Age-related changes in parahippocampal white matter integrity: a diffusion tensor imaging study.

The axons in the parahippocampal white matter (PWM) region that includes the perforant pathway relay multimodal sensory information, important for memory function, from the entorhinal cortex to the hippocampus. Previous work suggests that the integrity of the PWM shows changes in individuals with amnestic mild cognitive impairment and is further compromised as Alzheimer's disease progresses. The present study was undertaken to determine the effects of healthy aging on macro- and micro-structural alterations in the PWM. The study characterized in vivo white matter changes in the parahippocampal region that includes the perforant pathway in cognitively healthy young (YNG, n=21) compared to cognitively healthy older (OLD, n=21) individuals using volumetry, diffusion tensor imaging (DTI) and tractography. Results demonstrated a significant reduction in PWM volume in old participants, with further indications of reduced integrity of remaining white matter fibers. In logistic regressions, PWM volume, memory performance and DTI indices of PWM integrity were significant indicator variables for differentiating the young and old participants. Taken together, these findings suggest that age-related alterations do occur in the PWM region and may contribute to the normal decline in memory function seen in healthy aging by degrading information flow to the hippocampus.

Alzheimer-signature MRI biomarker predicts AD dementia in cognitively normal adults.

OBJECTIVE: Since Alzheimer disease (AD) neuropathology is thought to develop years before dementia, it may be possible to detect subtle AD-related atrophy in preclinical AD. Here we hypothesized that the "disease signature" of AD-related cortical thinning, previously identified in patients with mild AD dementia, would be useful as a biomarker to detect anatomic abnormalities consistent with AD in cognitively normal (CN) adults who develop AD dementia after longitudinal follow-up. METHODS: We studied 2 independent samples of adults who were CN when scanned. In sample 1, 8 individuals developing AD dementia (CN-AD converters) after an average of 11.1 years were compared to 25 individuals who remained CN (CN-stable). In sample 2, 7 CN-AD converters (average follow-up 7.1 years) were compared to 25 CN-stable individuals. RESULTS: AD-signature cortical thinning in CN-AD converters in both samples was remarkably similar, about 0.2 mm (p < 0.05). Despite this small absolute difference, Cohen d effect sizes for these differences were very large (> 1). Of the 11 CN individuals with baseline low AD-signature thickness (≥ 1 SD below cohort mean), 55% developed AD dementia over nearly the next decade, while none of the 9 high AD-signature thickness individuals (≥ 1 SD above mean) developed dementia. This marker predicted time to diagnosis of dementia (hazard ratio = 3.4, p < 0.0005); 1 SD of thinning increased dementia risk by 3.4. CONCLUSIONS: By focusing on cortical regions known to be affected in AD dementia, subtle but reliable atrophy is identifiable in asymptomatic individuals nearly a decade before dementia, making this measure a potentially important imaging biomarker of early neurodegeneration.

Rate of entorhinal and hippocampal atrophy in incipient and mild AD: relation to memory function.

In the present study, as part of a more extensive longitudinal investigation of the in vivo anatomical markers of early and incipient AD in our laboratory, three groups of elderly participants were followed with yearly clinical evaluations and high resolution MRI scans over a 6-year period (baseline and 5 years of follow-up). At baseline, participants consisted of: (1) 35 old subjects with no cognitive impairment (controls); (2) 33 participants with amnestic mild cognitive impairment (MCI); and (3) 14 patients with very mild AD. 11 participants with amnestic MCI received a diagnosis of AD over the follow-up period and 9 controls declined in cognitive function. T1 weighted MRI scans were acquired using a 3D SPGR pulse sequence. At baseline, both the amnestic MCI and mild AD groups differed from the controls in hippocampal and entorhinal cortex volume, but not from each other. Longitudinal analyses showed that the rate of atrophy of the entorhinal cortex and hippocampus for the stable controls differed significantly from MCI participants who converted to AD and the AD groups. Furthermore, longitudinal decreases in hippocampal and entorhinal volume were related to longitudinal decline in declarative memory performance. These findings suggest that the rate of atrophy of mesial temporal lobe structures can differentiate healthy from pathological aging.

MRI predictors of risk of incident Alzheimer disease: a longitudinal study.

OBJECTIVE: To determine if baseline entorhinal and hippocampal volumes and their rate of atrophy could predict the risk of incident Alzheimer disease (AD). METHODS: The authors used proportional odds models to assess the relationship between entorhinal and hippocampal size and risk of incident AD among 58 nondemented elderly people. All participants were followed with annual clinical evaluations and structural MRI scans for up to 5 years (baseline and 5 years of follow-up). At baseline, 23 of 58 participants received a diagnosis of amnestic mild cognitive impairment (MCI) and 35 of 58 were healthy control subjects with no cognitive impairment. Structural MRI scans were acquired with a T1-weighted three-dimensional spoiled gradient-recalled echo pulse sequence in a 1.5 T scanner. Entorhinal and hippocampal volumes were derived from 1.6-mm gapless coronal images reformatted to be perpendicular to the long axis of the hippocampus and were normalized by dividing with intracranial volume. RESULTS: Fourteen of 58 nondemented participants developed AD during the follow-up period. Initial diagnosis of MCI was a significant predictor of incident AD. In addition, both baseline entorhinal volume and its slope of decline were independent predictors of incident AD, but initial hippocampal size and its rate of decline were not, after controlling for entorhinal volume. CONCLUSION: In nondemented individuals, entorhinal cortex atrophy is associated with risk of Alzheimer disease.

MRI-derived entorhinal volume is a good predictor of conversion from MCI to AD.

With high-resolution quantitative magnetic resonance imaging (MRI) techniques, it is possible to examine alterations in brain anatomy in vivo and to identify regions affected in the earliest stages of Alzheimer's disease (AD). In the present study, 27 patients diagnosed with mild cognitive impairment (MCI) received a high-resolution MRI scan at baseline and were followed with yearly clinical evaluations. Ten of the 27 patients converted to AD during a 36-month period following the baseline clinical evaluation. Hippocampal and entorhinal cortex volumes derived from the baseline scan were compared to determine which of these two regions, known to be pathologically involved very early in the course of AD, could best differentiate MCI converters from non-converters. Although both entorhinal and hippocampal volumes were found to be independent predictors of the likelihood of conversion to AD, it was the right hemisphere entorhinal volume that best predicted conversion with a concordance rate of 93.5%.

MRI of human entorhinal cortex: a reliable protocol for volumetric measurement.

A new protocol for measuring the volume of the entorhinal cortex (EC) from magnetic resonance images (MRI) was developed specifically to measure the EC from oblique coronal sections used in hippocampal volumetric studies. The relative positions of the anatomic landmarks demarcating EC boundaries were transposed from standard coronal sections to oblique ones. The lateral EC border, which is the most controversial among anatomists, was defined in a standard and conservative manner at the medial edge of the collateral sulcus. Two raters measured the EC twice for 78 subjects (healthy aged individuals, very mild AD patients, and elderly patients who did not meet criteria for dementia) to study intra- and inter-rater reproducibility and reliability of measurements. The level of accuracy achieved (coefficients of reproducibility of 1.40-3.86%) and reliability of measurements (intraclass correlation coefficients of 0.959-0.997) indicated that this method provides a feasible tool for measuring the volume of the EC in vivo.