A worldwide study of white matter microstructural alterations in people living with Parkinson's disease.

The progression of Parkinson's disease (PD) is associated with microstructural alterations in neural pathways, contributing to both motor and cognitive decline. However, conflicting findings have emerged due to the use of heterogeneous methods in small studies. Here we performed a large diffusion MRI study in PD, integrating data from 17 cohorts worldwide, to identify stage-specific profiles of white matter differences. Diffusion-weighted MRI data from 1654 participants diagnosed with PD (age: 20-89 years; 33% female) and 885 controls (age: 19-84 years; 47% female) were analyzed using the ENIGMA-DTI protocol to evaluate white matter microstructure. Skeletonized maps of fractional anisotropy (FA) and mean diffusivity (MD) were compared across Hoehn and Yahr (HY) disease groups and controls to reveal the profile of white matter alterations at different stages. We found an enhanced, more widespread pattern of microstructural alterations with each stage of PD, with eventually lower FA and higher MD in almost all regions of interest: Cohen's d effect sizes reached d = -1.01 for FA differences in the fornix at PD HY Stage 4/5. The early PD signature in HY stage 1 included higher FA and lower MD across the entire white matter skeleton, in a direction opposite to that typical of other neurodegenerative diseases. FA and MD were associated with motor and non-motor clinical dysfunction. While overridden by degenerative changes in the later stages of PD, early PD is associated with paradoxically higher FA and lower MD in PD, consistent with early compensatory changes associated with the disorder.

Verbal Learning and Memory Deficits across Neurological and Neuropsychiatric Disorders: Insights from an ENIGMA Mega Analysis.

Deficits in memory performance have been linked to a wide range of neurological and neuropsychiatric conditions. While many studies have assessed the memory impacts of individual conditions, this study considers a broader perspective by evaluating how memory recall is differentially associated with nine common neuropsychiatric conditions using data drawn from 55 international studies, aggregating 15,883 unique participants aged 15-90. The effects of dementia, mild cognitive impairment, Parkinson's disease, traumatic brain injury, stroke, depression, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder on immediate, short-, and long-delay verbal learning and memory (VLM) scores were estimated relative to matched healthy individuals. Random forest models identified age, years of education, and site as important VLM covariates. A Bayesian harmonization approach was used to isolate and remove site effects. Regression estimated the adjusted association of each clinical group with VLM scores. Memory deficits were strongly associated with dementia and schizophrenia (p < 0.001), while neither depression nor ADHD showed consistent associations with VLM scores (p > 0.05). Differences associated with clinical conditions were larger for longer delayed recall duration items. By comparing VLM across clinical conditions, this study provides a foundation for enhanced diagnostic precision and offers new insights into disease management of comorbid disorders.

Early-phase amyloid PET reproduces metabolic signatures of cognitive decline in Parkinson's disease.

INTRODUCTION: Recent work suggests that amyloid beta (Aß) positron emission tomography (PET) tracer uptake shortly after injection ("early phase") reflects brain metabolism and perfusion. We assessed this modality in a predominantly amyloid-negative neurodegenerative condition, Parkinson's disease (PD), and hypothesized that early-phase 18F-florbetaben (eFBB) uptake would reproduce characteristic hypometabolism and hypoperfusion patterns associated with cognitive decline in PD. METHODS: One hundred fifteen PD patients across the spectrum of cognitive impairment underwent dual-phase Aß PET, structural and arterial spin labeling (ASL) magnetic resonance imaging (MRI), and neuropsychological assessments. Multiple linear regression models compared eFBB uptake to cognitive performance and ASL MRI perfusion. RESULTS: Reduced eFBB uptake was associated with cognitive performance in brain regions previously linked to hypometabolism-associated cognitive decline in PD, independent of amyloid status. Furthermore, eFBB uptake correlated with cerebral perfusion across widespread regions. DISCUSSION: EFBB uptake is a potential surrogate measure for cerebral perfusion/metabolism. A dual-phase PET imaging approach may serve as a clinical tool for assessing cognitive impairment. Highlights: Images taken at amyloid beta (Aß) positron emission tomography tracer injection may reflect brain perfusion and metabolism.Parkinson's disease (PD) is a predominantly amyloid-negative condition.Early-phase florbetaben (eFBB) in PD was associated with cognitive performance.eFBB uptake reflects hypometabolism-related cognitive decline in PD.eFBB correlated with arterial spin labeling magnetic resonance imaging measured cerebral perfusion.eFBB distinguished dementia from normal cognition and mild cognitive impairment.Findings were independent of late-phase Aß burden.Thus, eFBB may serve as a surrogate measure for brain metabolism/perfusion.

Cross-Sectional and Longitudinal Association of Clinical and Neurocognitive Factors With Apathy in Patients With Parkinson Disease.

BACKGROUND AND OBJECTIVES: A robust understanding of the natural history of apathy in Parkinson disease (PD) is foundational for developing effective clinical management tools. However, large longitudinal studies are lacking while the literature is inconsistent about even cross-sectional associations. We aimed to determine the longitudinal predictors of apathy development in a large cohort of people with PD and its cross-sectional associations and trajectories over time, using sophisticated Bayesian modeling techniques. METHODS: People with PD followed up in the longitudinal New Zealand Parkinson's progression project were included. Apathy was defined using the neuropsychiatric inventory subscale ≥4, and analyses were also repeated using a less stringent cutoff of ≥1. Both MoCA and comprehensive neuropsychological testing were used as appropriate to the model. Depression was assessed using the hospital anxiety and depression scale. Cross-sectional Bayesian regressions were conducted, and a multistate predictive model was used to identify factors that predict the initial onset of apathy in nonapathetic PD, while also accounting for the competing risk of death. The relationship between apathy presence and mortality was also investigated. RESULTS: Three hundred forty-six people with PD followed up for up to 14 years across a total of 1,392 sessions were included. Apathy occurrence did not vary significantly across the disease course (disease duration odds ratio [OR] = 0.55, [95% CI 0.28-1.12], affecting approximately 11% or 22% of people at any time depending on the NPI cutoff used. Its presence was associated with a significantly higher risk of death after controlling for all other factors (hazard ratio [HR] = 2.92 [1.50-5.66]). Lower cognition, higher depression levels, and greater motor severity predicted apathy development in those without motivational deficits (HR [cognition] = 0.66 [0.48-0.90], HR [depression] = 1.45 [1.04-2.02], HR [motor severity] = 1.37 [1.01-1.86]). Cognition and depression were also associated with apathy cross-sectionally, along with male sex and possibly lower dopaminergic therapy level, but apathy still occurred across the full spectrum of each variable (OR [cognition] = 0.58 [0.44-0.76], OR [depression] = 1.43 [1.04-1.97], OR [female sex] = 0.45 [0.22-0.92], and OR [levodopa equivalent dose] = 0.78 [0.59-1.04]. DISCUSSION: Apathy occurs across the PD time course and is associated with higher mortality. Depressive symptoms and cognitive impairment in particular predict its future development in those with normal motivation.

Multiple Genes Core to ERAD, Macroautophagy and Lysosomal Degradation Pathways Participate in the Proteostasis Response in α1-Antitrypsin Deficiency.

BACKGROUND & AIMS: In the classic form of α1-antitrypsin deficiency (ATD), the misfolded α1-antitrypsin Z (ATZ) variant accumulates in the endoplasmic reticulum (ER) of liver cells. A gain-of-function proteotoxic mechanism is responsible for chronic liver disease in a subgroup of homozygotes. Proteostatic response pathways, including conventional endoplasmic reticulum-associated degradation and autophagy, have been proposed as the mechanisms that allow cellular adaptation and presumably protection from the liver disease phenotype. Recent studies have concluded that a distinct lysosomal pathway called endoplasmic reticulum-to-lysosome completely supplants the role of the conventional macroautophagy pathway in degradation of ATZ. Here, we used several state-of-the-art approaches to characterize the proteostatic responses more fully in cellular systems that model ATD. METHODS: We used clustered regularly interspaced short palindromic repeats (CRISPR)-mediated genome editing coupled to a cell selection step by fluorescence-activated cell sorter to perform screening for proteostasis genes that regulate ATZ accumulation and combined that with selective genome editing in 2 other model systems. RESULTS: Endoplasmic reticulum-associated degradation genes are key early regulators and multiple autophagy genes, from classic as well as from ER-to-lysosome and other newly described ER-phagy pathways, participate in degradation of ATZ in a manner that is temporally regulated and evolves as ATZ accumulation persists. Time-dependent changes in gene expression are accompanied by specific ultrastructural changes including dilation of the ER, formation of globular inclusions, budding of autophagic vesicles, and alterations in the overall shape and component parts of mitochondria. CONCLUSIONS: Macroautophagy is a critical component of the proteostasis response to cellular ATZ accumulation and it becomes more important over time as ATZ synthesis continues unabated. Multiple subtypes of macroautophagy and nonautophagic lysosomal degradative pathways are needed to respond to the high concentrations of misfolded protein that characterizes ATD and these pathways are attractive candidates for genetic variants that predispose to the hepatic phenotype.

DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance.

Targeted protein degradation (TPD) mediates protein level through small molecule induced redirection of E3 ligases to ubiquitinate neo-substrates and mark them for proteasomal degradation. TPD has recently emerged as a key modality in drug discovery. So far only a few ligases have been utilized for TPD. Interestingly, the workhorse ligase CRBN has been observed to be downregulated in settings of resistance to immunomodulatory inhibitory drugs (IMiDs). Here we show that the essential E3 ligase receptor DCAF1 can be harnessed for TPD utilizing a selective, non-covalent DCAF1 binder. We confirm that this binder can be functionalized into an efficient DCAF1-BRD9 PROTAC. Chemical and genetic rescue experiments validate specific degradation via the CRL4DCAF1 E3 ligase. Additionally, a dasatinib-based DCAF1 PROTAC successfully degrades cytosolic and membrane-bound tyrosine kinases. A potent and selective DCAF1-BTK-PROTAC (DBt-10) degrades BTK in cells with acquired resistance to CRBN-BTK-PROTACs while the DCAF1-BRD9 PROTAC (DBr-1) provides an alternative strategy to tackle intrinsic resistance to VHL-degrader, highlighting DCAF1-PROTACS as a promising strategy to overcome ligase mediated resistance in clinical settings.

Cerebellar Volume and Disease Staging in Parkinson's Disease: An ENIGMA-PD Study.

BACKGROUND: Increasing evidence points to a pathophysiological role for the cerebellum in Parkinson's disease (PD). However, regional cerebellar changes associated with motor and non-motor functioning remain to be elucidated. OBJECTIVE: To quantify cross-sectional regional cerebellar lobule volumes using three dimensional T1-weighted anatomical brain magnetic resonance imaging from the global ENIGMA-PD working group. METHODS: Cerebellar parcellation was performed using a deep learning-based approach from 2487 people with PD and 1212 age and sex-matched controls across 22 sites. Linear mixed effects models compared total and regional cerebellar volume in people with PD at each Hoehn and Yahr (HY) disease stage, to an age- and sex- matched control group. Associations with motor symptom severity and Montreal Cognitive Assessment scores were investigated. RESULTS: Overall, people with PD had a regionally smaller posterior lobe (dmax = -0.15). HY stage-specific analyses revealed a larger anterior lobule V bilaterally (dmax = 0.28) in people with PD in HY stage 1 compared to controls. In contrast, smaller bilateral lobule VII volume in the posterior lobe was observed in HY stages 3, 4, and 5 (dmax = -0.76), which was incrementally lower with higher disease stage. Within PD, cognitively impaired individuals had lower total cerebellar volume compared to cognitively normal individuals (d = -0.17). CONCLUSIONS: We provide evidence of a dissociation between anterior "motor" lobe and posterior "non-motor" lobe cerebellar regions in PD. Whereas less severe stages of the disease are associated with larger motor lobe regions, more severe stages of the disease are marked by smaller non-motor regions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The thalamic reuniens is associated with consolidation of non-spatial memory too.

The nucleus reuniens (RE) is situated in the midline thalamus and provides a key link between the hippocampus and prefrontal cortex. This anatomical relationship positions the Re as an ideal candidate to facilitate memory consolidation. However, there is no evidence that this role extends beyond spatial memory and contextual fear memory, which are both strongly associated with hippocampal function. We, therefore, trained intact male Long-Evans rats on an odor-trace-object paired-associate task where the explicit 10-s delay between paired items renders the task sensitive to hippocampal function. Neurons in the RE showed significantly increased activation of the immediate early gene (Zif268) when rats were re-tested for previous non-spatial memory 25 days after acquisition training, compared to a group tested at 5-days post-acquisition, as well as a control group tested 25 days after acquisition but with a new pair of non-spatial stimuli, and home cage controls. The remote recall group also showed relatively augmented IEG expression in the superficial layers of the medial PFC (anterior cingulate cortex and prelimbic cortex). These findings support the conclusion that the RE is preferentially engaged during remote recall in this non-spatial task and thus has a role beyond spatial memory and contextual fear memory.

Expressed Barcoding Enables High-Resolution Tracking of the Evolution of Drug Tolerance.

For a majority of patients with non-small cell lung cancer with EGFR mutations, treatment with EGFR inhibitors (EGFRi) induces a clinical response. Despite this initial reduction in tumor size, residual disease persists that leads to disease relapse. Elucidating the preexisting biological differences between sensitive cells and surviving drug-tolerant persister cells and deciphering how drug-tolerant cells evolve in response to treatment could help identify strategies to improve the efficacy of EGFRi. In this study, we tracked the origins and clonal evolution of drug-tolerant cells at a high resolution by using an expressed barcoding system coupled with single-cell RNA sequencing. This platform enabled longitudinal profiling of gene expression and drug sensitivity in response to EGFRi across a large number of clones. Drug-tolerant cells had higher expression of key survival pathways such as YAP and EMT at baseline and could also differentially adapt their gene expression following EGFRi treatment compared with sensitive cells. In addition, drug combinations targeting common downstream components (MAPK) or orthogonal factors (chemotherapy) showed greater efficacy than EGFRi alone, which is attributable to broader targeting of the heterogeneous EGFRi-tolerance mechanisms present in tumors. Overall, this approach facilitates thorough examination of clonal evolution in response to therapy that could inform the development of improved diagnostic approaches and treatment strategies for targeting drug-tolerant cells. SIGNIFICANCE: The evolution and heterogeneity of EGFR inhibitor tolerance are identified in a large number of clones at enhanced cellular and temporal resolution using an expressed barcode technology coupled with single-cell RNA sequencing.

Acquired Stuttering in Parkinson's Disease.

Background: Parkinson's disease frequently causes communication impairments, but knowledge about the occurrence of new-onset stuttering is limited. Objectives: To determine the presence of acquired neurogenic stuttering and its relationship with cognitive and motor functioning in individuals with Parkinson's disease. Method: Conversation, picture description, and reading samples were collected from 100 people with Parkinson's disease and 25 controls to identify the presence of stuttered disfluencies (SD) and their association with neuropsychological test performance and motor function. Results: Participants with Parkinson's disease presented with twice as many stuttered disfluencies during conversation (2.2% ± 1.8%SD) compared to control participants (1.2% ± 1.2%SD; P < 0.01). 21% of people with Parkinson's disease (n = 20/94) met the diagnostic criterion for stuttering, compared with 1/25 controls. Stuttered disfluencies also differed significantly across speech tasks, with more disfluencies during conversation compared to reading (P < 0.01). Stuttered disfluencies in those with Parkinson's disease were associated with longer time since disease onset (P < 0.01), higher levodopa equivalent dosage (P < 0.01), and lower cognitive (P < 0.01) and motor scores (P < 0.01). Conclusion: One in five participants with Parkinson's disease presented with acquired neurogenic stuttering, suggesting that speech disfluency assessment, monitoring and intervention should be part of standard care. Conversation was the most informative task for identifying stuttered disfluencies. The frequency of stuttered disfluencies was higher in participants with worse motor functioning, and lower cognitive functioning. This challenges previous suggestions that the development of stuttered disfluencies in Parkinson's disease has purely a motoric basis.

Altered nucleus accumbens functional connectivity precedes apathy in Parkinson's disease.

Work in animal and human neuroscience has identified neural regions forming a network involved in the production of motivated, goal-directed behaviour. In particular, the nucleus accumbens and anterior cingulate cortex are recognized as key network nodes underlying decisions of whether to exert effort for reward, to drive behaviour. Previous work has convincingly shown that this cognitive mechanism, known as effort-based decision making, is altered in people with Parkinson's disease with a syndrome of reduced goal-directed behaviour-apathy. Building on this work, we investigated whether the neural regions implementing effort-based decision-making were associated with apathy in Parkinson's disease, and more importantly, whether changes to these regions were evident prior to apathy development. We performed a large, multimodal neuroimaging analysis in a cohort of people with Parkinson's disease (n = 199) with and without apathy at baseline. All participants had ∼2-year follow-up apathy scores, enabling examination of brain structure and function specifically in those with normal motivation who converted to apathy by ∼2-year follow-up. In addition, of the people with normal motivation, a subset (n = 56) had follow-up neuroimaging data, allowing for examination of the 'rate of change' in key nodes over time in those who did, and did not, convert to apathy. Healthy control (n = 54) data were also included to aid interpretation of findings. Functional connectivity between the nucleus accumbens and dorsal anterior cingulate cortex was higher in people with normal motivation who later converted to apathy compared to those who did not, whereas no structural differences were evident between these groups. In contrast, grey matter volume in these regions was reduced in the group with existing apathy. Furthermore, of those with normal motivation who had undergone longitudinal neuroimaging, converters to apathy showed a higher rate of change in grey matter volume within the nucleus accumbens. Overall, we show that changes in functional connectivity between nucleus accumbens and anterior cingulate cortex precedes apathy in people with Parkinson's disease, with conversion to apathy associated with higher rate of grey matter volume loss in nucleus accumbens, despite no baseline differences. These findings significantly add to an accumulating body of transdiagnostic evidence that apathy arises from disruption to key nodes within a network in which normal goal-directed behaviour is instantiated, and raise the possibility of identifying those at risk for developing apathy before overt motivational deficits have arisen.

Neuron arbor geometry is sensitive to the limited-range fractal properties of their dendrites.

Fractal geometry is a well-known model for capturing the multi-scaled complexity of many natural objects. By analyzing three-dimensional images of pyramidal neurons in the rat hippocampus CA1 region, we examine how the individual dendrites within the neuron arbor relate to the fractal properties of the arbor as a whole. We find that the dendrites reveal unexpectedly mild fractal characteristics quantified by a low fractal dimension. This is confirmed by comparing two fractal methods-a traditional "coastline" method and a novel method that examines the dendrites' tortuosity across multiple scales. This comparison also allows the dendrites' fractal geometry to be related to more traditional measures of their complexity. In contrast, the arbor's fractal characteristics are quantified by a much higher fractal dimension. Employing distorted neuron models that modify the dendritic patterns, deviations from natural dendrite behavior are found to induce large systematic changes in the arbor's structure and its connectivity within a neural network. We discuss how this sensitivity to dendrite fractality impacts neuron functionality in terms of balancing neuron connectivity with its operating costs. We also consider implications for applications focusing on deviations from natural behavior, including pathological conditions and investigations of neuron interactions with artificial surfaces in human implants.

Cyclic Glycine-Proline (cGP) Normalises Insulin-Like Growth Factor-1 (IGF-1) Function: Clinical Significance in the Ageing Brain and in Age-Related Neurological Conditions.

Insulin-like growth factor-1 (IGF-1) function declines with age and is associated with brain ageing and the progression of age-related neurological conditions. The reversible binding of IGF-1 to IGF binding protein (IGFBP)-3 regulates the amount of bioavailable, functional IGF-1 in circulation. Cyclic glycine-proline (cGP), a metabolite from the binding site of IGF-1, retains its affinity for IGFBP-3 and competes against IGF-1 for IGFBP-3 binding. Thus, cGP and IGFBP-3 collectively regulate the bioavailability of IGF-1. The molar ratio of cGP/IGF-1 represents the amount of bioavailable and functional IGF-1 in circulation. The cGP/IGF-1 molar ratio is low in patients with age-related conditions, including hypertension, stroke, and neurological disorders with cognitive impairment. Stroke patients with a higher cGP/IGF-1 molar ratio have more favourable clinical outcomes. The elderly with more cGP have better memory retention. An increase in the cGP/IGF-1 molar ratio with age is associated with normal cognition, whereas a decrease in this ratio with age is associated with dementia in Parkinson disease. In addition, cGP administration reduces systolic blood pressure, improves memory, and aids in stroke recovery. These clinical and experimental observations demonstrate the role of cGP in regulating IGF-1 function and its potential clinical applications in age-related brain diseases as a plasma biomarker for-and an intervention to improve-IGF-1 function.

Bridging Big Data: Procedures for Combining Non-equivalent Cognitive Measures from the ENIGMA Consortium.

Investigators in neuroscience have turned to Big Data to address replication and reliability issues by increasing sample sizes, statistical power, and representativeness of data. These efforts unveil new questions about integrating data arising from distinct sources and instruments. We focus on the most frequently assessed cognitive domain - memory testing - and demonstrate a process for reliable data harmonization across three common measures. We aggregated global raw data from 53 studies totaling N = 10,505 individuals. A mega-analysis was conducted using empirical bayes harmonization to remove site effects, followed by linear models adjusting for common covariates. A continuous item response theory (IRT) model estimated each individual's latent verbal learning ability while accounting for item difficulties. Harmonization significantly reduced inter-site variance while preserving covariate effects, and our conversion tool is freely available online. This demonstrates that large-scale data sharing and harmonization initiatives can address reproducibility and integration challenges across the behavioral sciences.

Extracellular vesicle biomarkers for cognitive impairment in Parkinson's disease.

Besides motor symptoms, many individuals with Parkinson's disease develop cognitive impairment perhaps due to coexisting α-synuclein and Alzheimer's disease pathologies and impaired brain insulin signalling. Discovering biomarkers for cognitive impairment in Parkinson's disease could help clarify the underlying pathogenic processes and improve Parkinson's disease diagnosis and prognosis. This study used plasma samples from 273 participants: 103 Parkinson's disease individuals with normal cognition, 121 Parkinson's disease individuals with cognitive impairment (81 with mild cognitive impairment, 40 with dementia) and 49 age- and sex-matched controls. Plasma extracellular vesicles enriched for neuronal origin were immunocaptured by targeting the L1 cell adhesion molecule, then biomarkers were quantified using immunoassays. α-Synuclein was lower in Parkinson's disease compared to control individuals (P = 0.004) and in cognitively impaired Parkinson's disease individuals compared to Parkinson's disease with normal cognition (P < 0.001) and control (P < 0.001) individuals. Amyloid-ß42 did not differ between groups. Phosphorylated tau (T181) was higher in Parkinson's disease than control individuals (P = 0.003) and in cognitively impaired compared to cognitively normal Parkinson's disease individuals (P < 0.001) and controls (P < 0.001). Total tau was not different between groups. Tyrosine-phosphorylated insulin receptor substrate-1 was lower in Parkinson's disease compared to control individuals (P = 0.03) and in cognitively impaired compared to cognitively normal Parkinson's disease individuals (P = 0.02) and controls (P = 0.01), and also decreased with increasing motor symptom severity (P = 0.005); serine312-phosphorylated insulin receptor substrate-1 was not different between groups. Mechanistic target of rapamycin was not different between groups, whereas phosphorylated mechanistic target of rapamycin trended lower in cognitively impaired compared to cognitively normal Parkinson's disease individuals (P = 0.05). The ratio of α-synuclein to phosphorylated tau181 was lower in Parkinson's disease compared to controls (P = 0.001), in cognitively impaired compared to cognitively normal Parkinson's disease individuals (P < 0.001) and decreased with increasing motor symptom severity (P < 0.001). The ratio of insulin receptor substrate-1 phosphorylated serine312 to insulin receptor substrate-1 phosphorylated tyrosine was higher in Parkinson's disease compared to control individuals (P = 0.01), in cognitively impaired compared to cognitively normal Parkinson's disease individuals (P = 0.02) and increased with increasing motor symptom severity (P = 0.003). α-Synuclein, phosphorylated tau181 and insulin receptor substrate-1 phosphorylated tyrosine contributed in diagnostic classification between groups. These findings suggest that both α-synuclein and tau pathologies and impaired insulin signalling underlie Parkinson's disease with cognitive impairment. Plasma neuronal extracellular vesicles biomarkers may inform cognitive prognosis in Parkinson's disease.

Anterior thalamic nuclei: A critical substrate for non-spatial paired-associate memory in rats.

Injury or dysfunction in the anterior thalamic nuclei (ATN) may be the key contributory factor in many instances of diencephalic amnesia. Experimental ATN lesions impair spatial memory and temporal discriminations, but there is only limited support for a more general role in non-spatial memory. To extend evidence on the effects of ATN lesions, we examined the acquisition of biconditional associations between odour and object pairings presented in a runway, either with or without a temporal gap between these items. Intact adult male rats acquired both the no-trace and 10-s trace versions of this non-spatial task. Intact rats trained in the trace version showed elevated Zif268 activation in the dorsal CA1 of the hippocampus, suggesting that the temporal component recruited additional neural processing. ATN lesions completely blocked acquisition on both versions of this association-memory task. This deficit was not due to poor inhibition to non-rewarded cues or impaired sensory processing, because rats with ATN lesions were unimpaired in the acquisition of simple odour discriminations and simple object discriminations using similar task demands in the same apparatus. This evidence challenges the view that impairments in arbitrary paired-associate learning after ATN lesions require the use of multimodal spatial stimuli. It suggests that diencephalic amnesia associated with the ATN stems from degraded attention to stimulus-stimulus associations and their representation across a distributed memory system.

Investigating Fractal Analysis as a Diagnostic Tool That Probes the Connectivity of Hippocampal Neurons.

Many of nature's fractal objects benefit from the favorable functionality that results from their pattern repetition at multiple scales. Our recent research focused on the importance of fractal scaling in establishing connectivity between neurons. Fractal dimension D A of the neuron arbors was shown to relate to the optimization of competing functional constraints-the ability of dendrites to connect to other neurons versus the costs associated with building the dendrites. Here, we consider whether pathological states of neurons might affect this fractal optimization and if changes in D A might therefore be used as a diagnostic tool in parallel with traditional measures like Sholl analyses. We use confocal microscopy to obtain images of CA1 pyramidal neurons in the coronal plane of the dorsal rat hippocampus and construct 3-dimensional models of the dendritic arbors using Neurolucida software. We examine six rodent groups which vary in brain condition (whether they had lesions in the anterior thalamic nuclei, ATN) and experience (their housing environment and experience in a spatial task). Previously, we showed ATN lesions reduced spine density in hippocampal CA1 neurons, whereas enriched housing increased spine density in both ATN lesion and sham rats. Here, we investigate whether ATN lesions and experience also effect the complexity and connectivity of CA1 dendritic arbors. We show that sham rats exposed to enriched housing and spatial memory training exhibited higher complexity (as measured by D A ) and connectivity compared to other groups. When we categorize the rodent groups into those with or without lesions, we find that both categories achieve an optimal balance of connectivity with respect to material cost. However, the D A value used to achieve this optimization does not change between these two categories, suggesting any morphological differences induced by the lesions are too small to influence the optimization process. Accordingly, we highlight considerations associated with applying our technique to publicly accessible repositories of neuron images with a broader range of pathological conditions.

Reproducibility and repeatability of magnetic resonance imaging in dementia.

PURPOSE: Individualised predictive models of cognitive decline require disease-monitoring markers that are repeatable. For wide-spread adoption, such markers also need to be reproducible at different locations. This study assessed the repeatability and reproducibility of MRI markers derived from a dementia protocol. METHODS: Six participants were scanned at three different sites with a 3T MRI scanner. The protocol employed: T1-weighted (T1w) imaging, resting state functional MRI (rsfMRI), arterial spin labelling (ASL), diffusion-weighted imaging (DWI), T2-weighted fluid attenuation inversion recovery (FLAIR), T2-weighted (T2w) imaging, and susceptibility weighted imaging (SWI). Participants were scanned repeatedly, up to six times over a maximum period of five years. One participant was also scanned a further three times on sequential days on one scanner. Fifteen derived metrics were computed from the seven different modalities. RESULTS: Reproducibility (coefficient of variation; CoV, across sites) was best for T1w derived grey matter, white matter and hippocampal volume (CoV < 1.5%), compared to rsfMRI and SWI derived metrics (CoV, 19% and 21%). For a given metric, long-term repeatability (CoV across time) was comparable to reproducibility, with short-term repeatability considerably better. CONCLUSIONS: Reproducibility and repeatability were assessed for a suite of markers calculated from a dementia MRI protocol. In general, structural markers were less variable than functional MRI markers. Variability over time on the same scanner was comparable to variability measured across different scanners. Overall, the results support the viability of multi-site longitudinal studies for monitoring cognitive decline.

Level I PD-MCI Using Global Cognitive Tests and the Risk for Parkinson's Disease Dementia.

Background: The criteria for PD-MCI allow the use of global cognitive tests. Their predictive value for conversion from PD-MCI to PDD, especially compared to comprehensive neuropsychological assessment, is unknown. Methods: The MDS PD-MCI Study Group combined four datasets containing global cognitive tests as well as a comprehensive neuropsychological assessment to define PD-MCI (n = 467). Risk for developing PDD was examined using a Cox model. Global cognitive tests were compared to neuropsychological test batteries (Level I&II) in determining risk for PDD. Results: PD-MCI based on a global cognitive test (MMSE or MoCA) increases the hazard for developing PDD (respectively HR = 2.57, P = 0.001; HR = 4.14, P = <0.001). The C-statistics for MMSE (0.72) and MoCA (0.70) were lower than those based on neuropsychological tests (Level I = 0.82; Level II = 0.81). Sensitivity, specificity and diagnostic accuracy balance was best in Level II. Conclusion: MMSE and MoCA predict conversion to PDD. However, Level II neuropsychological assessment seems the preferred assessment for PD-MCI.