Dimerization of the Alzheimer's disease pathogenic receptor SORLA regulates its association with retromer.

SORL1, the gene encoding the large multidomain SORLA protein, has emerged as only the fourth gene that when mutated can by itself cause Alzheimer's disease (AD), and as a gene reliably linked to both the early- and late-onset forms of the disease. SORLA is known to interact with the endosomal trafficking regulatory complex called retromer in regulating the recycling of endosomal cargo, including the amyloid precursor protein (APP) and the glutamate receptor GluA1. Nevertheless, SORLA's precise structural-functional relationship in endosomal recycling tubules remains unknown. Here, we address these outstanding questions by relying on crystallographic and artificial-intelligence evidence to generate a structural model for how SORLA folds and fits into retromer-positive endosomal tubules, where it is found to dimerize via both SORLA's fibronectin-type-III (3Fn)- and VPS10p-domains. Moreover, we identify a SORLA fragment comprising the 3Fn-, transmembrane, and cytoplasmic domains that has the capacity to form a dimer, and to enhance retromer-dependent recycling of APP by decreasing its amyloidogenic processing. Collectively, these observations generate a model for how SORLA dimer (and possibly polymer) formation can function in stabilizing and enhancing retromer function at endosome tubules. These findings can inform investigation of the many AD-associated SORL1 variants for evidence of pathogenicity and can guide discovery of novel drugs for the disease.

Dietary flavanols restore hippocampal-dependent memory in older adults with lower diet quality and lower habitual flavanol consumption.

Dietary flavanols are food constituents found in certain fruits and vegetables that have been linked to cognitive aging. Previous studies suggested that consumption of dietary flavanols might specifically be associated with the hippocampal-dependent memory component of cognitive aging and that memory benefits of a flavanol intervention might depend on habitual diet quality. Here, we tested these hypotheses in the context of a large-scale study of 3,562 older adults, who were randomly assigned to a 3-y intervention of cocoa extract (500 mg of cocoa flavanols per day) or a placebo [(COcoa Supplement and Multivitamin Outcomes Study) COSMOS-Web, NCT04582617]. Using the alternative Healthy Eating Index in all participants and a urine-based biomarker of flavanol intake in a subset of participants [n = 1,361], we show that habitual flavanol consumption and diet quality at baseline are positively and selectively correlated with hippocampal-dependent memory. While the prespecified primary end point testing for an intervention-related improvement in memory in all participants after 1 y was not statistically significant, the flavanol intervention restored memory among participants in lower tertiles of habitual diet quality or habitual flavanol consumption. Increases in the flavanol biomarker over the course of the trial were associated with improving memory. Collectively, our results allow dietary flavanols to be considered in the context of a depletion-repletion paradigm and suggest that low flavanol consumption can act as a driver of the hippocampal-dependent component of cognitive aging.

Magnetic Resonance Spectroscopy Spectral Registration Using Deep Learning.

BACKGROUND: Deep learning-based methods have been successfully applied to MRI image registration. However, there is a lack of deep learning-based registration methods for magnetic resonance spectroscopy (MRS) spectral registration (SR). PURPOSE: To investigate a convolutional neural network-based SR (CNN-SR) approach for simultaneous frequency-and-phase correction (FPC) of single-voxel Meshcher-Garwood point-resolved spectroscopy (MEGA-PRESS) MRS data. STUDY TYPE: Retrospective. SUBJECTS: Forty thousand simulated MEGA-PRESS datasets generated from FID Appliance (FID-A) were used and split into the following: 32,000/4000/4000 for training/validation/testing. A 101 MEGA-PRESS medial parietal lobe data retrieved from the Big GABA were used as the in vivo datasets. FIELD STRENGTH/SEQUENCE: 3T, MEGA-PRESS. ASSESSMENT: Evaluation of frequency and phase offsets mean absolute errors were performed for the simulation dataset. Evaluation of the choline interval variance was performed for the in vivo dataset. The magnitudes of the offsets introduced were -20 to 20 Hz and -90° to 90° and were uniformly distributed for the simulation dataset at different signal-to-noise ratio (SNR) levels. For the in vivo dataset, different additional magnitudes of offsets were introduced: small offsets (0-5 Hz; 0-20°), medium offsets (5-10 Hz; 20-45°), and large offsets (10-20 Hz; 45-90°). STATISTICAL TESTS: Two-tailed paired t-tests for model performances in the simulation and in vivo datasets were used and a P-value <0.05 was considered statistically significant. RESULTS: CNN-SR model was capable of correcting frequency offsets (0.014 ± 0.010 Hz at SNR 20 and 0.058 ± 0.050 Hz at SNR 2.5 with line broadening) and phase offsets (0.104 ± 0.076° at SNR 20 and 0.416 ± 0.317° at SNR 2.5 with line broadening). Using in vivo datasets, CNN-SR achieved the best performance without (0.000055 ± 0.000054) and with different magnitudes of additional frequency and phase offsets (i.e., 0.000062 ± 0.000068 at small, -0.000033 ± 0.000023 at medium, 0.000067 ± 0.000102 at large) applied. DATA CONCLUSION: The proposed CNN-SR method is an efficient and accurate approach for simultaneous FPC of single-voxel MEGA-PRESS MRS data. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

MR spectroscopy frequency and phase correction using convolutional neural networks.

PURPOSE: To introduce a novel convolutional neural network (CNN)-based approach for frequency-and-phase correction (FPC) of MR spectroscopy (MRS) spectra to achieve fast and accurate FPC of single-voxel MEGA-PRESS MRS data. METHODS: Two neural networks (one for frequency and one for phase) were trained and validated using published simulated and in vivo MEGA-PRESS MRS dataset with wide-range artificial frequency and phase offsets applied. The CNN-based approach was subsequently tested and compared to the current deep learning solution: multilayer perceptrons (MLP). Furthermore, random noise was added to the original simulated dataset to further investigate the model performance at varied signal-to-noise ratio (SNR) levels (i.e., 10, 5, and 2.5). Additional frequency and phase offsets (i.e., small, moderate, large) were also applied to the in vivo dataset, and the CNN model was compared to the conventional approach SR and model-based SR implementation (mSR). RESULTS: The CNN model is more robust to noise compared to the MLP-based approach due to having smaller mean absolute errors in both frequency (0.01 ± 0.01 Hz at SNR = 10 and 0.01 ± 0.02 Hz at SNR = 2.5) and phase (0.12 ± 0.09° at SNR = 10 and -0.07 ± 0.44° at SNR = 2.5) offset prediction. Furthermore, better performance was demonstrated for FPC when compared to the MLP-based approach, and SR when applied to the in vivo dataset for both with and without additional offsets. CONCLUSION: A CNN-based approach provides a solution to the automated preprocessing of MRS data, and the experimental results demonstrate the quantitatively improved spectra quality compared to the state-of-the-art approach.

Recency and intensification of positive symptoms enhance prediction of conversion to syndromal psychosis in clinical high-risk patients.

BACKGROUND: Early detection and intervention strategies in patients at clinical high-risk (CHR) for syndromal psychosis have the potential to contain the morbidity of schizophrenia and similar conditions. However, research criteria that have relied on severity and number of positive symptoms are limited in their specificity and risk high false-positive rates. Our objective was to examine the degree to which measures of recency of onset or intensification of positive symptoms [a.k.a., new or worsening (NOW) symptoms] contribute to predictive capacity. METHODS: We recruited 109 help-seeking individuals whose symptoms met criteria for the Progression Subtype of the Attenuated Positive Symptom Psychosis-Risk Syndrome defined by the Structured Interview for Psychosis-Risk Syndromes and followed every three months for two years or onset of syndromal psychosis. RESULTS: Forty-one (40.6%) of 101 participants meeting CHR criteria developed a syndromal psychotic disorder [mostly (80.5%) schizophrenia] with half converting within 142 days (interquartile range: 69-410 days). Patients with more NOW symptoms were more likely to convert (converters: 3.63 ± 0.89; non-converters: 2.90 ± 1.27; p = 0.001). Patients with stable attenuated positive symptoms were less likely to convert than those with NOW symptoms. New, but not worsening, symptoms, in isolation, also predicted conversion. CONCLUSIONS: Results suggest that the severity and number of attenuated positive symptoms are less predictive of conversion to syndromal psychosis than the timing of their emergence and intensification. These findings also suggest that the earliest phase of psychotic illness involves a rapid, dynamic process, beginning before the syndromal first episode, with potentially substantial implications for CHR research and understanding the neurobiology of psychosis.

Cholera toxin inhibits SNX27-retromer-mediated delivery of cargo proteins to the plasma membrane.

Cholera toxin (CT) causes severe diarrhea by increasing intracellular cAMP leading to a PKA-dependent increase in Cl- secretion through CFTR and decreased Na+ absorption through inhibition of Na+/H+ exchanger 3 (NHE3; also known as SLC9A3). The mechanism(s) by which CT inhibits NHE3 is partially understood, although no drug therapy has been successful at reversing this inhibition. We now describe that CT phosphorylates an amino acid in the PDZ domain of SNX27, which inhibits SNX27-mediated trafficking of NHE3 from the early endosomes to the plasma membrane (PM), and contributes to reduced basal NHE3 activity through a mechanism that involves reduced PM expression and reduced endocytic recycling. Importantly, mutagenesis studies (Ser to Asp) showed that the effect of this phosphorylation of SNX27 phenocopies the effects seen upon loss of SNX27 function, affecting PM trafficking of cargo proteins that bind SNX27-retromer. Additionally, CT destabilizes retromer function by decreasing the amount of core retromer proteins. These effects of CT can be partially rescued by enhancing retromer stability by using 'pharmacological chaperones'. Moreover, pharmacological chaperones can be used to increase basal and cholera toxin-inhibited NHE3 activity and fluid absorption by intestinal epithelial cells.This article has an associated First Person interview with the first author of the paper.

Retromer in Alzheimer disease, Parkinson disease and other neurological disorders.

Retromer is a protein assembly that has a central role in endosomal trafficking, and retromer dysfunction has been linked to a growing number of neurological disorders. First linked to Alzheimer disease, retromer dysfunction causes a range of pathophysiological consequences that have been shown to contribute to the core pathological features of the disease. Genetic studies have established that retromer dysfunction is also pathogenically linked to Parkinson disease, although the biological mechanisms that mediate this link are only now being elucidated. Most recently, studies have shown that retromer is a tractable target in drug discovery for these and other disorders of the nervous system.

In vivo detection and automatic analysis of GABA in the mouse brain with MEGA-PRESS at 9.4 T.

The goals of this study were to develop an acquisition protocol and the analysis tools for Meshcher-Garwood point-resolved spectroscopy (MEGA-PRESS) in mouse brain at 9.4 T, to allow the in vivo detection of γ-aminobutyric acid (GABA) and to examine whether isoflurane alters GABA levels in the thalamus during anesthesia. We implemented the MEGA-PRESS sequence on a Bruker 94/20 system with ParaVision 6.0.1, and magnetic resonance spectra were acquired from nine male wild-type C57BL/6 J mice at the thalamus. Four individual scans were obtained for each mouse in a 2-h time course whilst the mouse was anesthetized with isoflurane. We developed an automated analysis program with improved correction for frequency and phase drift compared with the standard creatine (Cr) fitting-based method and provided automatic quantification. During MEGA-PRESS acquisition, a single voxel with a size of 5 × 3 × 3 mm3 was placed at the thalamus to evaluate GABA to Cr (GABA/Cr) ratios during anesthesia. Detection and quantitative analysis of thalamic GABA levels were successfully achieved. We noticed a significant decrease in GABA/Cr during the 2-h anesthesia (by linear regression analysis: slope < 0, p < 0.0001). In summary, our findings demonstrate that MEGA-PRESS is a feasible technique to measure in vivo GABA levels in the mouse brain at 9.4 T.

Interneuron precursor transplants in adult hippocampus reverse psychosis-relevant features in a mouse model of hippocampal disinhibition.

GABAergic interneuron hypofunction is hypothesized to underlie hippocampal dysfunction in schizophrenia. Here, we use the cyclin D2 knockout (Ccnd2(-/-)) mouse model to test potential links between hippocampal interneuron deficits and psychosis-relevant neurobehavioral phenotypes. Ccnd2(-/-) mice show cortical PV(+) interneuron reductions, prominently in hippocampus, associated with deficits in synaptic inhibition, increased in vivo spike activity of projection neurons, and increased in vivo basal metabolic activity (assessed with fMRI) in hippocampus. Ccnd2(-/-) mice show several neurophysiological and behavioral phenotypes that would be predicted to be produced by hippocampal disinhibition, including increased ventral tegmental area dopamine neuron population activity, behavioral hyperresponsiveness to amphetamine, and impairments in hippocampus-dependent cognition. Remarkably, transplantation of cells from the embryonic medial ganglionic eminence (the major origin of cerebral cortical interneurons) into the adult Ccnd2(-/-) caudoventral hippocampus reverses these psychosis-relevant phenotypes. Surviving neurons from these transplants are 97% GABAergic and widely distributed within the hippocampus. Up to 6 mo after the transplants, in vivo hippocampal metabolic activity is lowered, context-dependent learning and memory is improved, and dopamine neuron activity and the behavioral response to amphetamine are normalized. These findings establish functional links between hippocampal GABA interneuron deficits and psychosis-relevant dopaminergic and cognitive phenotypes, and support a rationale for targeting limbic cortical interneuron function in the prevention and treatment of schizophrenia.

A pathophysiological framework of hippocampal dysfunction in ageing and disease.

The hippocampal formation has been implicated in a growing number of disorders, from Alzheimer's disease and cognitive ageing to schizophrenia and depression. How can the hippocampal formation, a complex circuit that spans the temporal lobes, be involved in a range of such phenotypically diverse and mechanistically distinct disorders? Recent neuroimaging findings indicate that these disorders differentially target distinct subregions of the hippocampal circuit. In addition, some disorders are associated with hippocampal hypometabolism, whereas others show evidence of hypermetabolism. Interpreted in the context of the functional and molecular organization of the hippocampal circuit, these observations give rise to a unified pathophysiological framework of hippocampal dysfunction.

Pharmacological chaperones stabilize retromer to limit APP processing.

Retromer is a multiprotein complex that trafficks cargo out of endosomes. The neuronal retromer traffics the amyloid-precursor protein (APP) away from endosomes, a site where APP is cleaved into pathogenic fragments in Alzheimer's disease. Here we determined whether pharmacological chaperones can enhance retromer stability and function. First, we relied on the crystal structures of retromer proteins to help identify the 'weak link' of the complex and to complete an in silico screen of small molecules predicted to enhance retromer stability. Among the hits, an in vitro assay identified one molecule that stabilized retromer against thermal denaturation. Second, we turned to cultured hippocampal neurons, showing that this small molecule increases the levels of retromer proteins, shifts APP away from the endosome, and decreases the pathogenic processing of APP. These findings show that pharmacological chaperones can enhance the function of a multiprotein complex and may have potential therapeutic implications for neurodegenerative diseases.

Hyperleucinemia causes hippocampal retromer deficiency linking diabetes to Alzheimer's disease.

Type 2 diabetes (T2D) is a major risk factor for late-onset Alzheimer's disease (AD). A variety of metabolic changes related to T2D (e.g. hyperinsulinemia, hyperglycemia, and elevated branched-chain amino acids) have been proposed as mechanistic links, but the basis for this association remains unknown. Retromer-dependent trafficking is implicated in the pathogenesis of AD, and two key retromer proteins, VPS35 and VPS26, are deficient in the hippocampal formation of AD patients. We characterized VPS35 levels in five different mouse models of T2D/obesity to identify specific metabolic factors that could affect retromer levels in the brain. Mouse models in which hyperleucinemia was present displayed hippocampus-selective retromer deficiency. Wild-type lean mice fed a high leucine diet also developed hippocampal-selective retromer deficiency, and neuronal-like cells grown in high ambient leucine had reduced retromer complex proteins. Our results suggest that hyperleucinemia may account, in part, for the association of insulin resistance/T2D with AD.

Retromer-dependent lysosomal stress in Parkinson's disease.

While causative mutations in complex disorders are rare, they can be used to extract a biological pathway whose pathogenicity can generalize to common forms of the disease. Here we begin by relying on the biological consequences of mutations in LRRK2 and VPS35, genetic causes of autosomal-dominant Parkinson's disease, to hypothesize that 'Retromer-dependent lysosomal stress' represents a pathway that can generalize to idiopathic Parkinson's disease. Next, we outline a series of studies that can test this hypothesis, including the development of biomarkers of pathway dysfunction. If validated, the hypothesis can suggest a unified mechanism of disease and might inform future diagnostic and therapeutic investigations. This article is part of a discussion meeting issue 'Understanding the endo-lysosomal network in neurodegeneration'.

Vps10 family proteins and the retromer complex in aging-related neurodegeneration and diabetes.

Members of the vacuolar protein sorting 10 (Vps10) family of receptors (including sortilin, SorL1, SorCS1, SorCS2, and SorCS3) play pleiotropic functions in protein trafficking and intracellular and intercellular signaling in neuronal and non-neuronal cells. Interactions have been documented between Vps10 family members and the retromer coat complex, a key component of the intracellular trafficking apparatus that sorts cargo from the early endosome to the trans-Golgi network. In recent years, genes encoding several members of the Vps10 family of proteins, as well as components of the retromer coat complex, have been implicated as genetic risk factors for sporadic and autosomal dominant forms of neurodegenerative diseases, including Alzheimer's disease, frontotemporal lobar degeneration, and Parkinson's disease, with risk for type 2 diabetes mellitus and atherosclerosis. In addition to their functions in protein trafficking, the Vps10 family proteins modulate neurotrophic signaling pathways. Sortilin can impact the intracellular response to brain-derived neurotrophic factor (BDNF) by regulating anterograde trafficking of Trk receptors to the synapse and direct control of BDNF levels, while both sortilin and SorCS2 function as cell surface receptors to mediate acute responses to proneurotrophins. This mini-review and symposium will highlight the emerging data from this rapidly growing area of research implicating the Vps10 family of receptors and the retromer in physiological intracellular trafficking signaling by neurotrophins and in the pathogenesis of neurodegeneration.

R6/2 Huntington's disease mice develop early and progressive abnormal brain metabolism and seizures.

A hallmark feature of Huntington's disease pathology is the atrophy of brain regions including, but not limited to, the striatum. Though MRI studies have identified structural CNS changes in several Huntington's disease (HD) mouse models, the functional consequences of HD pathology during the progression of the disease have yet to be investigated using in vivo functional MRI (fMRI). To address this issue, we first established the structural and functional MRI phenotype of juvenile HD mouse model R6/2 at early and advanced stages of disease. Significantly higher fMRI signals [relative cerebral blood volumes (rCBVs)] and atrophy were observed in both age groups in specific brain regions. Next, fMRI results were correlated with electrophysiological analysis, which showed abnormal increases in neuronal activity in affected brain regions, thus identifying a mechanism accounting for the abnormal fMRI findings. [(14)C] 2-deoxyglucose maps to investigate patterns of glucose utilization were also generated. An interesting mismatch between increases in rCBV and decreases in glucose uptake was observed. Finally, we evaluated the sensitivity of this mouse line to audiogenic seizures early in the disease course. We found that R6/2 mice had an increased susceptibility to develop seizures. Together, these findings identified seizure activity in R6/2 mice and show that neuroimaging measures sensitive to oxygen metabolism can be used as in vivo biomarkers, preceding the onset of an overt behavioral phenotype. Since fMRI-rCBV can also be obtained in patients, we propose that it may serve as a translational tool to evaluate therapeutic responses in humans and HD mouse models.

Comparative lipidomic analysis of mouse and human brain with Alzheimer disease.

Lipids are key regulators of brain function and have been increasingly implicated in neurodegenerative disorders including Alzheimer disease (AD). Here, a systems-based approach was employed to determine the lipidome of brain tissues affected by AD. Specifically, we used liquid chromatography-mass spectrometry to profile extracts from the prefrontal cortex, entorhinal cortex, and cerebellum of late-onset AD (LOAD) patients, as well as the forebrain of three transgenic familial AD (FAD) mouse models. Although the cerebellum lacked major alterations in lipid composition, we found an elevation of a signaling pool of diacylglycerol as well as sphingolipids in the prefrontal cortex of AD patients. Furthermore, the diseased entorhinal cortex showed specific enrichment of lysobisphosphatidic acid, sphingomyelin, the ganglioside GM3, and cholesterol esters, all of which suggest common pathogenic mechanisms associated with endolysosomal storage disorders. Importantly, a significant increase in cholesterol esters and GM3 was recapitulated in the transgenic FAD models, suggesting that these mice are relevant tools to study aberrant lipid metabolism of endolysosomal dysfunction associated with AD. Finally, genetic ablation of phospholipase D(2), which rescues the synaptic and behavioral deficits of an FAD mouse model, fully normalizes GM3 levels. These data thus unmask a cross-talk between the metabolism of phosphatidic acid, the product of phospholipase D(2), and gangliosides, and point to a central role of ganglioside anomalies in AD pathogenesis. Overall, our study highlights the hypothesis generating potential of lipidomics and identifies novel region-specific lipid anomalies potentially linked to AD pathogenesis.

Regional vulnerability in Huntington's disease: fMRI-guided molecular analysis in patients and a mouse model of disease.

Although the huntingtin gene is expressed in brain throughout life, phenotypically Huntington's disease (HD) begins only in midlife and affects specific brain regions. Here, to investigate regional vulnerability in the disease, we used functional magnetic resonance imaging (fMRI) to translationally link studies in patients with a mouse model of disease. Using fMRI, we mapped cerebral blood volume (CBV) in three groups: HD patients, symptom-free carriers of the huntingtin genetic mutation, and age-matched controls. In contrast to a region in the anterior caudate, in which dysfunction was linked to genotype independent of phenotype, a region in the posterior body of the caudate was differentially associated with disease phenotype. Guided by these observations, we harvested regions from the anterior and posterior body of the caudate in postmortem control and HD human brain tissue. Gene-expression profiling identified two molecules whose expression levels were most strongly correlated with regional vulnerability - protein phosphatase 1 regulatory subunit 7 (PPP1R7) and Wnt inhibitory factor-1 (WIF-1). To verify and potentially extend these findings, we turned to the YAC128 (C57BL/6J) HD transgenic mice. By fMRI we longitudinally mapped CBV in transgenic and wildtype (WT) mice, and over time, abnormally low fMRI signal emerged selectively in the dorsal striatum. A relatively unaffected brain region, primary somatosensory cortex (S1), was used as a control. Both dorsal striatum and S1 were harvested from transgenic and WT mice and molecular analysis confirmed that PPP1R7 deficiency was strongly correlated with the phenotype. Together, converging findings in human HD patients and this HD mouse model suggest a functional pattern of caudate vulnerability and that variation in expression levels of herein identified molecules correlate with this pattern of vulnerability.

Motor deficits correlate with resting state motor network connectivity in patients with brain tumours.

While a tumour in or abutting primary motor cortex leads to motor weakness, how tumours elsewhere in the frontal or parietal lobes affect functional connectivity in a weak patient is less clear. We hypothesized that diminished functional connectivity in a distributed network of motor centres would correlate with motor weakness in subjects with brain masses. Furthermore, we hypothesized that interhemispheric connections would be most vulnerable to subtle disruptions in functional connectivity. We used task-free functional magnetic resonance imaging connectivity to probe motor networks in control subjects and patients with brain tumours (n = 22). Using a control dataset, we developed a method for automated detection of key nodes in the motor network, including the primary motor cortex, supplementary motor area, premotor area and superior parietal lobule, based on the anatomic location of the hand-motor knob in the primary motor cortex. We then calculated functional connectivity between motor network nodes in control subjects, as well as patients with and without brain masses. We used this information to construct weighted, undirected graphs, which were then compared to variables of interest, including performance on a motor task, the grooved pegboard. Strong connectivity was observed within the identified motor networks between all nodes bilaterally, and especially between the primary motor cortex and supplementary motor area. Reduced connectivity was observed in subjects with motor weakness versus subjects with normal strength (P < 0.001). This difference was driven mostly by decreases in interhemispheric connectivity between the primary motor cortices (P < 0.05) and between the left primary motor cortex and the right premotor area (P < 0.05), as well as other premotor area connections. In the subjects without motor weakness, however, performance on the grooved pegboard did not relate to interhemispheric connectivity, but rather was inversely correlated with connectivity between the left premotor area and left supplementary motor area, for both the left and the right hands (P < 0.01). Finally, two subjects who experienced severe weakness following surgery for their brain tumours were followed longitudinally, and the subject who recovered showed reconstitution of her motor network at follow-up. The subject who was persistently weak did not reconstitute his motor network. Motor weakness in subjects with brain tumours that do not involve primary motor structures is associated with decreased connectivity within motor functional networks, particularly interhemispheric connections. Motor networks become weaker as the subjects become weaker, and may become strong again during motor recovery.

Polyamine pathway contributes to the pathogenesis of Parkinson disease.

The full complement of molecular pathways contributing to the pathogenesis of Parkinson disease (PD) remains unknown. Here we address this issue by taking a broad approach, beginning by using functional MRI to identify brainstem regions differentially affected and resistant to the disease. Relying on these imaging findings, we then profiled gene expression levels from postmortem brainstem regions, identifying a disease-related decrease in the expression of the catabolic polyamine enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1). Next, a range of studies were completed to support the pathogenicity of this finding. First, to test for a causal link between polyamines and α-synuclein toxicity, we investigated a yeast model expressing α-synuclein. Polyamines were found to enhance the toxicity of α-synuclein, and an unbiased genome-wide screen for modifiers of α-synuclein toxicity identified Tpo4, a member of a family of proteins responsible for polyamine transport. Second, to test for a causal link between SAT1 activity and PD histopathology, we investigated a mouse model expressing α-synuclein. DENSPM (N1, N11-diethylnorspermine), a polyamine analog that increases SAT1 activity, was found to reduce PD histopathology, whereas Berenil (diminazene aceturate), a pharmacological agent that reduces SAT1 activity, worsened the histopathology. Third, to test for a genetic link, we sequenced the SAT1 gene and a rare but unique disease-associated variant was identified. Taken together, the findings from human patients, yeast, and a mouse model implicate the polyamine pathway in PD pathogenesis.

Anatomical biology guides a search for nutrients for the aging brain.

Considerable evidence has established the importance of specific nutrients that have been found vital for the developing brain. We hypothesize that in a similar manner there should be nutrients vital to the aging brain and that based on aging's distinct pathophysiology they should be different than those essential to development. Specific brain networks that govern cognition are particularly vulnerable to the aging process, resulting in what is referred to as 'cognitive aging'. Common late-life disorders, however, such as Alzheimer's disease also target these same brain networks. Studies have disambiguated cognitive aging from late-life disease by isolating regions and biological pathways within each network differentially linked to one or the other. This anatomical biology anchors a framework to identify nutrients and/or dietary bioactives relevant to cognitive aging whose utility is illustrated via a decades-long research program into how dietary bioactive flavanols benefit the brain. As we are living longer in cognitively more demanding lives, the framework's ultimate goal is to generate specific dietary recommendations that will fortify our mind for its golden years.