Parkinson's disease CA2-CA3 hippocampal atrophy is accompanied by increased cholinergic innervation in patients with normal cognition but not in patients with mild cognitive impairment.

Although brain cholinergic denervation has been largely associated with cognitive decline in patients with Parkinson's disease (PD), new evidence suggests that cholinergic upregulation occurs in the hippocampus of PD patients without cognitive deficits. The specific hippocampal sectors and potential mechanisms of this cholinergic compensatory process have been further studied here, using MRI volumetry and morphometry coupled with molecular imaging using the PET radiotracer [18F]-Fluoroethoxybenzovesamicol ([18F]-FEOBV). Following a thorough screening procedure, 18 participants were selected and evenly distributed in three groups, including cognitively normal PD patients (PD-CN), PD patients with mild cognitive impairment (PD-MCI), and healthy volunteers (HV). Participants underwent a detailed neuropsychological assessment, structural MRI, and PET imaging with [18F]-FEOBV. Basal forebrain Ch1-Ch2 volumes were measured using stereotaxic mapping. Hippocampal subfields were automatically defined using the MAGeT-Brain segmentation algorithm. Cholinergic innervation density was quantified using [18F]-FEOBV uptake. Compared with HV, both PD-CN and PD-MCI displayed significantly reduced volumes in CA2-CA3 bilaterally. We found no other hippocampal subfield nor Ch1-Ch2 volume differences between the three groups. PET imaging revealed higher [18F]-FEOBV uptake in CA2-CA3 of the PD-CN compared with HV or PD-MCI. A positive correlation was observed between cognitive performances and [18F]-FEOBV uptake in the right CA2-CA3 subfield. Reduced volume, together with increased [18F]-FEOBV uptake, were observed specifically in the CA2-CA3 hippocampal subfields. However, while the volume change was observed in both PD-CN and PD-MCI, increased [18F]-FEOBV uptake was present only in the PD-CN group. This suggests that a cholinergic compensatory process takes place in the atrophied CA2-CA3 hippocampal subfields and might underlie normal cognition in PD.

Hippocampal subfield associations with memory depend on stimulus modality and retrieval mode.

Hippocampal atrophy is a well-known feature of age-related memory decline, and hippocampal subfields may contribute differently to this decline. In this cross-sectional study, we investigated the associations between hippocampal subfield volumes and performance in free recall and recognition memory tasks in both verbal and visual modalities in older adults without dementia. We collected MRIs from 97 (41 males) right-handed participants aged over 60. We segmented the right and left hippocampi into (i) dentate gyrus and cornu ammonis 4 (DG/CA4); (ii) CA2 and CA3 (CA2/CA3); (iii) CA1; (iv) strata radiatum, lacunosum and moleculare; and (v) subiculum. Memory was assessed with verbal free recall and recognition tasks, as well as visual free recall and recognition tasks. Amyloid-ß and hippocampal tau positivity were assessed using [18F]AZD4694 and [18F]MK6240 PET tracers, respectively. The verbal free recall and verbal recognition performances were positively associated with CA1 and strata radiatum, lacunosum and moleculare volumes. The verbal free recall and visual free recall were positively correlated with the right DG/CA4. The visual free recall, but not verbal free recall, was also associated with the right CA2/CA3. The visual recognition was not significantly associated with any subfield volume. Hippocampal tau positivity, but not amyloid-ß positivity, was associated with reduced DG/CA4, CA2/CA3 and strata radiatum, lacunosum and moleculare volumes. Our results suggest that memory performances are linked to specific subfields. CA1 appears to contribute to the verbal modality, irrespective of the free recall or recognition mode of retrieval. In contrast, DG/CA4 seems to be involved in the free recall mode, irrespective of verbal or visual modalities. These results are concordant with the view that DG/CA4 plays a primary role in encoding a stimulus' distinctive attributes, and that CA2/CA3 could be instrumental in recollecting a visual memory from one of its fragments. Overall, we show that hippocampal subfield segmentation can be useful for detecting early volume changes and improve our understanding of the hippocampal subfields' roles in memory.

Equivalence of plasma p-tau217 with cerebrospinal fluid in the diagnosis of Alzheimer's disease.

INTRODUCTION: Plasma biomarkers are promising tools for Alzheimer's disease (AD) diagnosis, but comparisons with more established biomarkers are needed. METHODS: We assessed the diagnostic performance of p-tau181 , p-tau217 , and p-tau231 in plasma and CSF in 174 individuals evaluated by dementia specialists and assessed with amyloid-PET and tau-PET. Receiver operating characteristic (ROC) analyses assessed the performance of plasma and CSF biomarkers to identify amyloid-PET and tau-PET positivity. RESULTS: Plasma p-tau biomarkers had lower dynamic ranges and effect sizes compared to CSF p-tau. Plasma p-tau181 (AUC = 76%) and p-tau231 (AUC = 82%) assessments performed inferior to CSF p-tau181 (AUC = 87%) and p-tau231 (AUC = 95%) for amyloid-PET positivity. However, plasma p-tau217 (AUC = 91%) had diagnostic performance indistinguishable from CSF (AUC = 94%) for amyloid-PET positivity. DISCUSSION: Plasma and CSF p-tau217 had equivalent diagnostic performance for biomarker-defined AD. Our results suggest that plasma p-tau217 may help reduce the need for invasive lumbar punctures without compromising accuracy in the identification of AD. HIGHLIGHTS: p-tau217 in plasma performed equivalent to p-tau217 in CSF for the diagnosis of AD, suggesting the increased accessibility of plasma p-tau217 is not offset by lower accuracy. p-tau biomarkers in plasma had lower mean fold-changes between amyloid-PET negative and positive groups than p-tau biomarkers in CSF. CSF p-tau biomarkers had greater effect sizes than plasma p-tau biomarkers when differentiating between amyloid-PET positive and negative groups. Plasma p-tau181 and plasma p-tau231 performed worse than p-tau181 and p-tau231 in CSF for AD diagnosis.

Direct and Indirect Effects of Filamin A on Tau Pathology in Neuronal Cells.

In Alzheimer disease (AD), Tau, an axonal microtubule-associated protein, becomes hyperphosphorylated, detaches from microtubules, accumulates, and self-aggregates in the somatodendritic (SD) compartment. The accumulation of hyperphosphorylated and aggregated Tau is also seen in other neurodegenerative diseases such as frontotemporal lobar degeneration (FTLD-Tau). Previous studies reported a link between filamin A (FLNA), an actin-binding protein found in the SD compartment, and Tau pathology. In the present study, we further explored this link. We confirmed the interaction of Tau with FLNA in neuroblastoma 2a (N2a) cells. This interaction was mediated by a domain located between the 157 and 383 amino acids (a.a.) of Tau. Our results also revealed that the overexpression of FLNA resulted in an intracellular accumulation of wild-type Tau and Tau mutants (P301L, V337M, and R406W) in N2a cells. Tau phosphorylation and cleavage by caspase-3 but not its aggregation were increased upon FLNA overexpression in N2a cells. In the parietal cortex of AD brain, insoluble FLNA was increased compared to control brain, but it did not correlate with Tau pathology. Interestingly, Tau binding to microtubules and F-actin was preserved upon FLNA overexpression in N2a cells. Lastly, our results revealed that FLNA also induced the accumulation of annexin A2, a Tau interacting partner involved in its axonal localization. Collectively, our data indicated that in Tauopathies, FLNA could contribute to Tau pathology by acting on Tau and annexin A2.

Evidence of Filamin A loss of solubility at the prodromal stage of neuropathologically-defined Alzheimer's disease.

Introduction: Alzheimer's disease (AD) is a multifactorial disorder diagnosed through the assessment of amyloid-beta (Aß) and tau protein depositions. Filamin A (FLNA) could be a key partner of both Aß and tau pathological processes and may be an important contributor to AD progression. The main aim of this study was to describe the differences in FLNA levels across clinicopathologic groups. Methods: From parietal cortex samples of 57 individuals (19 with no cognitive impairment (NCI), 19 mild cognitively impaired (MCI) and 19 with dementia) from the Religious Orders Study (ROS), we quantified total tau, phosphorylated tau (pTau), FLNA, synaptophysin, vesicular acetylcholine transporters (VAChT) and choline acetyltransferase (ChAT) by Western blot. Aß42 and neuritic plaques (NP) were quantified by ELISA and Bielschowsky silver impregnation, respectively. AD staging was determined using ABC method combining Thal, Braak and the CERAD staging. From this, clinicopathologic stages of AD were established by subdividing subjects with neuropathological AD between preclinical AD, prodromal AD and AD dementia (ADD). Receiver operating characteristics analyses were performed to predict AD neuropathology from FLNA quantifications. Results: Insoluble FLNA was significantly and positively correlated with Aß42, NP, Thal stages, ABC scores and AD clinicopathologic stages (p < 0.05 False discovery rate-corrected). No correlation of FLNA with tau measures was found. Insoluble FLNA levels were significantly higher in the prodromal AD, ADD and intermediate ABC groups. This was consistent with significantly lower levels of soluble FLNA specifically in prodromal AD. Insoluble (AUC: 0.830) and soluble FLNA levels (AUC: 0.830) as well as the ratio of soluble over insoluble FLNA (AUC: 0.852), were excellent predictors of prodromal AD among subjects with MCI from the ROS cohort. Discussion: We observed opposite level changes between insoluble and soluble FLNA in prodromal AD. As this stage coincides with the appearance of cognitive symptoms, this may be a key event in the transition from preclinical to prodromal AD. Insoluble FLNA could be useful to identify prodromal AD among subjects with an MCI, indicating that it might be a hallmark of prodromal AD.

Mapping neurotransmitter systems to the structural and functional organization of the human neocortex.

Neurotransmitter receptors support the propagation of signals in the human brain. How receptor systems are situated within macro-scale neuroanatomy and how they shape emergent function remain poorly understood, and there exists no comprehensive atlas of receptors. Here we collate positron emission tomography data from more than 1,200 healthy individuals to construct a whole-brain three-dimensional normative atlas of 19 receptors and transporters across nine different neurotransmitter systems. We found that receptor profiles align with structural connectivity and mediate function, including neurophysiological oscillatory dynamics and resting-state hemodynamic functional connectivity. Using the Neurosynth cognitive atlas, we uncovered a topographic gradient of overlapping receptor distributions that separates extrinsic and intrinsic psychological processes. Finally, we found both expected and novel associations between receptor distributions and cortical abnormality patterns across 13 disorders. We replicated all findings in an independently collected autoradiography dataset. This work demonstrates how chemoarchitecture shapes brain structure and function, providing a new direction for studying multi-scale brain organization.

Normal cognition in Parkinson's disease may involve hippocampal cholinergic compensation: An exploratory PET imaging study with [18F]-FEOBV.

BACKGROUND: Severe cholinergic degeneration is known to occur in Parkinson's disease (PD) and is thought to play a primary role in the cognitive decline associated with this disease. Although cholinergic losses occur in all patients with PD, cognitive performance remains normal for many of them, suggesting compensatory mechanisms in those. OBJECTIVES: This exploratory study aimed at verifying if normal cognition in PD may involve distinctive features of the brain cholinergic systems. METHODS: Following extensive neuropsychological screening in 25 patients with PD, 12 were selected and evenly distributed between a cognitively normal (PD-CN) group, and a mild cognitive impairment (PD-MCI) group. Each group was compared with matched healthy volunteers (HV) on standardized cognitive scales (MoCA, PDCRS), and PET imaging with [18F]-FEOBV, a sensitive measurement of brain cholinergic innervation density. RESULTS: [18F]-FEOBV uptake reductions were observed in PD-CN as well as in PD-MCI, with the lowest values located in the posterior cortical areas. However, in PD-CN but not in PD-MCI, there was a significant and bilateral increase of [18F]-FEOBV uptake, exclusively located in the hippocampus. Significant correlations were observed between cognitive performance and hippocampal [18F]-FEOBV uptake. CONCLUSION: These findings suggest a compensatory upregulation of the hippocampal cholinergic innervation in PD-CN, which might underly normal cognitive performances in spite of cortical cholinergic denervation in other regions.

FEOBV-PET to quantify cortical cholinergic denervation in AD: Relationship to basal forebrain volumetry.

BACKGROUND AND PURPOSE: Fluorine-18-fluoroethoxybenzovesamicol([18 F]-FEOBV) is a PET radiotracer previously used in neurodegenerative diseases to quantify brain cholinergic denervation. The current exploratory study aimed at verifying the reliability of such an approach in Alzheimer's disease (AD) by demonstrating its concordance with MRI volumetry of the cholinergic basal forebrain (ChBF). METHODS: The sample included 12 participants evenly divided between healthy volunteers and patients with AD. All participants underwent MRI ChBF volumetry and PET imaging with [18 F]-FEOBV. Comparisons were made between the two groups, and partial correlations were performed in the AD patients between [18 F]-FEOBV uptake in specific cortical regions of interest (ROIs) and volumetry of the corresponding ChBF subareas, which include the nucleus basalis of Meynert (Ch4), and the medial septum/vertical limb of the diagonal band of Broca (Ch1/2). RESULTS: Patients with AD showed both lower ChBF-Ch4 volumetric values and lower [18 F]-FEOBV cortical uptake than healthy volunteers. Volumes of the Ch4 subdivision were significantly correlated with the [18 F]-FEOBV uptake values observed in the relevant ROIs. Volumes of the Ch1/2, which remains relatively unaffected in AD, did not correlate with [18 F]-FEOBV uptake in the hippocampus, nor in any cortical area. CONCLUSION: These results suggest that cortical cholinergic denervation as measured with [18 F]-FEOBV PET is proportional to ChBF atrophy measured by MRI-based volumetry, further supporting the reliability and validity of [18 F]-FEOBV PET to quantify cholinergic degeneration in AD.

Increased flanker task and forward digit span performance in caudate-nucleus-dependent response strategies.

One of two memory systems can be used to navigate in a new environment. Hippocampus-dependent spatial strategy consists of creating a cognitive map of an environment and caudate nucleus-dependent response strategy consists of memorizing a rigid sequence of turns. Spontaneous use of the response strategy is associated with greater activity and grey matter within the caudate nucleus while the spatial strategy is associated with greater activity and grey matter in the hippocampus. The caudate nucleus is involved in executive functions such as working memory, cognitive control and certain aspects of attention such as attentional disengaging. This study therefore aimed to investigate whether response learners would display better performance on tests of executive and attention functioning compared to spatial learners. Fifty participants completed the 4/8 virtual maze to assess navigational strategy, the forward and backward visual digit span and the Attention Network Test - Revised to assess both attention disengagement and cognitive control. Results revealed that response learners showed significantly higher working memory capacity, more efficient attention disengagement and better cognitive control. Results suggest that response learners, who putatively display more grey matter and activity in the caudate nucleus, are associated with better working memory span, cognitive control and attentional disengagement.

Caudate nucleus-dependent navigation strategies are associated with increased risk-taking and set-shifting behavior.

When people navigate, they use strategies dependent on one of two memory systems. The hippocampus-based spatial strategy consists of using multiple landmarks to create a cognitive map of the environment. In contrast, the caudate nucleus-based response strategy is based on the memorization of a series of turns. Importantly, response learners display more gray matter and functional activity in the caudate nucleus and less gray matter in the hippocampus. In parallel, the caudate nucleus is involved in decision-making by mediating attention toward rewards and in set-shifting by mediating preparatory actions. The present study, therefore, examined the link between navigational strategy use, that are associated with gray matter differences in the caudate nucleus and hippocampus, and decision-making and set-shifting performance. Fifty-three participants completed the 4 on 8 virtual maze, the Iowa Gambling Task (IGT), the Wisconsin Card Sorting Test-64 (WCST-64), and a task-switching test. The results revealed that people who use response strategies displayed increased risk-taking behavior in the IGT compared to the people using hippocampus-dependent spatial strategies. Response strategy was also associated with enhanced set-shifting performance in the WCST-64 and task-switching test. These results confirm that risk-taking and set-shifting behavior, that are differentially impacted by the caudate nucleus and hippocampus memory systems, can be predicted by navigational strategy.