Longitudinal analysis of regional brain changes in anti-NMDAR encephalitis: a case report

Abstract Background Anti-NMDA receptor encephalitis is an immune-mediated disorder characterized by antibodies against the GluN1 subunit of the NMDA receptor that is increasingly recognized as a treatable cause of childhood epileptic encephalopathy. In adults, the disorder has been associated with reversible changes in brain volume over the course of treatment and recovery, but in children, little is known about its time course and associated imaging manifestations. Case presentation A previously healthy 20-month-old boy presented with first-time unprovoked seizures, dysautonomia, and dyskinesia. Paraneoplastic workup was negative, but CSF was positive for anti-NMDAR antibodies. The patient’s clinical condition waxed and waned over a 14-month course of treatment with first- and second-line immunotherapies (including steroids, IVIG, rituximab, and cyclophosphamide). Serial brain MRIs scans obtained at 5 time points spanning this same period showed no abnormal signal or enhancement but were remarkable for cycles of reversible regional cortical volume loss. All scans included identical 1-mm resolution 3D T1-weighted sequences obtained on the same 3 T scanner. Using a novel longitudinal processing stream in FreeSurfer6 (Reuter M, et. al, Neuroimage 61:1402–18, 2012) we quantified the rate of change in cortical volume at each vertex (% volume change per month) between consecutive scans and correlated these changes with the time course of the patient’s treatment and clinical response. We found regionally specific changes in cortical volume (up to 7% per month) that preferentially affected the frontal and occipital lobes and paralleled the patient’s clinical course, with clinical decline associated with volume loss and clinical improvement associated with volume gain. Conclusions Our results suggest that reversible cortical volume loss in anti-NMDA encephalitis has a regional specificity that mirrors many of the clinical symptoms associated with the disorder and tracks the dynamics of disease severity over time. This case illustrates how quantitative morphometric techniques can be applied to clinical imaging data to reveal patterns of brain change that may provide insight into disease pathophysiology. More widespread application of this approach might reveal regional and temporal patterns specific to different types of autoimmune encephalitis, providing a tool for diagnosis and a surrogate marker for monitoring treatment response.

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Modelling and treating GRIN2A developmental and epileptic encephalopathy in mice

Brain ◽

10.1093/brain/awaa147 ◽

2020 ◽

Vol 143 (7) ◽

pp. 2039-2057 ◽

Cited By ~ 2

Author(s):

Ariadna Amador ◽

Christopher D Bostick ◽

Heather Olson ◽

Jurrian Peters ◽

Chad R Camp ◽

...

Keyword(s):

Nmda Receptor ◽

Neurodevelopmental Disorders ◽

Time Course ◽

De Novo ◽

Hippocampal Slices ◽

Epileptic Encephalopathy ◽

Nmda Receptor Antagonists ◽

Receptor Antagonists ◽

Limbic Seizures ◽

Clonic Seizures

Abstract NMDA receptors play crucial roles in excitatory synaptic transmission. Rare variants in GRIN2A encoding the GluN2A subunit are associated with a spectrum of disorders, ranging from mild speech and language delay to intractable neurodevelopmental disorders, including but not limited to developmental and epileptic encephalopathy. A de novo missense variant, p.Ser644Gly, was identified in a child with this disorder, and Grin2a knock-in mice were generated to model and extend understanding of this intractable childhood disease. Homozygous and heterozygous mutant mice exhibited altered hippocampal morphology at 2 weeks of age, and all homozygotes exhibited lethal tonic-clonic seizures by mid-third week. Heterozygous adults displayed susceptibility to induced generalized seizures, hyperactivity, repetitive and reduced anxiety behaviours, plus several unexpected features, including significant resistance to electrically-induced limbic seizures and to pentylenetetrazole induced tonic-clonic seizures. Multielectrode recordings of neuronal networks revealed hyperexcitability and altered bursting and synchronicity. In heterologous cells, mutant receptors had enhanced NMDA receptor agonist potency and slow deactivation following rapid removal of glutamate, as occurs at synapses. NMDA receptor-mediated synaptic currents in heterozygous hippocampal slices also showed a prolonged deactivation time course. Standard anti-epileptic drug monotherapy was ineffective in the patient. Introduction of NMDA receptor antagonists was correlated with a decrease in seizure burden. Chronic treatment of homozygous mouse pups with NMDA receptor antagonists significantly delayed the onset of lethal seizures but did not prevent them. These studies illustrate the power of using multiple experimental modalities to model and test therapies for severe neurodevelopmental disorders, while revealing significant biological complexities associated with GRIN2A developmental and epileptic encephalopathy.

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Androgens Modulate NMDA Receptor–Mediated EPSCs in the Zebra Finch Song System

Journal of Neurophysiology ◽

10.1152/jn.1999.82.5.2221 ◽

1999 ◽

Vol 82 (5) ◽

pp. 2221-2234 ◽

Cited By ~ 68

Author(s):

Stephanie A. White ◽

Frederick S. Livingston ◽

Richard Mooney

Keyword(s):

Nmda Receptor ◽

Synaptic Transmission ◽

Time Course ◽

Song Learning ◽

Lateral Part ◽

Spine Density ◽

Song System ◽

Decay Times ◽

Soma Size

Androgens potently regulate the development of learned vocalizations of songbirds. We sought to determine whether one action of androgens is to functionally modulate the development of synaptic transmission in two brain nuclei, the lateral part of the magnocellular nucleus of the anterior neostriatum (LMAN) and the robust nucleus of the archistriatum (RA), that are critical for song learning and production. We focused on N-methyl-d-aspartate–excitatory postsynaptic currents (NMDA-EPSCs), because NMDA receptor activity in LMAN is crucial to song learning, and because the LMAN synapses onto RA neurons are almost entirely mediated by NMDA receptors. Whole cell recordings from in vitro brain slice preparations revealed that the time course of NMDA-EPSCs was developmentally regulated in RA, as had been shown previously for LMAN. Specifically, in both nuclei, NMDA-EPSCs become faster over development. We found that this developmental transition can be modulated by androgens, because testosterone treatment of young animals caused NMDA-EPSCs in LMAN and RA to become prematurely fast. These androgen-induced effects were limited to fledgling and juvenile periods and were spatially restricted, in that androgens did not accelerate developmental changes in NMDA-EPSCs recorded in a nonsong area, the Wulst. To determine whether androgens had additional effects on LMAN or RA neurons, we examined several other physiological and morphological parameters. In LMAN, testosterone affected α-amino-3-hydroxy-5-methyl-4-isoxazoleproprianate–EPSC (AMPA-EPSC) decay times and the ratio of peak synaptic glutamate to AMPA currents, as well as dendritic length and spine density but did not alter soma size or dendritic complexity. In contrast, testosterone did not affect any of these parameters in RA, which demonstrates that exogenous androgens can have selective actions on different song system neurons. These data are the first evidence for any effect of sex steroids on synaptic transmission within the song system. Our results support the idea that endogenous androgens limit sensitive periods for song learning by functionally altering synaptic transmission in song nuclei.

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Intrapleural liquid flow down a gravity-dependent hydraulic pressure gradient

Journal of Applied Physiology ◽

10.1152/jappl.1988.64.2.577 ◽

1988 ◽

Vol 64 (2) ◽

pp. 577-584 ◽

Cited By ~ 9

Author(s):

G. Miserocchi ◽

D. Negrini ◽

M. Pistolesi ◽

C. R. Bellina ◽

M. C. Gilardi ◽

...

Keyword(s):

Pressure Gradient ◽

Time Course ◽

Sudden Change ◽

Vertical Movement ◽

Rate Of Change ◽

Large Field ◽

Liquid Volume ◽

Hydraulic Pressure ◽

Albumin Clearance ◽

Turning Maneuver

We studied the vertical movement of 2 mg technetium-labeled albumin injected intrapleurally in 0.5 ml saline (15% of pleural liquid volume) in eight spontaneously breathing anesthetized dogs subject to a sudden change in posture (prone to supine or vice versa). The albumin movements were evaluated through a large field gamma camera placed laterally to the animal and detecting total (AT) and regional activities from two superimposed equal areas (At and Ab, top and bottom, respectively). The At/Ab ratio decreased from 2.1 to 1.3 in four animals up to 20 min from the change in posture and from 0.9 to 0.5 in four more animals studied from 50 to 90 min from turning maneuver. The rate of change in At and Ab was similar in the two groups of animals and unaffected by the acquisition posture. AT decreased by 7.7 and 3.5% for the two groups, respectively, reflecting albumin clearance from the pleural space. The opposite time course of regional activities and the independence of their rate of change of the At/Ab ratio and of the animal posture suggest a top-to-bottom albumin transfer occurring through a bulk flow of liquid estimated at 0.006 ml.kg-1.h-1. The data are consistent with a measured vertical pleural liquid pressure gradient that does not reflect a hydrostatic condition.

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Fast-phase transvascular fluid flux and the Fahraeus effect

Journal of Applied Physiology ◽

10.1152/jappl.1987.62.4.1513 ◽

1987 ◽

Vol 62 (4) ◽

pp. 1513-1520 ◽

Cited By ~ 6

Author(s):

W. N. Richardson ◽

D. Bilan ◽

M. Hoppensack ◽

L. Oppenheimer

Keyword(s):

Mechanical Properties ◽

Slow Rate ◽

Time Course ◽

Rate Of Change ◽

Distributed Model ◽

Slow Phase ◽

Fluid Flux ◽

Fast Phase ◽

Constant Rate ◽

Fahraeus Effect

Transvascular fluid flux was induced in six isolated blood-perfused canine lobes by increasing and decreasing hydrostatic inflow pressure (Pi). Fluid flux was followed against the change in concentration of an impermeable tracer (Blue Dextran) measured directly with a colorimetric device. The time course of fluid flux was biphasic with an initial fast transient followed by a slow phase. Hematocrit changes unrelated to fluid flux occurred due to the Fahraeus effect, and their contribution to the total color signal was subtracted to determine the rate of fast fluid flux (Qf). Qf was related to Pi to derive fast-phase conductance (Kf). Slow-phase Kf was calculated from the constant rate of change of lobe weight. For a mean change in Pi of 7 cmH2O, 40% of the color signal was due to fluid flux. Fast- and slow-phase Kf's were 0.86 +/- 0.15 and 0.27 +/- 0.05 ml X min-1. cmH2O–1 X 100 g dry wt-1. The fast-phase Kf is smaller than that reported for plasma-perfused lobes. Possible explanations discussed are the nature of the perfusate, the mechanical properties of the interstitium, and the slow rate of rise of the driving pressure at the filtration site on the basis of a distributed model of pulmonary vascular compliance.

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Glycine regulation of synaptic NMDA receptors in hippocampal neurons

Journal of Neurophysiology ◽

10.1152/jn.1996.76.5.3415 ◽

1996 ◽

Vol 76 (5) ◽

pp. 3415-3424 ◽

Cited By ~ 48

Author(s):

K. S. Wilcox ◽

R. M. Fitzsimonds ◽

B. Johnson ◽

M. A. Dichter

Keyword(s):

Nmda Receptor ◽

Nmda Receptors ◽

Hippocampal Neurons ◽

Time Course ◽

Hippocampal Slices ◽

Maximal Effect ◽

Patch Clamp Technique ◽

Whole Cell Patch Clamp ◽

Dissociated Cell Culture ◽

Cultured Hippocampal Neurons

1. Although glycine has been identified as a required coagonist with glutamate at N-methyl-D-aspartate (NMDA) receptors, the understanding of glycine's role in excitatory synaptic neurotransmission is quite limited. In the present study, we used the whole cell patch-clamp technique to examine the ability of glycine to regulate current flow through synaptic NMDA receptors at excitatory synapses between cultured hippocampal neurons and in acutely isolated hippocampal slices. 2. These studies demonstrate that the glycine modulatory site on the synaptic NMDA receptor is not saturated under baseline conditions and that increased glycine concentrations can markedly increased NMDA-receptor-mediated excitatory postsynaptic currents (EPSCs) in hippocampal neurons in both dissociated cell culture and in slice. Saturation of the maximal effect of glycine takes place at different concentrations for different cells in culture, suggesting the presence of heterogenous NMDA receptor subunit compositions. 3. Bath-applied glycine had no effect on the time course of EPSCs in either brain slice or culture, indicating that desensitization of the NMDA receptor is not prevented by glycine over the time course of an EPSC. 4. When extracellular glycine concentration is high, all miniature EPSCs recorded in the cultured hippocampal neurons contained NMDA components, indicating that segregation of non-NMDA receptors at individual synaptic boutons does not occur.

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Ferritin is associated with the severity of lung involvement but not with worse prognosis in patients with COVID-19: data from two Italian COVID-19 Units.

10.21203/rs.3.rs-103672/v1 ◽

2020 ◽

Author(s):

Francesco Carubbi ◽

Lia Salvati ◽

Alessia Alunno ◽

Fabio Maggi ◽

Erika Borghi ◽

...

Keyword(s):

Ct Scan ◽

Time Course ◽

Mediastinal Lymph Node ◽

Clinical Signs ◽

Pulmonary Involvement ◽

Imaging Data ◽

Age And Gender ◽

Disease Outcomes ◽

Wide Range ◽

And Gender

Abstract The coronavirus 2019 disease (COVID-19) is characterised by a heterogeneous clinical presentation, a complex pathophysiology and a wide range of imaging ﬁndings, depending on disease severity and time course. We conducted a retrospective evaluation of hospitalized patients with proven SARS-CoV-2 infection, clinical signs of COVID-19 and computed tomography (CT) scan-proven pulmonary involvement, in order to identify relationships between clinical, serological, imaging data and disease outcomes in patients with COVID-19. Clinical and serological records of patients admitted to two COVID-19 Units of the Abruzzo region in Italy with proven SARS-CoV-2 pulmonary involvement investigated with CT scan, assessed at the time of admission to the hospital, were retrospectively evaluated.Sixty-one patients (22 females and 39 males) of median age 65 years were enrolled. Fifty-six patients were discharged while death occurred in 5 patients. None of the lung abnormalities detected by CT was different between discharged and deceased patients. No differences were observed in the features and extent of pulmonary involvement according to age and gender. Logistic regression analysis with age and gender as covariates demonstrated that ferritin levels over the 25th percentile were associated with the involvement of all 5 pulmonary lobes (OR=14.5, 95% CI=2.3-90.9, p=0.004), the presence of septal thickening (OR=8.2, 95% CI=1.6-40.9, p=0.011) and the presence of mediastinal lymph node enlargement (OR=12.0, 95% CI=1.1-127.5, p=0.039) independently of age and gender.We demonstrated that ferritin levels over the 25th percentile are associated with a more severe pulmonary involvement, independently of age and gender and not associated with disease outcomes. The identification of reliable biomarkers in patients with COVID-19 may help guiding clinical decision, tailoring therapeutic approaches and ultimately improving the care and prognosis of patients with this disease.

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Surface-based analysis of cortical thickness and volume loss in Alzheimer’s disease

Proceedings of IMPRS ◽

10.18060/23524 ◽

2019 ◽

Vol 2 (1) ◽

Author(s):

Emily Iannopollo ◽

Ryan Plunkett ◽

Kara Garcia

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Magnetic Resonance ◽

Cortical Thickness ◽

Surface Matching ◽

Cortical Surface ◽

Volume Loss ◽

Cortical Volume ◽

Human Connectome Project ◽

And Control

Background and Hypothesis: Magnetic resonance imaging (MRI) has become a useful tool in monitoring the progression of Alzheimer's disease. Previous surface-based analysis has focused on changes in cortical thickness associated with the disease1. The objective of this study is to analyze MRI-derived cortical reconstructions for patterns of atrophy in terms of both cortical thickness and cortical volume. We hypothesize that Alzheimer’s Disease progression will be associated with a more significant change in volume than thickness. Experimental Design or Project Methods: MRI data was obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI). All subjects with baseline and two-year 3T MRI scans were included. Segmentation of MRIs into gray and white matter was performed with FreeSurfer2,3,4,5. Subjects whose scans did not segment accurately were excluded. Surfaces were then registered to a common atlas with Ciftify6, and anatomically-constrained Multimodal Surface Matching (aMSM) was used to analyze longitudinal changes in each subject7. This produced continuous surface maps showing changes in cortical surface area and thickness. These maps were multiplied to create cortical volume maps8. Permutation Analysis of Linear Models (PALM) was used to perform two-sample t-tests comparing the maps of the Alzheimer’s and control groups9. Results: Preliminary analysis of nine Alzheimer’s subjects and nine control subjects produced surface maps displaying patterns that were expected given previous research findings10,11. There was increased volume and thickness loss in Alzheimer’s subjects relative to controls, with relatively high loss in structures of the medial temporal lobe. Future analysis of a larger sample will determine whether statistically significant differences exist between the Alzheimer’s and control groups in terms of thickness loss and volume loss. Conclusion and Potential Impact: If significant results are found, surface-based analysis of cortical volume may allow for detection of atrophy at an earlier stage in disease progression than would be possible based on cortical thickness. References 1. Clarkson MJ, Cardoso MJ, Ridgway GR, Modat M, Leung KK, Rohrer JD, Fox NC, Ourselin S. A comparison of voxel and surface based cortical thickness estimation methods. NeuroImage. 2011 Aug 1; 57(3):856-65. 2. Dale AM, Fischl B, Sereno MI. Cortical surface-based analysis. I. Segmentation and surface reconstruction. Neuroimage. 1999;9:179194. 3. Fischl B, Sereno M, Dale A. Cortical surface-based analysis. II: Inflation, flattening, and a surface-based coordinate system. Neuroimage. 1999;9:195–207. 4. Fischl B, Salat DH, Busa E, Albert M, Dieterich M, Haselgrove C, van der Kouwe A, Killiany R, Kennedy D, Klaveness S, Montillo A, Makris N, Rosen B, Dale AM. Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron 2002;33:341-355. 5. Fischl B, Salat DH, van der Kouwe AJ, Makris N, Segonne F, Quinn BT, Dale AM. Sequence-independent segmentation of magnetic resonance images. Neuroimage 2004;23 Suppl 1:S69-84. 6. Glasser MF, Sotiropoulos SN, Wilson JA, Coalson TS, Fischl B, Andersson JL, Xu J, Jbabdi S, Webster M, Polimeni JR, Van Essen DC, Jenkinson M, WU-Minn HCP Consortium. The minimal preprocessing pipelines for the Human Connectome Project. Neuroimage. 2013 Oct 15;80:105-24. 7. Robinson EC, Garcia K, Glasser MF, Chen Z, Coalson TS, Makropoulos A, Bozek J, Wright R, Schuh A, Webster M, Hutter J, Price A, Cordero Grande L, Hughes E, Tusor N, Bayly PV, Van Essen DC, Smith SM, Edwards AD, Hajnal J, Jenkinson M, Glocker B, Rueckert D. Multimodal surface matching with higher-order smoothness constraints. Neuroimage. 2018;167:453-65. 8. Marcus DS, Harwell J, Olsen T, Hodge M, Glasser MF, Prior F, Jenkinson M, Laumann T, Curtiss SW, Van Essen DC. Informatics and data mining tools and strategies for the human connectome project. Front Neuroinform 2011;5:4. 9. Winkler AM, Ridgway GR, Webster MA, Smith SM, Nichols TE. Permutation inference for the general linear model. NeuroImage, 2014;92:381-397 10. Matsuda, H. MRI morphometry in Alzheimer’s disease. Ageing Research Reviews. 2016 Sep;30:17-24. 11. Risacher SL, Shen L, West JD, Kim S, McDonald BC, Beckett LA, Harvey DJ, Jack CR Jr, Weiner MW, Saykin AJ. Alzheimer's Disease Neuroimaging Initiative (ADNI). Longitudinal MRI atrophy biomarkers: relationship to conversion in the ADNI cohort. Neurobiol Aging. 2010 Aug;31(8):1401-18.

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BrainFD: Measuring the Intracranial Brain Volume With Fractal Dimension

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.765185 ◽

2021 ◽

Vol 13 ◽

Author(s):

Ghulam Md Ashraf ◽

Stylianos Chatzichronis ◽

Athanasios Alexiou ◽

Nikolaos Kyriakopoulos ◽

Badrah Saeed Ali Alghamdi ◽

...

Keyword(s):

Fractal Dimension ◽

Brain Volume ◽

Heterogeneous Data ◽

Imaging Biomarker ◽

Volume Loss ◽

Imaging Data ◽

Clinical Dementia Rating ◽

Brain Volume Loss ◽

Brain White Matter ◽

The Brain

A few methods and tools are available for the quantitative measurement of the brain volume targeting mainly brain volume loss. However, several factors, such as the clinical conditions, the time of the day, the type of MRI machine, the brain volume artifacts, the pseudoatrophy, and the variations among the protocols, produce extreme variations leading to misdiagnosis of brain atrophy. While brain white matter loss is a characteristic lesion during neurodegeneration, the main objective of this study was to create a computational tool for high precision measuring structural brain changes using the fractal dimension (FD) definition. The validation of the BrainFD software is based on T1-weighted MRI images from the Open Access Series of Imaging Studies (OASIS)-3 brain database, where each participant has multiple MRI scan sessions. The software is based on the Python and JAVA programming languages with the main functionality of the FD calculation using the box-counting algorithm, for different subjects on the same brain regions, with high accuracy and resolution, offering the ability to compare brain data regions from different subjects and on multiple sessions, creating different imaging profiles based on the Clinical Dementia Rating (CDR) scores of the participants. Two experiments were executed. The first was a cross-sectional study where the data were separated into two CDR classes. In the second experiment, a model on multiple heterogeneous data was trained, and the FD calculation for each participant of the OASIS-3 database through multiple sessions was evaluated. The results suggest that the FD variation efficiently describes the structural complexity of the brain and the related cognitive decline. Additionally, the FD efficiently discriminates the two classes achieving 100% accuracy. It is shown that this classification outperforms the currently existing methods in terms of accuracy and the size of the dataset. Therefore, the FD calculation for identifying intracranial brain volume loss could be applied as a potential low-cost personalized imaging biomarker. Furthermore, the possibilities measuring different brain areas and subregions could give robust evidence of the slightest variations to imaging data obtained from repetitive measurements to Physicians and Radiologists.

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Blood Transcriptional Signatures for Disease Progression in a Rat Model of Osteoarthritis

International Journal of Genomics ◽

10.1155/2017/1746426 ◽

2017 ◽

Vol 2017 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Michał Korostyński ◽

Natalia Małek ◽

Marcin Piechota ◽

Katarzyna Starowicz

Keyword(s):

Gene Expression ◽

Peripheral Blood ◽

Time Course ◽

Clinical Symptoms ◽

Gene Signature ◽

Study Cohort ◽

Blood Samples ◽

Peripheral Blood Gene Expression ◽

Transcriptional Alterations ◽

Monosodium Iodoacetate

Biomarkers of osteoarthritis (OA) that can accurately diagnose the disease at the earliest stage would significantly support efforts to develop treatments for prevention and early intervention. We have sought to determine the time course of alterations in peripheral blood gene expression profile associated with the development of OA. Blood samples were collected from a tail vein of individual rats with monosodium iodoacetate- (MIA-) induced OA (2, 14, 21, and 28 days after the treatment). We used whole-genome microarrays to reveal OA-related transcriptional alterations of 72 transcripts. Three main groups of coexpressed genes revealed diverse time-dependent profiles of up- and downregulation. Functional links that connect expression of the gradually downregulated genes to the G13 signaling pathway were indicated. The mRNA abundance levels of the identified transcripts were further analyzed in publicly available gene expression dataset obtained from a GARP study cohort of OA patients. We revealed three-gene signature differentially expressed in both rat and human blood (TNK2, KCTD2, and WDR37). The alterations in expression of the selected transcripts in peripheral blood samples of the patients indicate heterogeneity of the OA profiles potentially related to disease progress and severity of clinical symptoms. Our study identifies several potential stage-specific biomarkers of OA progression.

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The effect of amyloid deposition on longitudinal resting-state functional connectivity in cognitively normal older adults

Alzheimer s Research & Therapy ◽

10.1186/s13195-019-0573-1 ◽

2020 ◽

Vol 12 (1) ◽

Cited By ~ 2

Author(s):

Chemin Lin ◽

Maria Ly ◽

Helmet T. Karim ◽

Wenjing Wei ◽

Beth E. Snitz ◽

...

Keyword(s):

Neural Networks ◽

Older Adults ◽

Cognitive Function ◽

Functional Connectivity ◽

Resting State ◽

Clinical Symptoms ◽

Rate Of Change ◽

Resting State Functional Connectivity ◽

Cognitive Changes ◽

Cognitively Normal

Abstract Background Pathological processes contributing to Alzheimer’s disease begin decades prior to the onset of clinical symptoms. There is significant variation in cognitive changes in the presence of pathology, functional connectivity may be a marker of compensation to amyloid; however, this is not well understood. Methods We recruited 64 cognitively normal older adults who underwent neuropsychological testing and biannual magnetic resonance imaging (MRI), amyloid imaging with Pittsburgh compound B (PiB)-PET, and glucose metabolism (FDG)-PET imaging for up to 6 years. Resting-state MRI was used to estimate connectivity of seven canonical neural networks using template-based rotation. Using voxel-wise paired t-tests, we identified neural networks that displayed significant changes in connectivity across time. We investigated associations among amyloid and longitudinal changes in connectivity and cognitive function by domains. Results Left middle frontal gyrus connectivity within the memory encoding network increased over time, but the rate of change was lower with greater amyloid. This was no longer significant in an analysis where we limited the sample to only those with two time points. We found limited decline in cognitive domains overall. Greater functional connectivity was associated with better attention/processing speed and executive function (independent of time) in those with lower amyloid but was associated with worse function with greater amyloid. Conclusions Increased functional connectivity serves to preserve cognitive function in normal aging and may fail in the presence of pathology consistent with compensatory models.

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