetric and diffusion metrics were extracted and compared between groups. Diffusion metrics included those from a tensor model and from a generalized q-sampling imaging model. Results showed no significant differences in tract-derived fornix volumes but did show altered diffusion metrics within tissue classified as the fornix in the Alzheimer's disease group. Comparisons to a manual tracing method indicated the same pattern of results and high correlations between the methods. These results suggest that in Alzheimer's disease, diffusion characteristics may provide more sensitive measures of fornix degeneration than do volume measures and may be a potential early marker for loss of medial temporal lobe connectivity.

Structural tract alterations predict downstream tau accumulation in amyloid-positive older individuals.

Animal models of Alzheimer's disease have suggested that tau pathology propagation, facilitated by amyloid pathology, may occur along connected pathways. To investigate these ideas in humans, we combined amyloid scans with longitudinal data on white matter connectivity, hippocampal volume, tau positron emission tomography and memory performance in 256 cognitively healthy older individuals. Lower baseline hippocampal volume was associated with increased mean diffusivity of the connecting hippocampal cingulum bundle (HCB). HCB diffusivity predicted tau accumulation in the downstream-connected posterior cingulate cortex in amyloid-positive but not in amyloid-negative individuals. Furthermore, HCB diffusivity predicted memory decline in amyloid-positive individuals with high posterior cingulate cortex tau binding. Our results provide in vivo evidence that higher amyloid pathology strengthens the association between HCB diffusivity and tau accumulation in the downstream posterior cingulate cortex and facilitates memory decline. This confirms amyloid's crucial role in potentiating neural vulnerability and memory decline marking the onset of preclinical Alzheimer's disease.

Cognitive Function and White Matter Changes Associated with Renal Transplantation.

BACKGROUND: End-stage renal disease (ESRD) is a disease with an aging population and a high prevalence of cognitive impairment affecting quality of life, health care costs and mortality. Structural changes in the brain with decreased white matter integrity have been observed in ESRD. Understanding the changes in cognition and associated changes in brain structure after renal transplantation can help define the mechanisms underlying cognitive impairment in ESRD. METHODS: We conducted a prospective, observational cohort study in ESRD patients listed for renal transplantation and followed them post-transplantation. We assessed their cognitive function with a battery of neuropsychological tests and brain white matter integrity with diffusion tensor imaging (DTI) both before transplant and 3 months after transplant. RESULTS: Eleven patients, aged 56.5 ± 10.7 years, completed the study. Cognitive measures of memory and executive function improved after the transplant, specifically on tests of logical memory I (p = 0.004), logical memory II (p = 0.003) and digit symbol (p < 0.0001). DTI metrics also improved post the transplant with an increase in fractional anisotropy (p = 0.01) and decrease in mean diffusivity (p = 0.004). These changes were more prominent in tracts associated with memory and executive function. CONCLUSIONS: Cognitive function, particularly memory and executive function, improve post the transplant with concurrent improvements in white matter integrity in tracts associated with memory and executive function. These data suggest that abnormalities in cognition and brain structure seen in the ESRD population are at least partially reversible.

Modeling Percentile Rank of Cardiorespiratory Fitness Across the Lifespan.

PURPOSE: The purpose of this investigation was to create an equation for continuous percentile rank of maximal oxygen consumption (VO2 max) from ages 20 to 99. METHODS: We used a two-staged modeling approach with existing normative data from the American College of Sports Medicine for VO2 max. First, we estimated intercept and slope parameters for each decade of life as a logistic function. We then modeled change in intercept and slope as functions of age (stage two) using weighted least squares regression. The resulting equations were used to predict fitness percentile rank based on age, sex, and VO2 max, and included estimates for individuals beyond 79 years old. RESULTS: We created a continuous, sex specific model of VO2 max percentile rank across the lifespan. CONCLUSIONS: Percentile ranking of VO2 max can be made continuous and account for adults aged 20 to 99 with reasonable accuracy, improving the utility of this normalization procedure in practical and research settings, particularly in aging populations.

Characterizing the role of brain derived neurotrophic factor genetic variation in Alzheimer's disease neurodegeneration.

There is accumulating evidence that neurotrophins, like brain-derived neurotrophic factor (BDNF), may impact aging and Alzheimer's Disease. However, traditional genetic association studies have not found a clear relationship between BDNF and AD. Our goal was to test whether BDNF single nucleotide polymorphisms (SNPs) impact Alzheimer's Disease-related brain imaging and cognitive markers of disease. We completed an imaging genetics study on 645 Alzheimer's Disease Neuroimaging Initiative participants (ND=175, MCI=316, AD=154) who had cognitive, brain imaging, and genetics data at baseline and a subset of those with brain imaging data at two years. Samples were genotyped using the Illumina Human610-Quad BeadChip. 13 SNPs in BDNF were identified in the dataset following quality control measures (rs6265(Val66Met), rs12273363, rs11030094, rs925946, rs1050187, rs2203877, rs11030104, rs11030108, rs10835211, rs7934165, rs908867, rs1491850, rs1157459). We analyzed a subgroup of 8 SNPs that were in low linkage disequilibrium with each other. Automated brain morphometric measures were available through ADNI investigators, and we analyzed baseline cognitive scores, hippocampal and whole brain volumes, and rates of hippocampal and whole brain atrophy and rates of change in the ADAS-Cog over one and two years. Three out of eight BDNF SNPs analyzed were significantly associated with measures of cognitive decline (rs1157659, rs11030094, rs11030108). No SNPs were significantly associated with baseline brain volume measures, however six SNPs were significantly associated with hippocampal and/or whole brain atrophy over two years (rs908867, rs11030094, rs6265, rs10501087, rs1157659, rs1491850). We also found an interaction between the BDNF Val66Met SNP and age with whole brain volume. Our imaging-genetics analysis in a large dataset suggests that while BDNF genetic variation is not specifically associated with a diagnosis of AD, it appears to play a role in AD-related brain neurodegeneration.

A Comparative White Matter Study with Parkinson's disease, Parkinson's Disease with Dementia and Alzheimer's Disease.

Alzheimer's disease (AD) and Parkinson's disease (PD) are among the most common neurodegenerative disorders affecting older populations. AD is characterized by impaired memory and cognitive decline while the primary symptoms of PD include resting tremor, bradykinesia and rigidity. In PD, mild cognitive changes are frequently present, which could progress to dementia (PD dementia (PDD)). PDD and AD dementias are different in pathology although the difference in microstructural changes remains unknown. To further understand these diseases, it is essential to understand the distinct mechanism of their microstructural changes. We used diffusion tensor imaging (DTI) to investigate white matter tract differences between early stage individuals with AD (n=14), PD (n=12), PDD (n=9), and healthy non-demented controls (CON) (n=13). We used whole brain tract based spatial statistics (TBSS) and a region of interest (ROI) analysis focused on the substantia nigra (SN). We found that individuals with PDD had more widespread white matter degeneration compared to PD, AD, and CON. Individuals with AD had few regional abnormalities in the anterior and posterior projections of the corpus callosum while PD and CON did not appear to have significant white matter degeneration when compared to other groups. ROI analyses showed that PDD had the highest diffusivity in the SN and were significantly different from CON. There were no significant ROI differences between CON, PD, or AD. In conclusion, global white matter microstructural deterioration is evident in individuals with PDD, and DTI may provide a means with which to tease out pathological differences between AD and PD dementias.