Basal Ganglia Research Articles

Pharmacotherapies for the Treatment of Progressive Supranuclear Palsy: A Narrative Review.

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder resulting from the deposition of misfolded and neurotoxic forms of tau protein in specific areas of the midbrain, basal ganglia, and cortex. It is one of the most representative forms of tauopathy. PSP presents in several different phenotypic variations and is often accompanied by the development of concurrent neurodegenerative disorders. PSP is universally fatal, and effective disease-modifying therapies for PSP have not yet been identified. Several tau-targeting treatment modalities, including vaccines, monoclonal antibodies, and microtubule-stabilizing agents, have been investigated and have had no efficacy. The need to treat PSP and other tauopathies is critical, and many clinical trials investigating tau-targeted treatments are underway. In this review, the PubMed database was queried to collect information about preclinical and clinical research on PSP treatment. Additionally, the US National Library of Medicine's ClinicalTrials.gov website was queried to identify past and ongoing clinical trials relevant to PSP treatment. This narrative review summarizes our findings regarding these reports, which include potential disease-modifying drug trials, modifiable risk factor management, and symptom treatments.

Effectiveness of vestibular rehabilitation on postural balance in Parkinson’s disease: a systematic review and meta-analysis of randomized controlled trials

IntroductionPostural balance impairment can affect the quality of life of patients with Parkinson’s disease. Previous studies have described connections of the vestibular system with postural functions, suggesting a potential participation of the basal ganglia in receiving vestibular stimuli. This systematic review aims to summarize the evidence on the effectiveness of vestibular rehabilitation on postural balance in patients with Parkinson’s disease.MethodsA systematic review was conducted using the electronic databases: PubMed, Embase, Scopus and PEDro. The study selection was independently conducted by two reviewers, and disagreements were evaluated by a third reviewer. The included studies had no restrictions on publication dates or languages and the last update occurred in July 2023.ResultsFrom the 485 studies found in the searches, only 3 studies were deemed eligible for the systematic review involving a total of 130 participants. The Berg Balance Scale was described as the tool for evaluation of postural balance in all studies. The meta-analysis showed statistically significant results in favor of vestibular rehabilitation (MD = 5.35; 95% CI = 2.39, 8.31; P < 0.001), regardless of the stage of Parkinson’s disease. Although the effect size was suggested as a useful functional gain, the analysis was done with caution, as it only included 3 randomized controlled trials. The risk of bias using the RoB-2 was considered as being of “some concern” in all studies. Furthermore, the quality of the evidence based on the Grading of Recommendations Assessment Development and Evaluation system, produced by pooling the included studies was considered very low.ConclusionCompared to other interventions, vestibular rehabilitation has potential to assist the postural balance of patients with Parkinson’s disease. However, the very low quality of the evidence demonstrates uncertainty about the impact of this clinical practice. More robust studies are needed to confirm the benefits of this therapy in patients with Parkinson’s disease. This study was prospectively registered in PROSPERO: CRD42020210185.

Glutamate Signaling in Patients With Parkinson Disease With REM Sleep Behavior Disorder.

Clinical heterogeneity of patients with Parkinson disease (PD) is well recognized. PD with REM sleep behavior disorder (RBD) is a more malignant phenotype with faster motor progression and higher nonmotor symptom burden. However, the neural mechanisms underlying this clinical divergence concerning imbalances in neurotransmitter systems remain elusive. Combining magnetic resonance (MR) spectroscopy and [11C]ABP688 PET on a PET/MR hybrid system, we simultaneously investigated two different mechanisms of glutamate signaling in patients with PD. Patients were grouped according to their RBD status in overnight video-polysomnography and compared with age-matched and sex-matched healthy control (HC) participants. Total volumes of distribution (VT) of [11C]ABP688 were estimated with metabolite-corrected plasma concentrations during steady-state conditions between 45 and 60 minutes of the scan following a bolus-infusion protocol. Glutamate, glutamine, and glutathione levels were investigated with single-voxel stimulated echo acquisition mode MR spectroscopy of the left basal ganglia. We measured globally elevated VT of [11C]ABP688 in 16 patients with PD and RBD compared with 17 patients without RBD and 15 HC participants (F(2,45) = 5.579, p = 0.007). Conversely, glutamatergic metabolites did not differ between groups and did not correlate with the regional VT of [11C]ABP688. VT of [11C]ABP688 correlated with the amount of REM sleep without atonia (F(1,42) = 5.600, p = 0.023) and with dopaminergic treatment response in patients with PD (F(1,30) = 5.823, p = 0.022). Our results suggest that patients with PD and RBD exhibit altered glutamatergic signaling indicated by higher VT of [11C]ABP688 despite unaffected glutamate levels. The imbalance of glutamate receptors and MR spectroscopy glutamate metabolite levels indicates a novel mechanism contributing to the heterogeneity of PD and warrants further investigation of drugs targeting mGluR5.

Effects of Intracerebral Aminophylline Dosing on Catalepsy and Gait in an Animal Model of Parkinson’s Disease

Parkinson’s disease (PD) is a progressive disorder characterized by the apoptosis of dopaminergic neurons in the basal ganglia. This study explored the potential effects of aminophylline, a non-selective adenosine A1 and A2A receptor antagonist, on catalepsy and gait in a haloperidol-induced PD model. Sixty adult male Swiss mice were surgically implanted with guide cannulas that targeted the basal ganglia. After seven days, the mice received intraperitoneal injections of either haloperidol (experimental group, PD-induced model) or saline solution (control group, non-PD-induced model), followed by intracerebral infusions of aminophylline. The assessments included catalepsy testing on the bar and gait analysis using the Open Field Maze. A two-way repeated-measures analysis of variance (ANOVA), followed by Tukey’s post hoc tests, was employed to evaluate the impact of groups (experimental × control), aminophylline (60 nM × 120 nM × saline/placebo), and interactions. Significance was set at 5%. The results revealed that the systemic administration of haloperidol in the experimental group increased catalepsy and dysfunction of gait that paralleled the observations in PD. Co-treatment with aminophylline at 60 nM and 120 nM reversed catalepsy in the experimental group but did not restore the normal gait pattern of the animals. In the non-PD induced group, which did not present any signs of catalepsy or motor dysfunctions, the intracerebral dose of aminophylline did not exert any interference on reaction time for catalepsy but increased walking distance in the Open Field Maze. Considering the results, this study highlights important adenosine interactions in the basal ganglia of animals with and without signs comparable to those of PD. These findings offer valuable insights into the neurobiology of PD and emphasize the importance of exploring novel therapeutic strategies to improve patient’s catalepsy and gait.

Generalized sleep decoding with basal ganglia signals in multiple movement disorders

Sleep disturbances profoundly affect the quality of life in individuals with neurological disorders. Closed-loop deep brain stimulation (DBS) holds promise for alleviating sleep symptoms, however, this technique necessitates automated sleep stage decoding from intracranial signals. We leveraged overnight data from 121 patients with movement disorders (Parkinson’s disease, Essential Tremor, Dystonia, Essential Tremor, Huntington’s disease, and Tourette’s syndrome) in whom synchronized polysomnograms and basal ganglia local field potentials were recorded, to develop a generalized, multi-class, sleep specific decoder – BGOOSE. This generalized model achieved 85% average accuracy across patients and across disease conditions, even in the presence of recordings from different basal ganglia targets. Furthermore, we also investigated the role of electrocorticography on decoding performances and proposed an optimal decoding map, which was shown to facilitate channel selection for optimal model performances. BGOOSE emerges as a powerful tool for generalized sleep decoding, offering exciting potentials for the precision stimulation delivery of DBS and better management of sleep disturbances in movement disorders.

A model with dopamine depletion in basal ganglia and cerebellum predicts changes in thalamocortical beta oscillations

A model with dopamine depletion in basal ganglia and cerebellum predicts changes in thalamocortical beta oscillations

Brain structure comparison among Parkinson disease, essential tremor, and healthy controls using 7T MRI.

Both Parkinson disease (PD) and Essential tremor (ET) are movement disorders causing tremors in elderly individuals. Although PD and ET are different disease, they often present with similar initial symptoms, making their differentiation challenging with magnetic resonance imaging (MRI) techniques. This study aimed to identify structural brain differences among PD, ET, and health controls (HCs) using 7-Tesla (T) MRI. We assessed the whole-brain parcellation in gray matter volume, thickness, subcortical volume, and small regions of basal ganglia in PD (n = 18), ET (n = 15), and HCs (n = 18), who were matched for age and sex. Brain structure analysis was performed automatic segmentation through Freesurfer software. Small regions of basal ganglia were manually segmented by ITK-SNAP. Additionally, we examined the associations between clinical indicators (symptom duration, unified Parkinson diseases rating scale (UPDRS), and clinical rating scale for tremor (CRST)) and brain structure. PD showed a significant reduction in gray matter volume in the postcentral region compared to ET. ET showed a significant reduction in cerebellum volume compared to HCs. There was a negative correlation between CRST scores (B and C) and gray matter thickness in right superior frontal in ET. This study demonstrated potential of 7T MRI in differentiating brain structure differences among PD, ET, and HCs. Specific findings, such as parietal lobe atrophy in PD compared to ET and cerebellum atrophy in ET compared to HCs, the importance of advanced imaging techniques in accurately diagnosing and distinguishing between movement disorders that present with similar initial symptoms.

Early and extended erythropoietin monotherapy after hypoxic ischaemic encephalopathy: a multicentre double-blind pilot randomised controlled trial

ObjectiveTo examine the feasibility of early and extended erythropoietin monotherapy after hypoxic ischaemic encephalopathy (HIE).DesignDouble-blind pilot randomised controlled trial.SettingEight neonatal units in South Asia.PatientsNeonates (≥36 weeks) with moderate or severe...

New Case of Spinocerebellar Ataxia, Autosomal Recessive 4, Due to VPS13D Variants

Movement disorders such as bradykinesia, tremor, dystonia, chorea, and myoclonus most often arise in several neurodegenerative diseases with basal ganglia and white matter involvement. While the pathophysiology of these disorders remains incompletely understood, dysfunction of the basal ganglia and related brain regions is often implicated. The VPS13D gene, part of the VPS13 family, has emerged as a crucial player in neurological pathology, implicated in diverse phenotypes ranging from movement disorders to Leigh syndrome. We present a clinical case of VPS13D-associated disease with two variants in the VPS13D gene in an adult female. This case contributes to our evolving understanding of VPS13D-related diseases and underscores the importance of genetic screening in diagnosing and managing such conditions.

SGLT1 and SGLT2 inhibition, circulating metabolites, and cerebral small vessel disease: a mediation Mendelian Randomization study

BackgroundSodium-glucose cotransporter 2 (SGLT2) and SGLT1 inhibitors may have additional beneficial metabolic effects on circulating metabolites beyond glucose regulation, which could contribute to a reduction in the burden of cerebral small vessel disease (CSVD). Accordingly, we used Mendelian Randomization (MR) to examine the role of circulating metabolites in mediating SGLT2 and SGLT1 inhibition in CSVD.MethodsGenetic instruments for SGLT1/2 inhibition were identified as genetic variants, which were both associated with the expression of encoding genes of SGLT1/2 inhibitors and glycated hemoglobin A1c (HbA1c) level. A two-sample two-step MR was used to determine the causal effects of SGLT1/2 inhibition on CSVD manifestations and the mediating effects of 1400 circulating metabolites linking SGLT1/2 inhibition with CSVD manifestations.ResultsA lower risk of deep cerebral microbleeds (CMBs) and small vessel stroke (SVS) was linked to genetically predicted SGLT2 inhibition. Better white matter structure integrity was also achieved, as evidenced by decreased mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), as well as lower deep (DWMH) and periventrivular white matter hyperintensity (PWMH) volume. Inhibiting SGLT2 could also lessen the incidence of severe enlarged perivascular spaces (EPVS) located at white matter, basal ganglia (BG) and hippocampus (HIP). SGLT1 inhibition could preserve white matter integrity, shown as decreased MD of white matter and DWMH volume. The effect of SGLT2 inhibition on SVS and MD of white matter through the concentration of 4-acetamidobutanoate and the cholesterol to oleoyl-linoleoyl-glycerol (18:1 to 18:2) ratio, with a mediated proportion of 30.3% and 35.5% of the total effect, respectively.ConclusionsSGLT2 and SGLT1 inhibition play protective roles in CSVD development. The SGLT2 inhibition could lower the risk of SVS and improve the integrity of white matter microstructure via modulating the level of 4-acetamidobutanoate and cholesterol metabolism. Further mechanistic and clinical studies research are needed to validate our findings.

Multi-timescale neuromodulation strategy for closed-loop deep brain stimulation in Parkinson’s disease

Objective. Beta triggered closed–loop deep brain stimulation (DBS) shows great potential for improving the efficacy while reducing side effect for Parkinson’s disease. However, there remain great challenges due to the dynamics and stochasticity of neural activities. In this study, we aimed to tune the amplitude of beta oscillations with different time scales taking into account influence of inherent variations in the basal ganglia–thalamus–cortical circuit. Approach. A dynamic basal ganglia–thalamus–cortical mean–field model was established to emulate the medication rhythm. Then, a dynamic target model was designed to embody the multi-timescale dynamic of beta power with milliseconds, seconds and minutes. Moreover, we proposed a closed-loop DBS strategy based on a proportional–integral–differential (PID) controller with the dynamic control target. In addition, the bounds of stimulation amplitude increments and different parameters of the dynamic target were considered to meet the clinical constraints. The performance of the proposed closed-loop strategy, including beta power modulation accuracy, mean stimulation amplitude, and stimulation variation were calculated to determine the PID parameters and evaluate neuromodulation performance in the computational dynamic mean–field model. Main results. The Results show that the dynamic basal ganglia–thalamus–cortical mean–field model simulated the medication rhythm with the fasted and the slowest rate. The dynamic control target reflected the temporal variation in beta power from milliseconds to minutes. With the proposed closed-loop strategy, the beta power tracked the dynamic target with a smoother stimulation sequence compared with closed-loop DBS with the constant target. Furthermore, the beta power could be modulated to track the control target under different long-term targets, modulation strengths, and bounds of the stimulation increment. Significance. This work provides a new method of closed–loop DBS for multi-timescale beta power modulation with clinical constraints.

Abnormal global and local connectivity in patients with anti-N-methyl-D-aspartate receptor encephalitis: A resting-state functional MRI study

ObjectiveWe decided to investigate the changes of global and local connectivity in anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis patients based on eigenvector centrality (EC) and regional homogeneity (ReHo). We sought new biomarkers to identify the patients based on multivariate pattern analysis (MVPA). MethodsFunctional MRI (fMRI) was performed on all participants. EC, ReHo and MVPA were used to analyze the fMRI images. The correlation between the global or local connectivity and neuropsychology tests was detected. ResultsThe MoCA scores of the patients were lower than those of the healthy controls (HCs), while the HAMD24 and HAMA scores of the patients were higher than those of the HCs. Increased EC values in the right calcarine (CAL.R) and decreased EC values in the right putamen (PUT.R) distinguished these subjects with anti-NMDAR encephalitis from HCs. The higher ReHo values in the left postcentral gyrus (PoCG.L) were detected in the patients. The correlation analysis showed that the EC values in the PUT.R were negatively correlated with HAMD24 and HAMA scores, while the ReHo values in the PoCG.L were negatively correlated with MoCA scores. Better classification performance was reached in the EC-based classifier (AUC = 0.80), while weaker classification performance was achieved in the ReHo-based classifier (AUC = 0.74) or the classifier based on EC and ReHo (AUC = 0.74). The brain areas with large weights were located in the frontal lobe, parietal lobe, cerebellum and basal ganglia. ConclusionOur findings suggest that abnormal global and local connectivity may play an important part in the pathophysiological mechanism of neuropsychiatric symptoms in the anti-NMDAR encephalitis patients. The EC-based classifier may be better than the ReHo-based classifier in identifying anti-NMDAR encephalitis patients.

Primary central nervous system lymphoma: Imaging features and differential diagnosis.

Primary central nervous system lymphoma (PCNSL) represents 5% of malignant primary brain tumors. The clinical presentation typically includes focal neurological symptoms, increased intracranial pressure, seizures, and psychiatric symptoms. Although histological examination remains the gold standard for diagnostic confirmation, non-invasive imaging plays a crucial role for the diagnosis. In immunocompetent individuals, PCNSL usually appears as a single, well-defined, supratentorial lesion with a predilection for periventricular areas, iso- or hypointense on T1- and T2-weighted magnetic resonance imaging, with restricted diffusion, slightly increased perfusion, and homogenous gadolinium-enhancement. Differential diagnoses include high-grade glioma and pseudotumoral demyelinating disease. In immunocompromised patients, PCNSL may present as multiple lesions, with a higher likelihood of hemorrhage and necrosis and less restricted diffusion than immunocompetent individuals. Differential diagnoses include neurotoxoplasmosis, progressive multifocal leukoencephalopathy, and cerebral abscess. Atypical forms of lymphoma are characterized by extra-axial lymphoma, lymphomatosis cerebri, and intravascular lymphoma. Extra-axial lymphoma presents as single or multiple extra-axial dural lesions with diffuse leptomeningeal contrast-enhancement. Lymphomatosis cerebri appears as an infiltrative and symmetric lesion, primarily affecting deep white matter and basal ganglia, appearing hyperintense on T2-weighted imaging, without significant contrast-enhancement or perfusion changes. Intravascular lymphoma presents as multiple rounded or oval-shaped "infarct-like" lesions, located cortically or subcortically. This study aims to highlight the imaging characteristics of PCNSL, focusing on magnetic resonance imaging and its differential diagnosis.

Opioid Overdose-Induced Diffusion Restriction in the Bilateral Basal Ganglia Revealed on Brain Imaging

Opioid Overdose-Induced Diffusion Restriction in the Bilateral Basal Ganglia Revealed on Brain Imaging

Combined in vivo MRI assessment of locus coeruleus and nucleus basalis of Meynert integrity in amnestic Alzheimer’s disease, suspected-LATE and frontotemporal dementia

BackgroundThe locus coeruleus (LC) and the nucleus basalis of Meynert (NBM) are altered in early stages of Alzheimer’s disease (AD). Little is known about LC and NBM alteration in limbic-predominant age-related TDP-43 encephalopathy (LATE) and frontotemporal dementia (FTD). The aim of the present study is to investigate in vivo LC and NBM integrity in patients with suspected-LATE, early-amnestic AD and FTD in comparison with controls.MethodsSeventy-two participants (23 early amnestic-AD patients, 17 suspected-LATE, 17 FTD patients, defined by a clinical-biological diagnosis reinforced by amyloid and tau PET imaging, and 15 controls) underwent neuropsychological assessment and 3T brain MRI. We analyzed the locus coeruleus signal intensity (LC-I) and the NBM volume as well as their relation with cognition and with medial temporal/cortical atrophy.ResultsWe found significantly lower LC-I and NBM volume in amnestic-AD and suspected-LATE in comparison with controls. In FTD, we also observed lower NBM volume but a slightly less marked alteration of the LC-I, independently of the temporal or frontal phenotype. NBM volume was correlated with the global cognitive efficiency in AD patients. Strong correlations were found between NBM volume and that of medial temporal structures, particularly the amygdala in both AD and FTD patients.ConclusionsThe alteration of LC and NBM in amnestic-AD, presumed-LATE and FTD suggests a common vulnerability of these structures to different proteinopathies. Targeting the noradrenergic and cholinergic systems could be effective therapeutic strategies in LATE and FTD.

Neural processing in the primary auditory cortex following cholinergic lesions of the basal forebrain in ferrets

Cortical acetylcholine (ACh) release has been linked to various cognitive functions, including perceptual learning. We have previously shown that cortical cholinergic innervation is necessary for accurate sound localization in ferrets, as well as for their ability to adapt with training to altered spatial cues. To explore whether these behavioral deficits are associated with changes in the response properties of cortical neurons, we recorded neural activity in the primary auditory cortex (A1) of anesthetized ferrets in which cholinergic inputs had been reduced by making bilateral injections of the immunotoxin ME20.4-SAP in the nucleus basalis (NB) prior to training the animals. The pattern of spontaneous activity of A1 units recorded in the ferrets with cholinergic lesions (NB ACh–) was similar to that in controls, although the proportion of burst-type units was significantly lower. Depletion of ACh also resulted in more synchronous activity in A1. No changes in thresholds, frequency tuning or in the distribution of characteristic frequencies were found in these animals. When tested with normal acoustic inputs, the spatial sensitivity of A1 neurons in the NB ACh– ferrets and the distribution of their preferred interaural level differences also closely resembled those found in control animals, indicating that these properties had not been altered by sound localization training with one ear occluded. Simulating the animals’ previous experience with a virtual earplug in one ear reduced the contralateral preference of A1 units in both groups, but caused azimuth sensitivity to change in slightly different ways, which may reflect the modest adaptation observed in the NB ACh– group. These results show that while ACh is required for behavioral adaptation to altered spatial cues, it is not required for maintenance of the spectral and spatial response properties of A1 neurons.

Striatal cholinergic interneuron development in models of DYT1 dystonia

Dystonia is a neurodevelopmental disorder characterized by severe involuntary twisting movements, hypothesized to arise from a dysfunctional motor network involving the cortex, basal ganglia, and cerebellum. Within this network, striatal cholinergic interneurons have been identified as possible contributors to dystonia pathophysiology. However, little is known about striatal cholinergic interneuron development in the mammalian brain, limiting our understanding of its role in dystonia and therapeutic potential. Here, I review striatal cholinergic interneuron development in the context of early-onset DYT1 (or “DYT-TOR1A”) dystonia. I discuss clinical and laboratory research findings that support cholinergic dysfunction in DYT1 dystonia and the implications of abnormal cholinergic cell development on disease penetrance and striatal connectivity.

Clinical analysis and literature review of two paediatric cases of anti-IgLON5 antibody-related encephalitis

IntroductionAnti-IgLON5 antibody-related encephalitis is a rare autoimmune disorder of the central nervous system, predominantly occurring in middle-aged elderly individuals, with paediatric cases being exceptionally rare. This study aims to enhance the understanding of paediatric anti-IgLON5 antibody-related encephalitis by summarising its clinical and therapeutic characteristics.MethodA retrospective analysis was conducted on two paediatric patients diagnosed with anti-IgLON5 antibody-related encephalitis at Hunan Children’s Hospital from August 2022 to November 2023. This involved reviewing their medical records and follow-up data, in addition to a literature review.ResultsThe study involved two patients, one male and one female, aged between 2.5 and 9.6 years, both presenting with an acute/subacute course of illness. Clinically, both exhibited movement disorders (including dystonia, involuntary movements, and ataxia), cognitive impairments, sleep disturbances, and psychiatric symptoms. Patient 1 experienced epileptic seizures, while Patient 2 exhibited brainstem symptoms and abnormal eye movements. Neither patient showed autonomic dysfunction. Patient 1 had normal cerebrospinal fluid (CSF) and Brain MRI findings, whereas Patient 2 showed moderate leukocytosis and mild protein elevation in the CSF, and Brain MRI revealed symmetrical lesions in the basal ganglia and cerebellum. Oligoclonal bands in the CSF were positive in both cases. Both patients tested negative for HLA-DQB*05:01 and HLA-DRB*10:01. They received both first-line and second-line immunotherapies, with Patient 2 showing a poor response to treatment.DiscussionPaediatric cases of anti-IgLON5 antibody-related encephalitis similarly present sleep disturbances as a core symptom, alongside various forms of movement disorders. Immunotherapy is partially effective. Compared to adult patients, these paediatric cases tend to exhibit more pronounced psychiatric symptoms, a more rapid onset, and more evident inflammatory changes in the CSF. The condition appears to have a limited association with HLA-DQB*05:01 and HLA-DRB*10:01 polymorphisms.

Enlarged perivascular spaces in alcohol-related brain damage induced by dyslipidemia.

Perivascular spaces (PVSs) as the anatomical basis of the glymphatic system, are increasingly recognized as potential imaging biomarkers of neurological conditions. However, it is not clear whether enlarged PVSs are associated with alcohol-related brain damage (ARBD). We aimed to investigate the effect of long-term alcohol exposure on dyslipidemia and the glymphatic system in ARBD. We found that patients with ARBD exhibited significantly enlargement of PVSs in the frontal cortex and basal ganglia, as well as a notable increased levels of total cholesterol (TC) and triglycerides (TG). The anatomical changes of the glymphatic drainage system mentioned above were positively associated with TC and TG. To further explore whether enlarged PVSs affects the function of the glymphatic system in ARBD, we constructed long alcohol exposure and high fat diet mice models. The mouse model of long alcohol exposure exhibited increased levels of TC and TG, enlarged PVSs, the loss of aquaporin-4 polarity caused by reactive astrocytes and impaired glymphatic drainage function which ultimately caused cognitive deficits, in a similar way as high fat diet leading to impairment in glymphatic drainage. Our study highlights the contribution of dyslipidemia due to long-term alcohol abuse in the impairment of the glymphatic drainage system.

Molecular neuroimaging in dominantly inherited versus sporadic early-onset Alzheimer’s disease

Abstract Approximately 5% of Alzheimer’s Disease patients develop symptoms before age 65 (EOAD), with either sporadic (sEOAD) or dominantly inherited (DIAD) presentations. Both sEOAD and DIAD are characterized by brain amyloid-beta accumulation, tau tangles, hypometabolism and neurodegeneration, but differences in topography and magnitude of these pathological changes are not fully elucidated. In this study, we directly compared patterns of amyloid-beta plaque deposition and glucose hypometabolism in sEOAD and DIAD individuals. Our analysis included 134 symptomatic sEOAD Amyloid-PET positive cases from the University of California, San Francisco, Alzheimer’s Disease Research Center (mean ± standard deviation age 59.7 ± 5.6 years), 89 symptomatic DIAD cases (age 45.8 ± 9.3 years) and 102 cognitively unimpaired non-mutation carriers from the Dominantly Inherited Alzheimer Network study (age 44.9 ± 9.2). Each group underwent clinical and cognitive examinations, 11C-labeled Pittsburgh compound B-PET (PIB-PET) and structural Magnetic Resonance Imaging. 18F-fluorodeoxyglucose-PET (FDG-PET) was also available for most participants. PET scans from both studies were uniformly processed to obtain Standardized Uptake Value Ratio (SUVR, PIB50-70 cerebellar gray reference, FDG30-60 pons reference) images. Statistical analyses included pairwise global and voxelwise group comparisons and group-independent component analyses. Analyses were performed also adjusting for covariates including age, sex, Mini-Mental State Examination, Apolipoprotein-ε4 status, and average composite cortical of Standardized Uptake Value Ratio. Compared to DIAD, sEOAD participants were older at age of onset (mean ± standard deviation, 54.8 ± 8.2 vs. 41.9 ± 8.2, Cohen’s d = 1.91), with more years of education (16.4 ± 2.8 vs. 13.5 ± 3.2, d = 1) and more likely to be Apolipoprotein-ε4 carriers (54.6% ε4 vs. 28.1%, Cramer’s V = 0.26), but similar Mini-Mental State Examination (20.6 ± 6.1 vs. 21.2 ± 7.4, d = 0.08). sEOAD had higher global cortical PIB-PET binding (mean ± standard deviation SUVR, 1.92 ± 0.29 vs. 1.58 ± 0.44, d = 0.96) and greater global cortical FDG-PET hypometabolism (mean ± standard deviation SUVR, 1.32 ± 0.1 vs. 1.39 ± 0.19, d = 0.48) compared to DIAD. Fully adjusted comparisons demonstrated relatively higher PIB-PET SUVR in the medial occipital, thalami, basal ganglia and medial/dorsal frontal regions in DIAD vs. sEOAD. sEOAD showed relatively greater FDG-PET hypometabolism in Alzheimer’s Disease signature temporoparietal regions and caudate nuclei, whereas DIAD showed relatively greater hypometabolism in frontal white matter and pericentral regions. Independent component analyses largely replicated these findings by highlighting common and unique PIB-PET and FDG-PET binding patterns. In summary, our findings suggest both common and distinct patterns of amyloid and glucose hypometabolismin in sporadic and dominantly inherited EOAD.