Cognitive reserve moderates the relationship between neuropsychological performance and white matter fiber bundle length in healthy older adults.

Recent work using novel neuroimaging methods has revealed shorter white matter fiber bundle length (FBL) in older compared to younger adults. Shorter FBL also corresponds to poorer performance on cognitive measures sensitive to advanced age. However, it is unclear if individual factors such as cognitive reserve (CR) effectively moderate the relationship between FBL and cognitive performance. This study examined CR as a potential moderator of cognitive performance and brain integrity as defined by FBL. Sixty-three healthy adults underwent neuropsychological evaluation and 3T brain magnetic resonance imaging. Cognitive performance was measured using the Repeatable Battery of Assessment of Neuropsychological Status (RBANS). FBL was quantified from tractography tracings of white matter fiber bundles, derived from the diffusion tensor imaging. CR was determined by estimated premorbid IQ. Analyses revealed that lower scores on the RBANS were associated with shorter whole brain FBL (p = 0.04) and lower CR (p = 0.01) CR moderated the relationship between whole brain FBL and RBANS score (p < 0.01). Tract-specific analyses revealed that CR also moderated the association between FBL in the hippocampal segment of the cingulum and RBANS performance (p = 0.03). These results demonstrate that lower cognitive performance on the RBANS is more common with low CR and short FBL. On the contrary, when individuals have high CR, the relationship between FBL and cognitive performance is attenuated. Overall, CR protects older adults against lower cognitive performance despite age-associated reductions in FBL.

REDUCING CSF PARTIAL VOLUME EFFECTS TO ENHANCE DIFFUSION TENSOR IMAGING METRICS OF BRAIN MICROSTRUCTURE.

Technological advances over recent decades now allow for in vivo observation of human brain tissue through the use of neuroimaging methods. While this field originated with techniques capable of capturing macrostructural details of brain anatomy, modern methods such as diffusion tensor imaging (DTI) that are now regularly implemented in research protocols have the ability to characterize brain microstructure. DTI has been used to reveal subtle micro-anatomical abnormalities in the prodromal phase ofº various diseases and also to delineate "normal" age-related changes in brain tissue across the lifespan. Nevertheless, imaging artifact in DTI remains a significant limitation for identifying true neural signatures of disease and brain-behavior relationships. Cerebrospinal fluid (CSF) contamination of brain voxels is a main source of error on DTI scans that causes partial volume effects and reduces the accuracy of tissue characterization. Several methods have been proposed to correct for CSF artifact though many of these methods introduce new limitations that may preclude certain applications. The purpose of this review is to discuss the complexity of signal acquisition as it relates to CSF artifact on DTI scans and review methods of CSF suppression in DTI. We will then discuss a technique that has been recently shown to effectively suppress the CSF signal in DTI data, resulting in fewer errors and improved measurement of brain tissue. This approach and related techniques have the potential to significantly improve our understanding of "normal" brain aging and neuropsychiatric and neurodegenerative diseases. Considerations for next-level applications are discussed.

Neuromarkers of the common angiotensinogen polymorphism in healthy older adults: A comprehensive assessment of white matter integrity and cognition.

The common angiotensinogen (AGT) M268T polymorphism (rs699; historically referred to as M235T) has been identified as a significant risk factor for cerebrovascular pathologies, yet it is unclear if healthy older adults carrying the threonine amino acid variant have a greater risk for white matter damage in specific fiber tracts. Further, the impact of the threonine variant on cognitive function remains unknown. The present study utilized multiple indices of diffusion tensor imaging (DTI) and neuropsychological assessment to examine the integrity of specific white matter tracts and cognition between individuals with homozygous genotypes of M268T (MetMet n=27, ThrThr n=27). Differences in subcortical hyperintensity (SH) volume were also examined between groups. Results indicated that the threonine variant was associated with significantly reduced integrity in the superior longitudinal fasciculus (SLF) and the cingulate gyrus segment of the cingulum bundle (cingulum CG) compared to those with the methionine variant, and poorer cognitive performance on tests of attention/processing speed and language. Despite these associations, integrity of these tracts did not significantly mediate relationships between cognition and genetic status, and SH did not differ significantly between groups. Collectively our results suggest that the threonine variant of M268T is a significant risk factor for abnormalities in specific white matter tracts and cognitive domains in healthy older adults, independent of SH burden.

Regional age differences in gray matter diffusivity among healthy older adults.

Aging is associated with microstructural changes in brain tissue that can be visualized using diffusion tensor imaging (DTI). While previous studies have established age-related changes in white matter (WM) diffusion using DTI, the impact of age on gray matter (GM) diffusion remains unclear. The present study utilized DTI metrics of mean diffusivity (MD) to identify age differences in GM/WM microstructure in a sample of healthy older adults (N = 60). A secondary aim was to determine the functional significance of whole-brain GM/WM MD on global cognitive function using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Participants were divided into three age brackets (ages 50-59, 60-69, and 70+) to examine differences in MD and cognition by decade. MD was examined bilaterally in the frontal, temporal, parietal, and occipital lobes for the primary analyses and an aggregate measure of whole-brain MD was used to test relationships with cognition. Significantly higher MD was observed in bilateral GM of the temporal and parietal lobes, and in right hemisphere WM of the frontal and temporal lobes of older individuals. The most robust differences in MD were between the 50-59 and 70+ age groups. Higher whole-brain GM MD was associated with poorer RBANS performance in the 60-69 age group. Results suggest that aging has a significant and differential impact on GM/WM diffusion in healthy older adults, which may explain a modest degree of cognitive variability at specific time points during older adulthood.

Fiber bundle length and cognition: a length-based tractography MRI study.

Executive function (EF) and cognitive processing speed (CPS) are two cognitive performance domains that decline with advanced age. Reduced EF and CPS are known to correlate with age-related frontal-lobe volume loss. However, it remains unclear whether white matter microstructure in these regions is associated with age-related decline in EF and/or CPS. We utilized quantitative tractography metrics derived from diffusion-tensor MRI to investigate the relationship between the mean fiber bundle lengths (FBLs) projecting to different lobes, and EF/CPS performance in 73 healthy aging adults. We measured aspects of EF and CPS with the Trail Making Test (TMT), Color-Word Interference Test, Letter-Number Sequencing (L-N Seq), and Symbol Coding. Results revealed that parietal and occipital FBLs explained a significant portion of variance in EF. Frontal, temporal, and occipital FBLs explained a significant portion of variance in CPS. Shorter occipital FBLs were associated with poorer performance on the EF tests TMT-B and CWIT 3. Shorter frontal, parietal, and occipital FBLs were associated with poorer performance on L-N Seq and Symbol Coding. Shorter frontal and temporal FBLs were associated with lower performance on CPS tests TMT-A and CWIT 1. Shorter FBLs were also associated with increased age. Results suggest an age-related FBL shortening in specific brain regions related to poorer EF and CPS performance among older adults. Overall, results support both the frontal aging hypothesis and processing speed theory, suggesting that each mechanism is contributing to age-related cognitive decline.

Impact of the AGTR1 A1166C polymorphism on subcortical hyperintensities and cognition in healthy older adults.

Vascular aging consists of complex and multifaceted processes that may be influenced by genetic polymorphisms of the renin-angiotensin system. A polymorphism in the angiotensin II type 1 receptor gene (AGTR1/rs5186) has been associated with an increased risk for arterial stiffness, hypertension, and ischemic stroke. Despite these identified relationships, the impact of AGTR1 A1166C on white matter integrity and cognition is less clear in a healthy aging population. The present study utilized indices of neuroimaging and neuropsychological assessment to examine the impact of the A1166C polymorphism on subcortical hyperintensities (SH) and cognition in 49 healthy adults between ages 51-85. Using a dominant statistical model (CC + CA (risk) vs. AA), results revealed significantly larger SH volume for individuals with the C1166 variant (p < 0.05, partial eta(2) = 0.117) compared with those with the AA genotype. Post hoc analyses indicated that increased SH volume in C allele carriers could not be explained by vascular factors such as pulse pressure or body mass index. In addition, cognitive performance did not differ significantly between groups and was not significantly associated with SH in this cohort. Results suggest that presence of the C1166 variant may serve as a biomarker of risk for suboptimal brain integrity in otherwise healthy older adults prior to changes in cognition.

White matter changes with age utilizing quantitative diffusion MRI.

OBJECTIVE: To investigate the relationship between older age and mean cerebral white matter fiber bundle lengths (FBLs) in specific white matter tracts in the brain using quantified diffusion MRI. METHODS: Sixty-three healthy adults older than 50 years underwent diffusion tensor imaging. Tractography tracings of cerebral white matter fiber bundles were derived from the diffusion tensor imaging data. RESULTS: Results revealed significantly shorter FBLs in the anterior thalamic radiation for every 1-year increase over the age of 50 years. CONCLUSIONS: We investigated the effects of age on FBL in specific white matter tracts in the brains of healthy older individuals utilizing quantified diffusion MRI. The results revealed a significant inverse relationship between age and FBL. Longitudinal studies of FBL across a lifespan are needed to examine the specific changes to the integrity of white matter.

Neuronal fiber bundle lengths in healthy adult carriers of the ApoE4 allele: a quantitative tractography DTI study.

The epsilon 4 (e4) isoform of apolipoprotein E (ApoE) is a known genetic risk factor for suboptimal brain health. Morphometry studies of brains with Alzheimer's disease have reported significant alterations in temporal lobe brain structure of e4 carriers, yet it remains unclear if the presence of an e4 allele is associated with alterations in the microstructure of white matter fiber bundles in healthy populations. The present study used quantitative tractography based on diffusion tensor imaging (qtDTI) to examine the influence of the e4 allele on temporal lobe fiber bundle lengths (FBLs) in 64 healthy older adults with at least one e4 allele (carriers, N = 23) versus no e4 allele (non-carriers, N = 41). Subtests from the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) were also analyzed to examine memory performance between groups. Analyses revealed shorter FBLs in the left uncinate fasciculus (UF) (p = .038) of e4 carriers compared to non-carriers. By contrast, neither FBLs specific to the temporal lobe nor memory performances differed significantly between groups. Increased age correlated significantly with shorter FBL in the temporal lobe and UF, and with decreased performance on tests of memory. This is the first study to utilize qtDTI to examine relationships between FBL and ApoE genotype. Results suggest that FBL in the UF is influenced by the presence of an ApoE e4 allele (ApoE4) in healthy older adults. Temporal lobe FBLs, however, are more vulnerable to aging than the presence of an e4 allele.

Neuroimaging signatures and cognitive correlates of the montreal cognitive assessment screen in a nonclinical elderly sample.

The Montreal Cognitive Assessment (MoCA) screen was developed as a brief instrument to identify mild cognitive impairment and dementia among older individuals. To date, limited information is available regarding the neuroimaging signatures associated with performance on the scale, or the relationship between the MoCA and more comprehensive cognitive screening measures. The present study examined performances on the MoCA among 111 non-clinical older adults (ages 51-85) enrolled in a prospective study of cognitive aging. Participants were administered the MoCA, Mini-Mental State Exam (MMSE), and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). A subset of participants (N = 69) underwent structural 3 T magnetic resonance imaging (MRI) to define the volumes of total frontal gray matter, total hippocampus, T2-weighted subcortical hyperintensities (SH), and total brain volume. The results revealed significant correlations between the total score on the MoCA and total score on the RBANS and MMSE, though the strength of the correlations was more robust between the MoCA and the RBANS. Modest correlations between individual subscales of the MoCA and neuroimaging variables were evident, but no patterns of shared variance emerged between the MoCA total score and neuroimaging indices. In contrast, total brain volume correlated significantly with total score on the RBANS. These results suggest that additional studies are needed to define the significance of MoCA scores relative to brain integrity among an older population.

Anterior thalamic radiation integrity in schizophrenia: a diffusion-tensor imaging study.

The anterior limb of the internal capsule (ALIC) is a white matter structure, the medial portion of which includes the anterior thalamic radiation (ATR) carrying nerve fibers between thalamus and prefrontal cortex. ATR abnormalities have a possible link with cognitive abnormalities and negative symptoms in schizophrenia. We aimed to study the fiber integrity of the ATR more selectively by isolating the medial portion of the ALIC using region-of-interest based methodology. Diffusion-tensor imaging was used to measure the anisotropy of total ALIC (tALIC) and medial ALIC (mALIC) in 39 schizophrenia and 33 control participants, matched for age/gender/handedness. Relationships between anisotropy, psychopathology, and cognitive performance were analyzed. Compared with controls, schizophrenia participants had 4.55% lower anisotropy in right tALIC, and 5.38% lower anisotropy in right mALIC. There were no significant group anisotropy differences on the left. Significant correlations were observed between right ALIC integrity and relevant domains of cognitive function (e.g., executive function, working memory). Our study suggests an asymmetric microstructural change in ALIC in schizophrenia involving the right side, which is only minimally stronger in mALIC, and which correlates with cognitive impairment. Microstructural changes in the ALIC may be linked to cognitive dysfunction in schizophrenia.

Topographic organization of macaque area LIP.

Despite several attempts to define retinotopic maps in the macaque lateral intraparietal area (LIP) using histological, electrophysiological, and neuroimaging methods, the degree to which this area is topographically organized remains controversial. We recorded blood oxygenation level-dependent signals with functional MRI from two macaques performing a difficult visual search task on stimuli presented at the fovea or in the periphery of the visual field. The results revealed the presence of a single topographic representation of the contralateral hemifield in the ventral subdivision of the LIP (LIPv) in both hemispheres of both monkeys. Also, a foveal representation was localized in rostral LIPv rather than in dorsal LIP (LIPd) as previous experiments had suggested. Finally, both LIPd and LIPv responded only to contralateral stimuli. In contrast, human studies have reported multiple topographic maps in intraparietal cortex and robust responses to ipsilateral stimuli. These blood oxygenation level-dependent functional MRI results provide clear evidence for the topographic organization of macaque LIP that complements the results of previous electrophysiology studies, and also reveal some unexpected characteristics of this organization that have eluded these previous studies. The results also delineate organizational differences between LIPv and LIPd, providing support for these two histologically defined areas may subserve different visuospatial functions. Finally, these findings point to potential evolutionary differences in functional organization with human posterior parietal cortex.

MRI diffusion tensor tracking of a new amygdalo-fusiform and hippocampo-fusiform pathway system in humans.

PURPOSE: To use MRI diffusion-tensor tracking (DTT) to test for the presence of unknown neuronal fiber pathways interconnecting the mid-fusiform cortex and anteromedial temporal lobe in humans. Such pathways are hypothesized to exist because these regions coactivate in functional MRI (fMRI) studies of emotion-valued faces and words, suggesting a functional link that could be mediated by neuronal connections. MATERIALS AND METHODS: A total of 15 normal human subjects were studied using unbiased DTT approaches designed for probing unknown pathways, including whole-brain seeding and large pathway-selection volumes. Several quality-control steps verified the results. RESULTS: Parallel amygdalo-fusiform and hippocampo-fusiform pathways were found in all subjects. The pathways begin/end at the mid-fusiform gyrus above the lateral occipitotemporal sulcus bilaterally. The superior pathway ends/begins at the superolateral amygdala. The inferior pathway crosses medially and ends/begins at the hippocampal head. The pathways are left-lateralized, with consistently larger cross-sectional area, higher anisotropy, and lower minimum eigenvalue (D-min) on the left, where D-min assesses intrinsic cross-fiber diffusivity independent of curvature. CONCLUSION: A previously-undescribed pathway system interconnecting the mid-fusiform region with the amygdala/hippocampus has been revealed. This pathway system may be important for recognition, memory consolidation, and emotional modulation of face, object, and lexical information, which may be disrupted in conditions such as Alzheimer's disease.

Neuronal fiber pathway abnormalities in autism: an initial MRI diffusion tensor tracking study of hippocampo-fusiform and amygdalo-fusiform pathways.

MRI diffusion-tensor tracking (DTT) was performed in 17 high-functioning adolescents/adults with autism and 17 pairwise-matched controls. White matter pathways involved in face processing were examined due to the relevance of face perception to the social symptoms of autism, and due to known behavioral and functional imaging findings in autism. The hippocampo-fusiform (HF) and amygdalo-fusiform (AF) pathways had normal size and shape but abnormal microstructure in the autism group. The right HF had reduced across-fiber diffusivity (D-min) compared with controls, opposite to the whole-brain effect of increased D-min. In contrast, left HF, right AF, and left AF had increased D-min and increased along-fiber diffusivity (D-max), more consistent with the whole-brain effect. There was a general loss of lateralization compared with controls. The right HF D-min was markedly low in the autism subgroup with lower Benton face recognition scores, compared with the lower-Benton control subgroup, and compared with the higher-Benton autism subgroup. Similar behavioral relationships were found for performance IQ. Such results suggest an early functionally-significant pathological process in right HF consistent with small-diameter axons (with correspondingly slower neural transmission) and/or higher packing density. In left AF and HF, changes were interpreted as secondary, possibly reflecting axonal loss and/or decreased myelination.

Changing human visual field organization from early visual to extra-occipital cortex.

BACKGROUND: The early visual areas have a clear topographic organization, such that adjacent parts of the cortical surface represent distinct yet adjacent parts of the contralateral visual field. We examined whether cortical regions outside occipital cortex show a similar organization. METHODOLOGY/PRINCIPAL FINDINGS: The BOLD responses to discrete visual field locations that varied in both polar angle and eccentricity were measured using two different tasks. As described previously, numerous occipital regions are both selective for the contralateral visual field and show topographic organization within that field. Extra-occipital regions are also selective for the contralateral visual field, but possess little (or no) topographic organization. A regional analysis demonstrates that this weak topography is not due to increased receptive field size in extra-occipital areas. CONCLUSIONS/SIGNIFICANCE: A number of extra-occipital areas are identified that are sensitive to visual field location. Neurons in these areas corresponding to different locations in the contralateral visual field do not demonstrate any regular or robust topographic organization, but appear instead to be intermixed on the cortical surface. This suggests a shift from processing that is predominately local in visual space, in occipital areas, to global, in extra-occipital areas. Global processing fits with a role for these extra-occipital areas in selecting a spatial locus for attention and/or eye-movements.

Precision, signal-to-noise ratio, and dose optimization of magnitude and phase arterial input functions in dynamic susceptibility contrast MRI.

PURPOSE: To determine optimal conditions for precise measurement of arterial input function (AIFs) in dynamic susceptibility contrast (DSC) perfusion MRI. MATERIALS AND METHODS: Magnitude-based (DeltaR(2)*) and phase-based (Deltaphi) AIFs were numerically simulated for several doses and baseline MRI noise levels [SNR(I(0))]. Random noise (1000 realizations) was added to real/imaginary MRI signals (derived from an internal carotid AIF), and AIF signal, noise, and signal-to-noise ratio (SNR) were determined. The optimal dose was defined as the dose that maximizes mean AIF SNR over the first-pass (SNR(mean)), rather than SNR at the AIF peak (SNR(peak)) because, compared to SNR(peak), doses predicted by SNR(mean) reduced the AIF-induced variability in cerebral blood flow (CBF) by 24% to 40%. RESULTS: The AIF SNR is most influenced by choice of AIF signal, then optimal dosing, each with little penalty. Compared to DeltaR(2)*, Deltaphi signal has 4 to 80 times the SNR over all doses and time points, and approximately 10-fold SNR(mean) at respective optimal doses. Optimal doses induce 85% to 90% signal drop for the DeltaR(2)* method, and 70% to 75% for Deltaphi, with two-fold dose errors causing approximately 1.7-fold loss in SNR(mean). Increases in SNR(I(0)) proportionally increase AIF SNR, but at a cost. CONCLUSION: AIF SNR is affected most by signal type, then dosing, and lastly, SNR(I(0)).

Performance of interventions with manipulator-driven real-time MR guidance: implementation and initial in vitro tests.

The purpose of this work was to implement and assess the performance of interventions inside a cylindrical magnetic resonance imaging (MRI) scanner with an MR-compatible manipulator system and manipulator-driven real-time MR guidance. The interventional system is based on a seven degree-of-freedom MR-compatible manipulator, which offers man-in-the-loop control either with a graphical user interface or with a master/slave device. The position and the orientation of the interventional tool are sent to an MR scanner for a manipulator-driven dynamic update of the imaging plane to track, visualize and guide the motion of an end-effector. Studies on phantoms were performed with a cylindrical 1.5-T scanner using an operator-managed triggered gradient-recalled echo (GRE) or a computer-managed dynamic True Fast Imaging with Steady Precession (TrueFISP). Targets were acquired with an accuracy of 3.2 mm and with an in-plane path orientation of 2.5 degrees relative to the prescribed one. Path planning, including negotiation of obstacles and needle bending, was successfully performed. The signal-to-noise ratio (SNR) of TrueFISP was 25.3+/-2.1 when the manipulator was idle and was 18.6+/-2.4 during its operation. The SNR of triggered GRE (acquired only when the manipulator was idle) was 61.3+/-1.8. In conclusion, this study shows the feasibility of performing manually directed interventions inside cylindrical MR scanners with real-time MRI.

Arterial input functions for dynamic susceptibility contrast MRI: requirements and signal options.

Cerebral perfusion imaging using dynamic susceptibility contrast (DSC) has been the subject of considerable research and shows promise for basic science and clinical use. In DSC, the MRI signals in brain tissue and feeding arteries are monitored dynamically in response to a bolus injection of paramagnetic agents, such as gadolinium (Gd) chelates. DSC has the potential to allow quantitative imaging of parameters such as cerebral blood flow (CBF) with a high signal-to-noise ratio (SNR) in a short scan time; however, quantitation depends critically on accurate and precise measurement of the arterial input function (AIF). We discuss many requirements and factors that make it difficult to measure the AIF. The AIF signal should be linear with respect to Gd concentration, convertible to the same concentration scale as the tissue signal, and independent of hematocrit. Complicated relationships between signal and concentration can violate these requirements. The additional requirements of a high SNR and high spatial/temporal resolution are technically challenging. AIF measurements can also be affected by signal saturation and aliasing, as well as dispersion/delay between the AIF sampling site and the tissue. We present new in vivo preliminary results for magnitude-based (DeltaR2*) and phase-based (Deltaphi) AIF measurements that show a linearity advantage of phase, and a disparity in the scaling of Deltaphi AIFs, DeltaR2* AIFs, and DeltaR2* tissue curves. Finally, we discuss issues related to the choice of AIF signal for quantitative perfusion imaging.

Differential vulnerability of anterior white matter in nondemented aging with minimal acceleration in dementia of the Alzheimer type: evidence from diffusion tensor imaging.

White matter microstructural integrity was assessed using diffusion tensor imaging (DTI) in 25 young adults, 25 nondemented older adults, and 25 age-matched older adults with dementia of the Alzheimer type (DAT). For each individual, measures of anisotropy and diffusivity were obtained from atlas-transformed images in the anterior and posterior callosum and in the frontal, parietal, temporal and occipital white matter. These data revealed age differences in anisotropy and diffusivity in all assessed regions. Age effects were greater in the anterior as opposed to the posterior corpus callosum and greater in the frontal white matter than in the temporal, parietal and occipital white matter, suggesting age-associated differences in white matter that exhibit a roughly anterior-to-posterior gradient. In contrast, individuals with early-stage dementia exhibited minimal, if any, additional change in anterior regions but did show greater deterioration of white matter in posterior lobar regions. Taken collectively, these results indicate that nondemented aging is characterized by significant changes in white matter most prominently in anterior brain regions. The dissociation between the regional effects of age and dementia status suggests that the mechanisms underlying age-associated cognitive decline are likely distinct from those underlying DAT.

Functional reorganization and stability of somatosensory-motor cortical topography in a tetraplegic subject with late recovery.

The functional organization of somatosensory and motor cortex was investigated in an individual with a high cervical spinal cord injury, a 5-year absence of nearly all sensorymotor function at and below the shoulders, and rare recovery of some function in years 6-8 after intense and sustained rehabilitation therapies. We used functional magnetic resonance imaging to study brain activity to vibratory stimulation and voluntary movements of body parts above and below the lesion. No response to vibratory stimulation of the hand was observed in the primary somatosensory cortex (SI) hand area, which was conversely recruited during tongue movements that normally evoke responses only in the more lateral face area. This result suggests SI reorganization analogous to previously reported neuroplasticity changes after peripheral lesions in animals and humans. In striking contradistinction, vibratory stimulation of the foot evoked topographically appropriate responses in SI and second somatosensory cortex (SII). Motor cortex responses, tied to a visuomotor tracking task, displayed a near-typical topography, although they were more widespread in premotor regions. These findings suggest possible preservation of motor and some somatosensory cortical representations in the absence of overt movements or conscious sensations for several years after spinal cord injury and have implications for future rehabilitation and neural-repair therapies.