Genetic overlap between Alzheimer's disease and Parkinson's disease at the MAPT locus.

We investigated the genetic overlap between Alzheimer's disease (AD) and Parkinson's disease (PD). Using summary statistics (P-values) from large recent genome-wide association studies (GWAS) (total n=89 904 individuals), we sought to identify single nucleotide polymorphisms (SNPs) associating with both AD and PD. We found and replicated association of both AD and PD with the A allele of rs393152 within the extended MAPT region on chromosome 17 (meta analysis P-value across five independent AD cohorts=1.65 × 10(-7)). In independent datasets, we found a dose-dependent effect of the A allele of rs393152 on intra-cerebral MAPT transcript levels and volume loss within the entorhinal cortex and hippocampus. Our findings identify the tau-associated MAPT locus as a site of genetic overlap between AD and PD, and extending prior work, we show that the MAPT region increases risk of Alzheimer's neurodegeneration.

An expanded role for neuroimaging in the evaluation of memory impairment.

SUMMARY: Alzheimer disease affects millions of people worldwide. The neuropathologic process underlying this disease begins years, if not decades, before the onset of memory decline. Recent advances in neuroimaging suggest that it is now possible to detect Alzheimer-associated neuropathologic changes well before dementia onset. Here, we evaluate the role of recently developed in vivo biomarkers in the clinical evaluation of Alzheimer disease. We discuss how assessment strategies might incorporate neuroimaging markers to better inform patients, families, and clinicians when memory impairment prompts a search for diagnosis and management options.

Parietal and frontal contributions to episodic encoding of location.

Specific contributions of frontal and parietal regions to visuospatial encoding and attention remain controversial. This study used fMRI to examine associative encoding of sequentially-presented spatial cues and object stimuli. The cue preceded the centrally-displayed object by a jittered-delay-interval to better isolate attempt and success in episodically integrating pure location information with separately presented objects. Superior parietal response was modulated by attempted location binding, while superior/middle frontal response was predictive of successful location binding.

Apolipoprotein E epsilon4 does not modulate amyloid-ß-associated neurodegeneration in preclinical Alzheimer disease.

BACKGROUND AND PURPOSE: Among cognitively healthy older individuals, the relationship among the 2 hallmark proteins of AD (Aß and τ APOE ε4) and neurodegeneration is not well-understood. Here, we investigated the relationship between Aß, p-τ, and APOE ε4 on longitudinal brain atrophy in preclinical AD. MATERIALS AND METHODS: We examined 107 cognitively healthy older adults who underwent longitudinal MR imaging and baseline lumbar puncture. Within the same linear mixed-effects model, we concurrently investigated main and interactive effects between the APOE ε4 genotype and CSF Aß(1-42), CSF p-τ and CSF Aß(1-42), and the APOE ε4 genotype and CSF p-τ on entorhinal cortex atrophy rate. We also examined the relationship of APOE ε4, CSF p-τ, and CSF Aß(1-42) on the atrophy rate of other AD-vulnerable neuroanatomic regions. RESULTS: The full model with main and interactive effects demonstrated a significant interaction only between CSF p-τ and CSF Aß(1-42) on entorhinal cortex atrophy rate, indicating elevated atrophy with time in individuals with increased CSF p-τ and decreased CSF Aß(1-42). The APOE ε4 genotype was significantly and specifically associated with CSF Aß(1-42). However, the interaction between the APOE ε4 genotype and either CSF Aß(1-42) or CSF p-τ on entorhinal cortex atrophy rate was not significant. We found similar results in other AD-vulnerable regions. CONCLUSIONS: On the basis of our findings and building on prior experimental evidence, we propose a model of the pathogenic cascade underlying preclinical AD in which APOE ε4 primarily influences the pathology of Alzheimer disease via Aß-related mechanisms, and in turn, Aß-associated neurodegeneration occurs only in the presence of p-τ.

Predicting MCI outcome with clinically available MRI and CSF biomarkers.

OBJECTIVE: To determine the ability of clinically available volumetric MRI (vMRI) and CSF biomarkers, alone or in combination with a quantitative learning measure, to predict conversion to Alzheimer disease (AD) in patients with mild cognitive impairment (MCI). METHODS: We stratified 192 MCI participants into positive and negative risk groups on the basis of 1) degree of learning impairment on the Rey Auditory Verbal Learning Test; 2) medial temporal atrophy, quantified from Food and Drug Administration-approved software for automated vMRI analysis; and 3) CSF biomarker levels(.) We also stratified participants based on combinations of risk factors. We computed Cox proportional hazards models, controlling for age, to assess 3-year risk of converting to AD as a function of risk group and used Kaplan-Meier analyses to determine median survival times. RESULTS: When risk factors were examined separately, individuals testing positive showed significantly higher risk of converting to AD than individuals testing negative (hazard ratios [HR] 1.8-4.1). The joint presence of any 2 risk factors substantially increased risk, with the combination of greater learning impairment and increased atrophy associated with highest risk (HR 29.0): 85% of patients with both risk factors converted to AD within 3 years, vs 5% of those with neither. The presence of medial temporal atrophy was associated with shortest median dementia-free survival (15 months). CONCLUSIONS: Incorporating quantitative assessment of learning ability along with vMRI or CSF biomarkers in the clinical workup of MCI can provide critical information on risk of imminent conversion to AD.

The timing of associative memory formation: frontal lobe and anterior medial temporal lobe activity at associative binding predicts memory.

The process of associating items encountered over time and across variable time delays is fundamental for creating memories in daily life, such as for stories and episodes. Forming associative memory for temporally discontiguous items involves medial temporal lobe structures and additional neocortical processing regions, including prefrontal cortex, parietal lobe, and lateral occipital regions. However, most prior memory studies, using concurrently presented stimuli, have failed to examine the temporal aspect of successful associative memory formation to identify when activity in these brain regions is predictive of associative memory formation. In the current study, functional MRI data were acquired while subjects were shown pairs of sequentially presented visual images with a fixed interitem delay within pairs. This design allowed the entire time course of the trial to be analyzed, starting from onset of the first item, across the 5.5-s delay period, and through offset of the second item. Subjects then completed a postscan recognition test for the items and associations they encoded during the scan and their confidence for each. After controlling for item-memory strength, we isolated brain regions selectively involved in associative encoding. Consistent with prior findings, increased regional activity predicting subsequent associative memory success was found in anterior medial temporal lobe regions of left perirhinal and entorhinal cortices and in left prefrontal cortex and lateral occipital regions. The temporal separation within each pair, however, allowed extension of these findings by isolating the timing of regional involvement, showing that increased response in these regions occurs during binding but not during maintenance.

Activity in the hippocampus and neocortical working memory regions predicts successful associative memory for temporally discontiguous events.

Models of mnemonic function suggest that the hippocampus binds temporally discontiguous events in memory (Wallenstein, Eichenbaum, & Hasselmo, 1998), which has been supported by recent studies in humans. Less is known, however, about the involvement of working memory in bridging the temporal gap between to-be-associated events. In this study, subsequent memory for associations between temporally discontiguous stimuli was examined using functional magnetic resonance imaging. In the scanner, subjects were instructed to remember sequentially presented images. Occasionally, a plus-sign was presented during the interstimulus interval between two images, instructing subjects to associate the two images as a pair. Following the scan, subjects identified remembered images and their pairs. Images following the plus-sign were separated into trials in which items were later recognized and the pair remembered, recognized and the pair forgotten, or not recognized. Blood-oxygen-level-dependent responses were measured to identify regions where response amplitude predicted subsequent associative- or item memory. Distinct neocortical regions were involved in each memory condition, where activity in bilateral frontal and parietal regions predicted memory for associative information and bilateral occipital and medial frontal regions for item information. While activity in posterior regions of the medial temporal lobe showed an intermediate response predicting memory for both conditions, bilateral hippocampal activity only predicted associative memory.

Six-month atrophy in MTL structures is associated with subsequent memory decline in elderly controls.

Neurodegeneration precedes the onset of dementias such as Alzheimer's by several years. Recent advances in volumetric imaging allow quantification of subtle neuroanatomical change over time periods as short as six months. This study investigates whether neuroanatomical change in medial temporal lobe subregions is associated with later memory decline in elderly controls. Using high-resolution, T1-weighted magnetic resonance images acquired at baseline and six-month follow-up, change in cortical thickness and subcortical volumes was measured in 142 healthy elderly subjects (aged 59-90 years) from the ADNI cohort. Regression analysis was used to identify whether change in fourteen subregions, selected a priori, was associated with declining performance on memory tests from baseline to two-year follow-up. Percent thickness change in the right fusiform and inferior temporal cortices and expansion of the right inferior lateral ventricle were found to be significant predictors of subsequent decline on memory-specific neuropsychological measures. These results demonstrate that six-month regional neurodegeneration can be quantified in the healthy elderly and might help identify those at risk for subsequent cognitive decline.

Fully-automated volumetric MRI with normative ranges: translation to clinical practice.

Neurodegenerative disorders, such as Alzheimer's disease (AD), are associated with characteristic patterns of neuropathological spread in the brain. Disease progression is usually accompanied by regional atrophy that can be detected noninvasively using structural magnetic resonance imaging (MRI). A wealth of data has demonstrated the value of quantitative measurements of regional atrophy in AD, suggesting that volumetric MRI (vMRI) may be a useful clinical tool. vMRI provides biological evidence of neurodegenerative disease in patients with cognitive impairment. However, several hurdles impede implementation of vMRI in clinical practice. These include a lack of standardized MRI acquisition protocols, spatial distortions in MRI data, labor-intensive vMRI methods susceptible to interoperator variability, a lack of normative ranges for volume measures, and difficulty integrating vMRI in clinical workflow. Advances in vMRI have resulted from multi-institutional studies of brain imaging, such as the Alzheimer's Disease Neuroimaging Initiative (ADNI), and help address these challenges. New, fully-automated measures of brain structure volumes coupled with large, multi-center studies using standardized MRI protocols now allow the development of age-adjusted normative ranges for vMRI. Such advances are critical for providing physicians a framework for assessing the pattern and degree of regional atrophy in a patient's brain and applying vMRI in clinical practice.

Regional rates of neocortical atrophy from normal aging to early Alzheimer disease.

OBJECTIVE: To evaluate the spatial pattern and regional rates of neocortical atrophy from normal aging to early Alzheimer disease (AD). METHODS: Longitudinal MRI data were analyzed using high-throughput image analysis procedures for 472 individuals diagnosed as normal, mild cognitive impairment (MCI), or AD. Participants were divided into 4 groups based on Clinical Dementia Rating Sum of Boxes score (CDR-SB). Annual atrophy rates were derived by calculating percent cortical volume loss between baseline and 12-month scans. Repeated-measures analyses of covariance were used to evaluate group differences in atrophy rates across regions as a function of impairment. Planned comparisons were used to evaluate the change in atrophy rates across levels of disease severity. RESULTS: In patients with MCI-CDR-SB 0.5-1, annual atrophy rates were greatest in medial temporal, middle and inferior lateral temporal, inferior parietal, and posterior cingulate. With increased impairment (MCI-CDR-SB 1.5-2.5), atrophy spread to parietal, frontal, and lateral occipital cortex, followed by anterior cingulate cortex. Analysis of regional trajectories revealed increasing rates of atrophy across all neocortical regions with clinical impairment. However, increases in atrophy rates were greater in early disease within medial temporal cortex, whereas increases in atrophy rates were greater at later stages in prefrontal, parietal, posterior temporal, parietal, and cingulate cortex. CONCLUSIONS: Atrophy is not uniform across regions, nor does it follow a linear trajectory. Knowledge of the spatial pattern and rate of decline across the spectrum from normal aging to Alzheimer disease can provide valuable information for detecting early disease and monitoring treatment effects at different stages of disease progression.

Fully-automated quantification of regional brain volumes for improved detection of focal atrophy in Alzheimer disease.

Volumetric analysis of structural MR images of the brain may provide quantitative evidence of neurodegeneration and help identify patients at risk for rapid clinical deterioration. This note describes tests of a fully automated MR imaging postprocessing system for volumetric analysis of structures (such as the hippocampus) known to be affected in early Alzheimer disease (AD). The system yielded results that correlated highly with independent computer-aided manual segmentation and were sensitive to the anatomic atrophy characteristic of mild AD.

Material-specific lateralization in the medial temporal lobe and prefrontal cortex during memory encoding.

Numerous observations in patients with unilateral lesions of the medial temporal lobe (MTL) and the prefrontal cortex indicate that memory processes are lateralized according to content. Left-sided lesions interfere with verbal memory processes, whereas right-sided lesions interfere with visuospatial (non-verbal) memory processes. However, functional imaging studies have resulted in contradictory data, some studies showing lateralization in the prefrontal cortex determined by stage of processing (encoding versus retrieval) and others suggesting that lateralization is dependent on the type of material. Few studies have examined this issue in the MTL. In order to test the hypothesis that the lateralization of encoding processes in the MTL and frontal regions is dependent on the verbalizability of the material, we performed behavioural and functional imaging studies. We demonstrated differing verbalizabilities of three classes of non-verbal stimuli (scenes > faces > abstract patterns) using a dual-task verbal interference behavioural paradigm. A functional neuroimaging study of encoding was carried out using these three types of stimuli, plus words. During whole-brain functional MRI at 1.5 T, eight normal right-handed adults were presented with alternating blocks of novel and repeated stimuli under intentional memory encoding conditions. Verbal encoding resulted in left-lateralized activation of the inferior prefrontal cortex and the MTL. Pattern encoding activated the right inferior prefrontal cortex and the right MTL. Scenes and faces resulted in approximately symmetrical activation in both regions. The data indicate that the lateralization of encoding processes is determined by the verbalizability of stimuli.

Level of sustained entorhinal activity at study correlates with subsequent cued-recall performance: a functional magnetic resonance imaging study with high acquisition rate.

Functional magnetic resonance imaging (fMRI) with high acquisition rate was performed during the intentional memorizing of words to specify which medial temporal lobe structure is important in determining what words are subsequently remembered in a cued-recall test and to characterize the time course of activation in that structure. Functional images of six healthy young subjects were analyzed by two subject- and voxel-wise statistics: First, to identify brain areas transiently engaged in encoding of words, brain activity during memorizing visually presented words and watching a fixation cross was compared by a Kolmogorov-Smirnov statistic (KS-test). Second, to identify brain areas whose activity correlates with memory encoding success, a Kendall's correlation was calculated between signal intensity at study and performance in a subsequent cued-recall test. Averaged signal intensities were plotted as a function of time to depict the time course of brain activity detected by both statistical tests. The level of slowly modulated, sustained activity in Brodmann area 28 (entorhinal cortex) did not respond transiently as study words appeared, but did correlate positively with subsequent test performance. More left than right activity in Brodmann area 45 (dorso-lateral prefrontal cortex) and bilateral activity in Brodmann area 44 (premotor cortex) exhibited transient hemodynamic responses that did not show any relation to subsequent memory performance. Thus, the study identified a novel pattern of slowly modulated brain activity in human entorhinal cortex that may represent a declarative memory encoding state whose level predicts whether experiences will be remembered or forgotten.

Images of medial temporal lobe functions in human learning and memory.

Investigations of the neural basis of mammalian memory have focused more often on the medial temporal lobe (MTL) than on any other brain region. In humans, the amnesic syndrome revealed the essential importance of the multiple structures located in the MTL system for declarative memory (the remembrance of events and facts). Other neural systems mediate procedural forms of memory, including delay eyeblink conditioning, which depends on the cerebellum, and cognitive skill learning, which depends on the striatum. We review three functional imaging studies that reveal different patterns of MTL activation associated with declarative and procedural memory tasks. One study shows separate MTL activations during the encoding or retrieval of declarative memories. A second study shows MTL activation that occurs in parallel with cerebellum-dependent delay eyeblink conditioning, but does not appear to influence that form of procedural memory. A third study reveals suppression of the MTL during striatum-dependent cognitive skill learning. These studies provide images of MTL activations that are correlated with, independent from, or antagonistic to memory performance.

Making memories: brain activity that predicts how well visual experience will be remembered.

Experiences are remembered or forgotten, but the neural determinants for the mnemonic fate of experience are unknown. Event-related functional magnetic resonance imaging was used to identify specific brain activations that differentiated between visual experiences that were later remembered well, remembered less well, or forgotten. During scanning of medial temporal lobe and frontal lobe regions, subjects viewed complex, color photographs. Subjects later received a test of memory for the photographs. The magnitudes of focal activations in right prefrontal cortex and in bilateral parahippocampal cortex predicted which photographs were later remembered well, remembered less well, or forgotten.

Separate neural bases of two fundamental memory processes in the human medial temporal lobe.

The participation of medial temporal-lobe structures in memory performance was examined by functional magnetic resonance imaging of local blood oxygenation level-dependent signals. Signals were measured during encoding into memory complex scenes or line drawings and during retrieval from memory of previously studied line drawings or words. Encoding tasks yielded increased signals for unfamiliar information in a posterior medial-temporal region that were focused in the parahippocampal cortex. Retrieval tasks yielded increased signals for successfully remembered information in an anterior medial-temporal region that were focused in the subiculum. These results indicate that separate components of the human medial temporal-lobe memory system are active during distinct memory processes.