Biology subjects

Wolk, D. A.

Publications and source records attributed to Wolk, D. A..

14 recordsLinked to original sources

bioRxiv2025

Postmortem brain MRI reveals differential associations of subcortical and limbic volumes with cortical thinning and neuropathology patterns

Structured AbstractO_ST_ABSIntroductionC_ST_ABSThe impact of different neuropathologies on deep brain structures remains to be understood. We examine subcortical and limbic volumetry in neurodegenerative diseases involving p-tau, -synuclein and TDP-43. MethodsWe acquired neuropathological measures and brain segmentations from postmortem analysis of 132 donors with Alzheimers disease (AD), Lewy body disease (LBD), Frontotemporal Lobar Degeneration with TDP-43 (FTLD-TDP) and FTLD-Tau. ResultsLBD had the least subcortical, limbic and cortical atrophy compared to AD, FTLD-TDP and FTLD-Tau. In donors with both AD and LBD pathologies, primary LBD was associated with less atrophy than primary AD. While AD had cortico-subcortical and cortico-limbic morphometric associations, LBD had more limited parieto-occipital cortico-limbic associations. FTLD-TDP had cortico-subcortical while FTLD-Tau had cortico-subcortical and cortico-limbic associations. In AD and FTLD-Tau, hippocampal volumes correlated with p-tau burden, neuron loss and gliosis. In LBD, thalamic -synuclein severity was associated with subcortical/limbic volumes. DiscussionPostmortem neuroimaging reveals disease- and region-specific structure-pathology relationships.

neuroscience↗

bioRxiv2025

Characterization of hippocampal subfields using histology-based annotated postmortem MRI: Lessons for in vivo segmentation II

High-resolution in vivo magnetic resonance imaging (MRI) of hippocampal subfields is a rapidly advancing field due to their implication in cognition, disorder, and disease. Hippocampal subfield segmentation on in vivo MRI is generally guided by postmortem reference material, which has been limited by small sample sizes that preclude comprehensive characterization of subfield border locations and their variability. Addressing this, we characterized hippocampal subfield border variability in two ultra-high-resolution postmortem MRI datasets with combined annotated histological sections, including cases with and without dementia. We examined: 1) the order of appearance and disappearance of subfields along the long axis of the hippocampus; 2) the order of appearance and disappearance of subicular subregions; 3) the medial-lateral position of subicular subregional boundaries along the hippocampal body; 4) the location of the CA3 relative to hippocampal head digitations; 5) the subfield borders in the hippocampal body relative to a volume proportion of the dark band; and 6) the association of hippocampal length and subiculum-CA1 border location with diagnosis, demographic factors, and factors related to postmortem imaging. Our findings reaffirmed that there is a consistent order of appearance and disappearance of subfields in the hippocampal head and tail, respectively. The subicular subregions exhibited a first in, last out order of appearance and disappearance, and pre/parasubiculum consistently occupied half of the subicular complex in coronal slices throughout the hippocampal body. Hippocampal head digitations were not a reliable landmark for CA3 appearance, but SRLM proportionality did offer a potentially consistent approach for estimating CA2 and CA3 subfield borders in relation to the hippocampal border. No clear relationship was found between the anatomical features and diagnosis, demographic factors, and factors related to postmortem imaging. These findings have implications for the development and harmonization of hippocampal subfield segmentation protocols and interpretation of high-resolution functional MRI studies of the human hippocampus.

neuroscience↗

bioRxiv2025

Developing an anatomically valid segmentation protocol for anterior regions of the medial temporal lobe for neurodegenerative diseases

BackgroundThe anterior portion of the medial temporal lobe (MTL) is one of the first regions targeted by pathology in sporadic Alzheimers disease (AD) and Limbic-predominant Age-related TDP-43 Encephalopathy (LATE) indicating a potential for metrics from this region to serve as imaging biomarkers. Leveraging a unique post-mortem dataset of histology and magnetic resonance imaging (MRI) scans we aimed to 1) develop an anatomically valid segmentation protocol for anterior entorhinal cortex (ERC), Brodmann Area (BA) 35, and BA36 for in vivo 3 tesla (T) MRI and 2) incorporate this protocol in an automated approach. MethodsWe included 20 cases (61-97 years old, 50% females) with and without neurodegenerative diseases (11 vs. 9 cases) to ensure generalizability of the developed protocol. Digitized MTL Nissl-stained coronal histology sections from these cases were annotated and registered to same-subject post-mortem MRI. The protocol was developed by determining the location of histological borders of the MTL cortices in relation to anatomical landmarks. Subsequently the protocol was applied to 15 cases twice, with a 2-week interval, to assess intra-rater reliability with the Dice Similarity Index (DSI). Thereafter it was implemented in our in- house Automatic Segmentation of Hippocampal Subfields (ASHS)-T1 approach and evaluated with DSIs. ResultsThe anterior histological border distances of ERC, BA35 and BA36 were evaluated with respect to various anatomical landmarks and the distance relative to the beginning of the hippocampus was chosen. To formulate segmentation rules, we examined the histological sections for the location of borders in relationship to anatomical landmarks in the coronal sections. The DSI for the anterior MTL cortices for the intra-rater reliability was 0.85-0.88 and for the ASHS-T1 against the manual segmentation was 0.62-0.65. DiscussionWe developed a reliable segmentation protocol and incorporated it in an automated approach. Given the vulnerability of the anterior MTL cortices to tau deposition in AD and LATE, the updated approach is expected to improve imaging biomarkers for these diseases.

neuroscience↗

bioRxiv2024

Neural correlates of age-related changes in social decisions from episodic memory

Older adults are frequent victims of financial scams. Previous behavioral research suggests that this may be due to systematic biases in how they make decisions about whom to trust: for instance, Lempert et al. (2022) found that relative to younger adults, older adults were more likely to base decisions about whether to re-engage with someone on how generous that person looked, rather than on their memory for how they had previously behaved. Here, we aimed to identify the neural correlates of these age-dependent changes in social decision-making in order to clarify the mechanism by which they emerge. Using functional Magnetic Resonance Imaging (fMRI), we measured neural activity while a total of 86 participants - 45 younger and 41 older adults - learned about how much of a $10 endowment an individual, represented by a picture of their face, was willing to share with them in a dictator game. After this encoding phase, participants then made decisions about whom they wanted to play another round of the dictator game with. In line with previous findings, we found that older adults did not reliably prefer to re-engage with people who had proven themselves to be generous. This bias was the result of several factors: (1) older adults had worse associative memory for how much each person had shared, possibly due to an age-dependent decrease in neural activity in the medial temporal lobe (MTL) during encoding, (2) older adults had a stronger tendency to re-engage with familiar over novel faces regardless of their past behavior, and (3) while activity in value-responsive brain regions tracked with how generous a face looked across the age range, older adults were less able to inhibit the influence of these irrelevant perceptual features when it was necessary to do so. In line with this behavioral effect, younger adults showed greater activation in the inferior frontal gyrus (IFG) during choices that required suppressing irrelevant perceptual features in favor of associative memory. Taken together, our findings highlight age-dependent changes in both the ability to encode relevant information and to adaptively deploy it in service of social decisions.

neuroscience↗

bioRxiv2024

Automatic segmentation of medial temporal lobe subregions in multi-scanner, multi-modality MRI of variable quality

ObjectivesVolumetry of subregions in the medial temporal lobe (MTL) computed from automatic segmentation in MRI can track neurodegeneration in Alzheimers disease. However, poor quality MR images can lead to unreliable segmentation of MTL subregions. Considering that different MRI contrast mechanisms and field strengths (jointly referred to as "modalities" here) offer distinct advantages in imaging different parts of the MTL, we developed a muti-modality segmentation model using both 7 tesla (7T) and 3 tesla (3T) structural MRI to obtain robust segmentation in poor-quality images. MethodMRI modalities including 3T T1-weighted, 3T T2-weighted, 7T T1-weighted and 7T T2-weighted (7T-T2w) of 197 participants were collected from a longitudinal aging study at the Penn Alzheimers Disease Research Center. Among them, 7T-T2w was used as the primary modality, and all other modalities were rigidly registered to the 7T-T2w. A model derived from nnU-Net took these registered modalities as input and outputted subregion segmentation in 7T-T2w space. 7T-T2w images most of which had high quality from 25 selected training participants were manually segmented to train the multi-modality model. Modality augmentation, which randomly replaced certain modalities with Gaussian noise, was applied during training to guide the model to extract information from all modalities. ResultsThe multi-modality model delivered good performance regardless of 7T-T2w quality, while the single-modality model under-segmented subregions in poor-quality images. The multi-modality model generally demonstrated stronger discrimination of A+MCI versus A-CU. Intra-class correlation and Bland-Altman plots demonstrate that the multi-modality model had higher longitudinal segmentation consistency in all subregions while the single-modality model had low consistency in poor-quality images. ConclusionThe multi-modality MRI segmentation model provides an improved biomarker for neurodegeneration in the MTL that is robust to image quality. It also provides a framework for other studies which may benefit from multimodal imaging.

bioengineering↗

bioRxiv2024

α-Synuclein Conformations in Plasma Distinguish Parkinson's Disease from Dementia with Lewy Bodies

AbstractSpread and aggregation of misfolded -synuclein (aSyn) within the brain is the pathologic hallmark of Lewy body diseases (LBD), including Parkinsons disease (PD) and dementia with Lewy bodies (DLB). While evidence exists for multiple aSyn protein conformations, often termed "strains" for their distinct biological properties, it is unclear whether PD and DLB result from aSyn strain differences, and biomarkers that differentiate PD and DLB are lacking. Moreover, while pathological forms of aSyn have been detected outside the brain (e.g., in skin, gut, blood), the functional significance of these peripheral aSyn species is unclear. Here, we developed assays using monoclonal antibodies selective for two different aSyn species generated in vitro - termed Strain A and Strain B - and used them to evaluate human brain tissue, cerebrospinal fluid (CSF), and plasma, through immunohistochemistry, enzyme-linked immunoassay, and immunoblotting. Surprisingly, we found that plasma aSyn species detected by these antibodies differentiated individuals with PD vs. DLB in a discovery cohort (UPenn, n=235, AUC 0.83) and a multi-site replication cohort (Parkinsons Disease Biomarker Program, or PDBP, n=200, AUC 0.72). aSyn plasma species detected by the Strain A antibody also predicted rate of cognitive decline in PD. We found no evidence for aSyn strains in CSF, and ability to template aSyn fibrillization differed for species isolated from plasma vs. brain, and in PD vs. DLB. Taken together, our findings suggest that aSyn conformational differences may impact clinical presentation and cortical spread of pathological aSyn. Moreover, the enrichment of these aSyn strains in plasma implicates a non-central nervous system source.

neuroscience↗

bioRxiv2022

Multiscale functional connectivity patterns of the aging brain learned from rsfMRI data of 4,259 individuals of the multi-cohort iSTAGING study

To learn multiscale functional connectivity patterns of the aging brain, we built a brain age prediction model of functional connectivity measures at seven scales on a large fMRI dataset, consisting of resting-state fMRI scans of 4259 individuals with a wide age range (22 to 97 years, with an average of 63) from five cohorts. We computed multiscale functional connectivity measures of individual subjects using a personalized functional network computational method, harmonized the functional connectivity measures of subjects from multiple datasets in order to build a functional brain age model, and finally evaluated how functional brain age gap correlated with cognitive measures of individual subjects. Our study has revealed that functional connectivity measures at multiple scales were more informative than those at any single scale for the brain age prediction, the data harmonization significantly improved the brain age prediction performance, and harmonization in the tangent space worked better than in the original space. Moreover, brain age gap scores of individual subjects derived from the brain age prediction model were significantly correlated with clinical and cognitive measures. Overall, these results demonstrated that multiscale functional connectivity patterns learned from a large-scale multi-site rsfMRI dataset were informative for characterizing the aging brain and the derived brain age gap was associated with cognitive and clinical measures.

bioengineering↗

bioRxiv2021

Joint ex vivo MRI and histology detect iron-rich cortical gliosis in Tau and TDP-43 proteinopathies

Frontotemporal lobar degeneration (FTLD) is a heterogeneous spectrum of age-associated neurodegenerative diseases that include two main pathologic categories of tau (FTLD-Tau) and TDP-43 (FTLD-TDP) proteinopathies. These distinct proteinopathies are often clinically indistinguishable during life, posing a major obstacle for diagnosis and emerging therapeutic trials tailored to disease-specific mechanisms. Moreover, MRI-derived measures have had limited success to date discriminating between FTLD-Tau or FTLD-TDP. T2*-weighted (T2*w) ex vivo MRI has previously been shown to be sensitive to non-heme iron in healthy intracortical lamination and myelin, and to pathological iron deposits in amyloid-beta plaques and activated microglia in Alzheimers disease (AD). However, an integrated, ex vivo MRI and histopathology approach is understudied in FTLD. We apply joint, whole-hemisphere ex vivo MRI at 7T and histopathology to the study autopsy-confirmed FTLD-Tau (n=3) and FTLD-TDP (n=2), relative to an AD disease-control brain with antemortem clinical symptoms of frontotemporal dementia and an age-matched healthy control. We detect distinct laminar patterns of novel iron-laden glial pathology in both FTLD-Tau and FTLD-TDP brains. We find iron-positive ameboid and hypertrophic microglia and astrocytes largely in deeper GM and adjacent WM in FTLD-Tau. In contrast, FTLD-TDP presents prominent superficial cortical layer iron reactivity in astrocytic processes enveloping small blood vessels with limited involvement of adjacent WM, as well as more diffuse distribution of punctate iron-rich dystrophic microglial processes across all GM lamina. This integrated MRI/histopathology approach reveals ex vivo MRI features that are consistent with these pathological observations distinguishing FTLD-Tau and FTLD-TDP, including prominent irregular hypointense signal in deeper cortex in FTLD-Tau whereas FTLD-TDP showed upper cortical layer hypointense bands and diffuse cortical speckling. Moreover, differences in adjacent WM degeneration and iron-rich gliosis on histology between FTLD-Tau and FTLD-TDP were also readily apparent on MRI as hyperintense signal and irregular areas of hypointensity, respectively that were more prominent in FTLD-Tau compared to FTLD-TDP. These unique histopathological and radiographic features were distinct from HC and AD brains, suggesting that iron-sensitive T2*w MRI, adapted to in vivo application at sufficient resolution, may offer an opportunity to improve antemortem diagnosis of FTLD proteinopathies using tissue-validated methods.

neuroscience↗

bioRxiv2021

3D Mapping of Neurofibrillary Tangle Burden in the Human Medial Temporal Lobe

Tau protein neurofibrillary tangles (NFT) are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimers disease (AD) and related dementias. Our knowledge of the pattern of NFT progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in AD, is based on conventional 2D histology studies that only sample the brain sparsely. To address this limitation, ex vivo MRI and dense serial histological imaging in 18 human medial temporal lobe (MTL) specimens were used to construct 3D quantitative maps of NFT burden in the MTL at individual and group levels. These maps reveal significant variation in NFT burden along the anterior-posterior axis. While early NFT pathology is thought to be confined to the transentorhinal region, we find similar levels of NFT burden in this region and other MTL subregions, including amygdala, temporopolar cortex, and subiculum/CA1.

neuroscience↗

bioRxiv2019

ATN status in amnestic and non-amnestic Alzheimer's disease and frontotemporal lobar degeneration

Under the ATN framework, cerebrospinal fluid analytes provide evidence of the presence or absence of Alzheimers disease pathological hallmarks: amyloid plaques (A), phosphorylated tau (T), and accompanying neurodegeneration (N). Still, differences in cerebrospinal fluid levels across amnestic and non-amnestic variants or due to co-occurring pathologies might lead to misdiagnoses. We assess the diagnostic accuracy of cerebrospinal fluid markers for amyloid, tau, and neurodegeneration in an autopsy cohort of 118 Alzheimers disease patients (98 amnestic; 20 non-amnestic) and 64 frontotemporal lobar degeneration patients (five amnestic; 59 non-amnestic). We calculated between-group differences in cerebrospinal fluid concentrations of amyloid-{beta}1-42 peptide, tau protein phosphorylated at threonine 181, total tau, and the ratio of phosphorylated tau to amyloid-{beta}1-42. Results show that non-amnestic Alzheimers disease patients were less likely to be correctly classified under the ATN framework using independent, published biomarker cutoffs for positivity. Amyloid-{beta}1-42 did not differ between amnestic and non-amnestic Alzheimers disease, and receiver operating characteristic curve analyses indicated that amyloid-{beta}1-42 was equally effective in discriminating both groups from frontotemporal lobar degeneration. However, cerebrospinal fluid concentrations of phosphorylated tau, total tau, and the ratio of phosphorylated tau to amyloid-{beta}1-42 were significantly lower in non-amnestic compared to amnestic Alzheimers disease patients. Receiver operating characteristic curve analyses for these markers showed reduced area under the curve when discriminating non-amnestic Alzheimers disease from frontotemporal lobar degeneration, compared to discrimination of amnestic Alzheimers disease from frontotemporal lobar degeneration. In addition, the ATN framework was relatively insensitive to frontotemporal lobar degeneration, and these patients were likely to be classified as having normal biomarkers or biomarkers suggestive of primary Alzheimers disease pathology. We conclude that amyloid-{beta}1-42 maintains high sensitivity to A status, although with lower specificity, and this single biomarker provides better sensitivity to non-amnestic Alzheimers disease than either the ATN framework or the phosphorylated-tau/amyloid-{beta}1-42 ratio. In contrast, T and N status biomarkers differed between amnestic and non-amnestic Alzheimers disease; standard cutoffs for phosphorylated tau and total tau may thus result in misclassifications for non-amnestic Alzheimers patients. Consideration of clinical syndrome may help improve the accuracy of ATN designations for identifying true non-amnestic Alzheimers disease. Abbreviated SummaryCousins et al. assess the 2018 ATN framework and find that non-amnestic patients with Alzheimers disease (AD) have lower cerebrospinal fluid (CSF) phosphorylated tau and total tau than amnestic AD, while CSF amyloid-{beta} accurately stratifies both non-amnestic and amnestic AD from frontotemporal lobar degeneration.

neuroscience↗

bioRxiv2019

Harmonization of large multi-site imaging datasets: Application to 10,232 MRIs for the analysis of imaging patterns of structural brain change throughout the lifespan

As medical imaging enters its information era and presents rapidly increasing needs for big data analytics, robust pooling and harmonization of imaging data across diverse cohorts with varying acquisition protocols have become critical. We describe a comprehensive effort that merges and harmonizes a large-scale dataset of 10,232 structural brain MRI scans from participants without known neuropsychiatric disorder from 18 different studies that represent geographic diversity. We use this dataset and multi-atlas-based image processing methods to obtain a hierarchical partition of the brain from larger anatomical regions to individual cortical and deep structures and derive normative age trends of brain structure through the lifespan (3 to 96 years old). Critically, we present and validate a methodology for harmonizing this pooled dataset in the presence of nonlinear age trends. We provide a web-based visualization interface to generate and present the resulting age trends, enabling future studies of brain structure to compare their data with this normative reference of brain development and aging, and to examine deviations from normative ranges, potentially related to disease.

bioinformatics↗

bioRxiv2019

Links between autobiographical memory richness and temporal discounting in older adults

When making choices between smaller, sooner rewards and larger, later ones, people tend to discount or devalue future outcomes. This propensity can be maladaptive, especially as individuals age and their decisions about health, investments, and relationships become increasingly consequential. Individual differences in temporal discounting in older adults have been associated with episodic memory abilities, as well as with cortical thickness in the entorhinal cortex. The mechanism by which better memory might lead to more future-oriented choice remains unclear, however. Here we used a fine-grained measure of autobiographical memory richness (Autobiographical Interview scoring protocol) to examine which categories of episodic details are associated with temporal discounting in cognitively normal older adults. We also examined whether recalling autobiographical memories prior to choice can alter temporal discounting in this group. Time, place, and perceptual details, but not event or emotion/thought details, were associated with temporal discounting. Furthermore, time, place, and perceptual details and temporal discount rates were associated with entorhinal cortical thickness. Retrieving autobiographical memories prior to choice did not affect temporal discounting overall, but the extent to which the memories were rich in event and time details predicted whether they would reduce discounting after they were recalled. Thus, more future-oriented decision-makers may have more contextual (i.e., time, place, and perceptual) details in their recollections overall, and retrieving central event details at the time of choice may shift decisions toward being more patient. These findings will help with the development of interventions to nudge intertemporal choices, especially in older adults with memory decline.

neuroscience↗

bioRxiv2019

Neural and behavioral correlates of declarative memory are associated with temporal discounting in older adults

When facing decisions involving trade-offs between smaller, sooner and larger, delayed rewards, people tend to discount the value of future rewards. There are substantial individual differences in this tendency toward temporal discounting, however. One neurocognitive system that may underlie these individual differences is episodic memory, given the overlap in the neural circuitry involved in imagining the future and remembering the past. Here we tested this hypothesis in older adults, including both those that were cognitively normal and those with amnestic mild cognitive impairment (MCI). We found that performance on neuropsychological measures of episodic memory retrieval was associated with temporal discounting, such that people with better memory discounted delayed rewards less. This relationship was specific to episodic memory and temporal discounting, since executive function (another cognitive ability) was unrelated to temporal discounting, and episodic memory was unrelated to risk tolerance (another decision-making preference). We also examined cortical thickness and volume in medial temporal lobe regions critical for episodic memory. Entorhinal cortical thickness was associated with reduced temporal discounting, with episodic memory performance partially mediating this association. The inclusion of MCI participants was critical to revealing these associations between episodic memory and entorhinal cortical thickness and temporal discounting. These effects were larger in the MCI group, reduced after controlling for MCI status, and statistically significant only when including MCI participants in analyses. Overall, these findings suggest that individual differences in temporal discounting are driven by episodic memory function, and that a decline in medial temporal lobe structural integrity may impact temporal discounting.

neuroscience↗

bioRxiv2019

Preserved global cerebral blood flow accounts for youthful processing speed in older adults

Preserved cognitive performance is one of the key contributors to successful aging. The processing speed theory and prefrontal executive theory - are competing theories regarding the general causes of cognitive aging. Here, we used a theoretically-driven framework to investigate the neural correlates of older adults with preserved processing speed. Older adults with youth-like processing speed (SuperAgers) were compared with normal aged adults (TypicalAgers) using neuroimaging methods. Global cerebral blood flow (CBF) accounted for approximately 45% of the variance in processing speed, while neither regional CBF nor other structural measures predicted additional variance. In addition, despite having significantly cortical thinning, SuperAgers still shown comparable global CBF levels with young adults. These results support the global mechanism suggested by processing speed theory and indicate that global CBF may serve as a biomarker of cognitive aging.

neuroscience↗