Choroid Plexus Volume, Amyloid Burden, and Cognition in the Alzheimer's Disease Continuum.

As a part of the glymphatic system, the choroid plexus (CP) is involved in the clearance of harmful metabolites from the brain. We investigated the association between CP volume (CPV), amyloid-ß (Aß) burden, and cognition in patients on the Alzheimer's disease (AD) continuum. We retrospectively reviewed the records of 203 patients on the AD continuum and 82 healthy controls who underwent brain magnetic resonance imaging and 18F-florbetaben positron emission tomography. Automatic segmentation was performed, and the CPV was calculated. Cognitive function was assessed using detailed neuropsychological tests, and patients on the AD continuum were categorized into the non-dementia and dementia groups. The relationships between CPV, Aß burden, and cognitive function were assessed using multivariate linear regression and linear mixed model. CPV was greater in the AD group than in the healthy control group (1.50 vs. 1.30, P < 0.001), but was comparable between the AD non-dementia and dementia groups (1.50 vs. 1.48, P = 0.585). After adjusting for age and sex, a larger CPV was significantly associated with greater global Aß deposition (ß = 0.20, P = 0.002). Larger CPV was also associated with worse general cognitive function assessed using the sum of boxes of the clinical dementia rating scale (ß = 0.85, P = 0.034) and lower composite scores for memory (ß = -0.68, P = 0.002) and frontal/executive function domains (ß = -0.65, P < 0.001). In addition, a larger CPV was associated with a more rapid decline in Mini-Mental State Examination scores in the AD dementia group (ß = -0.58, P = 0.004). The present study demonstrated that CP enlargement was associated with increased Aß deposition and impaired memory and frontal/executive function in patients on the AD continuum.

Seizure-induced LIN28A disrupts pattern separation via aberrant hippocampal neurogenesis.

Prolonged seizures can disrupt stem cell behavior in the adult hippocampus, an important brain structure for spatial memory. Here, using a mouse model of pilocarpine-induced status epilepticus (SE), we characterized spatiotemporal expression of Lin28a mRNA and proteins after SE. Unlike Lin28a transcripts, induction of LIN28A protein after SE was detected mainly in the subgranular zone, where immunoreactivity was found in progenitors, neuroblasts, and immature and mature granule neurons. To investigate roles of LIN28A in epilepsy, we generated Nestin-Cre:Lin28aloxP/loxP (conditional KO [cKO]) and Nestin-Cre:Lin28a+/+ (WT) mice to block LIN28A upregulation in all neuronal lineages after acute seizure. Adult-generated neuron- and hippocampus-associated cognitive impairments were absent in epileptic LIN28A-cKO mice, as evaluated by pattern separation and contextual fear conditioning tests, respectively, while sham-manipulated WT and cKO animals showed comparable memory function. Moreover, numbers of hilar PROX1-expressing ectopic granule cells (EGCs), together with PROX1+/NEUN+ mature EGCs, were significantly reduced in epileptic cKO mice. Transcriptomics analysis and IHC validation at 3 days after pilocarpine administration provided potential LIN28A downstream targets such as serotonin receptor 4. Collectively, our findings indicate that LIN28A is a potentially novel target for regulation of newborn neuron-associated memory dysfunction in epilepsy by modulating seizure-induced aberrant neurogenesis.

Different effect of hypo- and hypermetabolism on cognition in dementia with Lewy bodies: are they coupled or independent?

Patients with dementia with Lewy bodies (DLB) show widespread brain metabolic changes. This study investigated whether brain hypo- and hypermetabolism in DLB have differential effects on cognition. We enrolled 55 patients with DLB (15 prodromal DLB [MCI-LB] and 40 probable DLB) and 13 healthy controls who underwent 18F-fluorodeoxyglucose positron emission tomography and detailed neuropsychological tests. Metabolic indices reflecting associated changes in regional cerebral glucose metabolism were calculated as follows: index(-) for hypometabolism [DLB-hypo] and index(+) for hypermetabolism [DLB-hyper]. The effects of DLB-hypo or DLB-hyper on cognitive function were assessed using a multivariate linear regression model. Additionally, a linear mixed model was used to investigate the association between each index and the longitudinal cognitive decline. There was no correlation between DLB-hypo and DLB-hyper in the disease group. The multivariate linear regression model showed that DLB-hypo was associated with language, visuospatial, visual memory, and frontal/executive functions; whereas DLB-hyper was responsible for attention and verbal memory. There was significant interaction between DLB-hypo and DLB-hyper for verbal and visual memory, which was substantially affected by DLB-hyper in relatively preserved DLB-hypo status. A linear mixed model showed that DLB-hypo was associated with longitudinal cognitive outcomes, regardless of cognitive status, and DLB-hyper contributed to cognitive decline only in the MCI-LB group. The present study suggests that DLB-hypo and DLB-hyper may be independent of each other and differentially affect the baseline and longitudinal cognitive function in patients with DLB.

Whole brain network effects of subcallosal cingulate deep brain stimulation for treatment-resistant depression.

Ongoing experimental studies of subcallosal cingulate deep brain stimulation (SCC DBS) for treatment-resistant depression (TRD) show a differential timeline of behavioral effects with rapid changes after initial stimulation, and both early and delayed changes over the course of ongoing chronic stimulation. This study examined the longitudinal resting-state regional cerebral blood flow (rCBF) changes in intrinsic connectivity networks (ICNs) with SCC DBS for TRD over 6 months and repeated the same analysis by glucose metabolite changes in a new cohort. A total of twenty-two patients with TRD, 17 [15 O]-water and 5 [18 F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) patients, received SCC DBS and were followed weekly for 7 months. PET scans were collected at 4-time points: baseline, 1-month after surgery, and 1 and 6 months of chronic stimulation. A linear mixed model was conducted to examine the differential trajectory of rCBF changes over time. Post-hoc tests were also examined to assess postoperative, early, and late ICN changes and response-specific effects. SCC DBS had significant time-specific effects in the salience network (SN) and the default mode network (DMN). The rCBF in SN and DMN was decreased after surgery, but responder and non-responders diverged thereafter, with a net increase in DMN activity in responders with chronic stimulation. Additionally, the rCBF in the DMN uniquely correlated with depression severity. The glucose metabolic changes in a second cohort show the same DMN changes. The trajectory of PET changes with SCC DBS is not linear, consistent with the chronology of therapeutic effects. These data provide novel evidence of both an acute reset and ongoing plastic effects in the DMN that may provide future biomarkers to track clinical improvement with ongoing treatment.

Cingulate dynamics track depression recovery with deep brain stimulation.

Deep brain stimulation (DBS) of the subcallosal cingulate (SCC) can provide long-term symptom relief for treatment-resistant depression (TRD)1. However, achieving stable recovery is unpredictable2, typically requiring trial-and-error stimulation adjustments due to individual recovery trajectories and subjective symptom reporting3. We currently lack objective brain-based biomarkers to guide clinical decisions by distinguishing natural transient mood fluctuations from situations requiring intervention. To address this gap, we used a new device enabling electrophysiology recording to deliver SCC DBS to ten TRD participants (ClinicalTrials.gov identifier NCT01984710). At the study endpoint of 24 weeks, 90% of participants demonstrated robust clinical response, and 70% achieved remission. Using SCC local field potentials available from six participants, we deployed an explainable artificial intelligence approach to identify SCC local field potential changes indicating the patient's current clinical state. This biomarker is distinct from transient stimulation effects, sensitive to therapeutic adjustments and accurate at capturing individual recovery states. Variable recovery trajectories are predicted by the degree of preoperative damage to the structural integrity and functional connectivity within the targeted white matter treatment network, and are matched by objective facial expression changes detected using data-driven video analysis. Our results demonstrate the utility of objective biomarkers in the management of personalized SCC DBS and provide new insight into the relationship between multifaceted (functional, anatomical and behavioural) features of TRD pathology, motivating further research into causes of variability in depression treatment.

Distinct amyloid-dependent patterns of nigra dopamine depletion in Lewy body diseases.

Introduction: Concomitant amyloid pathology is not uncommon and contributes to the clinical characteristics of Lewy body disease (LBD). We investigated the effect of amyloid on striatal18F-FP-CIT uptake patterns in LBD, including Parkinson's disease (PD) and dementia with Lewy bodies. Methods: We enrolled 125 patients with LBD who underwent18F-florbetaben positron emission tomography (PET) and18F-FP-CIT PET. Patients were divided into amyloid-positive and amyloid-negative groups. We investigated the effect of amyloid on striatal dopamine transporter (DAT) availability, depending on the type of LBD, using general linear models with interaction analysis after controlling for age, sex, education, deep white matter hyperintensity (WMH), periventricular WMH, and cognitive status. Results: There was a significant interaction effect between the disease group and the presence of amyloid on DAT availability in the anterior putamen, posterior putamen, caudate, and ventral striatum. In the presence of amyloid, only the PD group exhibited decreased DAT availability in the anterior and posterior putamen. In both groups, the presence of amyloid was not associated with DAT availability in the caudate and ventral striatum. The presence of amyloid was not directly related to the worse parkinsonian motor symptoms in both groups. However, there was a significant indirect effect of amyloid on parkinsonian motor symptoms, which was mediated by anterior and posterior putaminal DAT availability in the PD group alone. Discussion: This study demonstrates different amyloid-dependent or amyloid-independent18F-FP-CIT PET patterns in patients with LBD, suggesting distinctive interactions between α-synuclein and amyloid pathology based on the type of LBD.

Whole Brain Network effects of subcallosal cingulate deep brain stimulation for treatment-resistant depression.

Ongoing experimental studies of subcallosal cingulate deep brain stimulation (SCC DBS) for treatment-resistant depression (TRD) show a differential timeline of behavioral effects with rapid changes after initial stimulation, and both early and delayed changes over the course of ongoing chronic stimulation. This study examined the longitudinal resting-state regional cerebral blood ow (rCBF) changes in intrinsic connectivity networks (ICNs) with SCC DBS for TRD over 6 months and repeated the same analysis by glucose metabolite changes in a new cohort. A total of twenty-two patients with TRD, 17 [15O]-water and 5 [18]-Fluorodeoxyglucose (FDG) positron emission tomography (PET) patients, received SCC DBS and were followed weekly for 7 months. PET scans were collected at 4-time points: baseline, 1-month after surgery, and 1 and 6 months of chronic stimulation. A linear mixed model was conducted to examine the differential trajectory of rCBF changes over time. Post-hoc tests were also examined to assess postoperative, early, and late ICN changes and response-specific effects. SCC DBS had significant time-specific effects in the salience network (SN) and the default mode network (DMN). The rCBF in SN and DMN was decreased after surgery, but responder and non-responders diverged thereafter, with a net increase in DMN activity in responders with chronic stimulation. Additionally, the rCBF in the DMN uniquely correlated with depression severity. The glucose metabolic changes in a second cohort show the same DMN changes. The trajectory of PET changes with SCC DBS is not linear, consistent with the chronology of therapeutic effects. These data provide novel evidence of both an acute reset and ongoing plastic effects in the DMN that may provide future biomarkers to track clinical improvement with ongoing treatment.

Functional connectivity of salience and affective networks among remitted depressed patients predicts episode recurrence.

Recurrent episodes in major depressive disorder (MDD) are common but the neuroimaging features predictive of recurrence are not established. Participants in the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study who achieved remission after 12 weeks of treatment withcognitive behavior therapy, duloxetine, or escitalopram were prospectively monitored for up to 21 months for recurrence. Neuroimaging markers predictive of recurrence were identified from week 12 functional magnetic resonance imaging scans by analyzing whole-brain resting state functional connectivity (RSFC) using seeds for four brain networks that are altered in MDD. Neuroimaging correlates of established clinical predictors of recurrence, including the magnitude of depressive (Hamilton Depression Rating Scale), anxiety (Hamilton Anxiety Rating Scale) symptom severity at time of remission, and a comorbid anxiety disorder were examined for their similarity to the neuroimaging predictors of recurrence. Of the 344 patients randomized in PReDICT, 61 achieved remission and had usable scans for analysis, 9 of whom experienced recurrence during follow-up. Recurrence was predicted by: 1) increased RSFC between subcallosal cingulate cortex (SCC) and right anterior insula, 2) decreased RSFC between SCC and bilateral primary visual cortex, and 3) decreased RSFC between insula and bilateral caudate. Week 12 depression and anxiety scores were negatively correlated with RSFC strength between executive control and default mode networks, but they were not correlated with the three RSFC patterns predicting recurrence. We conclude that altered RSFC in SCC and anterior insula networks are prospective risk factors associated with MDD recurrence, reflecting additional sources of risk beyond clinical measures.

Phase shift optimization of III/V-on-bulk-Si DFB LD for single-mode stability.

A III/V-on-Bulk-Si DFB laser with a long phase shift section optimized for single-mode stability is presented. The optimized phase shift allows stable single-mode operations up to 20 times a threshold current. This mode stability is achieved by a gain difference between fundamental and higher modes maximized by sub-wavelength-scale tuning of the phase shift section. In SMSR-based yield analyses, the long-phase-shifted DFB laser showed superior performance compared to the conventional λ/4-phase-shifted ones.

Occipital Amyloid Deposition Is Associated with Rapid Cognitive Decline in the Alzheimer's Disease Continuum.

BACKGROUND: Clinical significance of additional occipital amyloid-ß (Aß) plaques in Alzheimer's disease (AD) remains unclear. OBJECTIVE: In this study, we investigated the effect of regional Aß deposition on cognition in patients on the AD continuum, especially in the occipital region. METHODS: We retrospectively reviewed the medical record of 208 patients with AD across the cognitive continuum (non-dementia and dementia). Multivariable linear regression analyses were performed to determine the effect of regional Aß deposition on cognitive function. A linear mixed model was used to assess the effect of regional deposition on longitudinal changes in Mini-Mental State Examination (MMSE) scores. Additionally, the patients were dichotomized according to the occipital-to-global Aß deposition ratio (ratio ≤1, Aß-OCC- group; ratio >1, Aß-OCC+ group), and the same statistical analyses were applied for between-group comparisons. RESULTS: Regional Aß burden itself was not associated with baseline cognitive function. In terms of Aß-OCC group effect, the Aß-OCC+ group exhibited a poorer cognitive performance on language function compared to the Aß-OCC- group. High Aß retention in each region was associated with a rapid decline in MMSE scores, only in the dementia subgroup. Additionally, Aß-OCC+ individuals exhibited a faster annual decline in MMSE scores than Aß-OCC- individuals in the non-dementia subgroup (ß= -0.77, standard error [SE] = 0.31, p = 0.013). CONCLUSION: The present study demonstrated that additional occipital Aß deposition was associated with poor baseline language function and rapid cognitive deterioration in patients on the AD continuum.

Shared and Unique Changes in Brain Connectivity Among Depressed Patients After Remission With Pharmacotherapy Versus Psychotherapy.

OBJECTIVE: The authors sought to determine the shared and unique changes in brain resting-state functional connectivity (rsFC) between patients with major depressive disorder who achieved remission with cognitive-behavioral therapy (CBT) or with antidepressant medication. METHODS: The Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) trial randomized adults with treatment-naive major depressive disorder to 12 weeks of treatment with CBT (16 1-hour sessions) or medication (duloxetine 30-60 mg/day or escitalopram 10-20 mg/day). Resting-state functional MRI scans were performed at baseline and at week 12. The primary outcome was change in the whole-brain rsFC of four seeded brain networks among participants who achieved remission. RESULTS: Of the 131 completers with usable MRI data (74 female; mean age, 39.8 years), remission was achieved by 19 of 40 CBT-treated and 45 of 91 medication-treated patients. Three patterns of connectivity changes were observed. First, those who remitted with either treatment shared a pattern of reduction in rsFC between the subcallosal cingulate cortex and the motor cortex. Second, reciprocal rsFC changes were observed across multiple networks, primarily increases in CBT remitters and decreases in medication remitters. And third, in CBT remitters only, rsFC increased within the executive control network and between the executive control network and parietal attention regions. CONCLUSIONS: Remission from major depression via treatment with CBT or medication is associated with changes in rsFC that are mostly specific to the treatment modality, providing biological support for the clinical practice of switching between or combining these treatment approaches. Medication is associated with broadly inhibitory effects. In CBT remitters, the increase in rsFC strength between networks involved in cognitive control and attention provides biological support for the theorized mechanism of CBT. Reducing affective network connectivity with motor systems is a shared process important for remission with both CBT and medication.

Association of Enlarged Perivascular Spaces With Amyloid Burden and Cognitive Decline in Alzheimer Disease Continuum.

BACKGROUND AND OBJECTIVES: To investigate the effects of enlarged perivascular space (EPVS) on amyloid burden and cognitive function in Alzheimer's disease (AD) continuum. METHODS: We retrospectively reviewed 208 patients with AD across the cognitive continuum (preclinical, prodromal, and AD dementia) who showed amyloid deposition on 18F-florbetaben positron emission tomography scans and 82 healthy controls. EPVSs were counted for each patient in the basal ganglia (BG), centrum semiovale (CSO), and hippocampus (HP) on axial T2-weighted images. Patients were then classified according to the number of EPVS into the EPVS+ (> 10 EPVSs) and EPVS- (0-10 EPVSs) groups for the BG and CSO, respectively. In terms of HP-EPVS, equal or more than seven EPVSs on bilateral hemisphere were regarded as the presence of HP-EPVS. After adjusting for markers of small vessel disease (SVD), multiple linear regression analyses were performed to determine the inter-group differences in global and regional amyloid deposition and cognitive function at the time of diagnosis of AD continuum. A linear mixed model was used to assess the effects of EPVSs on the longitudinal changes in the Mini-Mental State Examination (MMSE) scores. RESULTS: Amyloid burden at the time of diagnosis of AD continuum was not associated with the degree of BG-, CSO-, or HP-EPVS. BG-EPVS affected language and frontal/executive function via SVD markers and HP-EPVS was associated with general cognition via SVD markers. However, CSO-EPVS was not associated with baseline cognition. A higher number of CSO-EPVS was significantly associated with a more rapid decline in MMSE scores (ß = -0.58, SE = 0.23, p = 0.011) independent of the amyloid burden. In terms of BG and HP, there was no difference between the EPVS+ and EPVS- groups in the rate of longitudinal decreases in MMSE scores. DISCUSSION: Our findings suggest that BG-, CSO-, and HP-EPVS are not associated with baseline ß-amyloid burden or cognitive function independently of SVD at the diagnosis of AD continuum. However, CSO-EPVS appears to be associated with the progression of cognitive decline in an amyloid-independent manner. Further studies are needed to investigate whether CSO-EPVS is a potential therapeutic target in patients with AD continuum.

Proceedings of the Ninth Annual Deep Brain Stimulation Think Tank: Advances in Cutting Edge Technologies, Artificial Intelligence, Neuromodulation, Neuroethics, Pain, Interventional Psychiatry, Epilepsy, and Traumatic Brain Injury.

DBS Think Tank IX was held on August 25-27, 2021 in Orlando FL with US based participants largely in person and overseas participants joining by video conferencing technology. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers and researchers (from industry and academia) can freely discuss current and emerging deep brain stimulation (DBS) technologies as well as the logistical and ethical issues facing the field. The consensus among the DBS Think Tank IX speakers was that DBS expanded in its scope and has been applied to multiple brain disorders in an effort to modulate neural circuitry. After collectively sharing our experiences, it was estimated that globally more than 230,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. As such, this year's meeting was focused on advances in the following areas: neuromodulation in Europe, Asia and Australia; cutting-edge technologies, neuroethics, interventional psychiatry, adaptive DBS, neuromodulation for pain, network neuromodulation for epilepsy and neuromodulation for traumatic brain injury.

Altered cerebrocerebellar functional connectivity in patients with obstructive sleep apnea and its association with cognitive function.

STUDY OBJECTIVES: Previous functional MRI studies have reported altered brain networks in patients with obstructive sleep apnea (OSA). However, the extent and pattern of abnormal connectivity were inconsistent across studies, and cerebrocerebellar connections have been rarely assessed. We investigated functional network changes in cerebral and cerebellar cortices of OSA patients. METHODS: Resting-state functional MRI, polysomnography, and neuropsychological (NP) test data were acquired from 74 OSA patients (age: 45.8 ± 10.7 years) and 33 healthy subjects (39.6 ± 9.3 years). Connectivity matrices were extracted by computing correlation coefficients from various regions of interest, and Fisher r-to-z transformations. In the functional connections that showed significant group differences, linear regression was conducted to examine the association between connectivity and clinical characteristics. RESULTS: Patients with OSA showed reduced functional connectivity (FC) in cerebrocerebellar connections linking different functional networks, and greater FC in cortical between-network connections in prefrontal regions involving the default mode network (DMN) and the control network. For OSA group, we found no correlation between FC and sleep parameters including lowest SaO2 and arousal index in the connections where significant associations were observed in healthy subjects. FC changes in DMN areas were related to reduced verbal fluency in OSA. Lower local efficiency and lower clustering coefficient of the salience network in the left cerebellum were also observed in OSA. CONCLUSIONS: OSA affects mainly the cerebrocerebellar pathway. The disruption of function in these connections are related to sleep fragmentation and hypoxia during sleep. These abnormal network functions, especially DMN, are suggested to participate in cognitive decline of OSA.

Indoxyl sulfate, a gut microbiome-derived uremic toxin, is associated with psychic anxiety and its functional magnetic resonance imaging-based neurologic signature.

It is unknown whether indoles, metabolites of tryptophan that are derived entirely from bacterial metabolism in the gut, are associated with symptoms of depression and anxiety. Serum samples (baseline, 12 weeks) were drawn from participants (n = 196) randomized to treatment with cognitive behavioral therapy (CBT), escitalopram, or duloxetine for major depressive disorder. Baseline indoxyl sulfate abundance was positively correlated with severity of psychic anxiety and total anxiety and with resting state functional connectivity to a network that processes aversive stimuli (which includes the subcallosal cingulate cortex (SCC-FC), bilateral anterior insula, right anterior midcingulate cortex, and the right premotor areas). The relation between indoxyl sulfate and psychic anxiety was mediated only through the metabolite's effect on the SCC-FC with the premotor area. Baseline indole abundances were unrelated to post-treatment outcome measures, and changes in symptoms were not correlated with changes in indole concentrations. These results suggest that CBT and antidepressant medications relieve anxiety via mechanisms unrelated to modulation of indoles derived from gut microbiota; it remains possible that treatment-related improvement stems from their impact on other aspects of the gut microbiome. A peripheral gut microbiome-derived metabolite was associated with altered neural processing and with psychiatric symptom (anxiety) in humans, which provides further evidence that gut microbiome disruption can contribute to neuropsychiatric disorders that may require different therapeutic approaches. Given the exploratory nature of this study, findings should be replicated in confirmatory studies.Clinical trial NCT00360399 "Predictors of Antidepressant Treatment Response: The Emory CIDAR" https://clinicaltrials.gov/ct2/show/NCT00360399 .

Diffusion tensor imaging-based pontine damage as a degeneration marker in synucleinopathy.

The pons is one of the earliest affected regions in patients with synucleinopathies. We aimed to investigate the diagnostic value of measuring pontine damage using diffusion tensor imaging (DTI) in these patients. We enrolled 49 patients with Parkinson's disease (PD), 16 patients with idiopathic rapid eye movement sleep behavior disorder (iRBD), 23 patients with multiple system atrophy (MSA), and 39 healthy controls in this study. All the participants underwent high-resolution T1-weighted imaging and DTI. Mean diffusivity (MD) and fraction anisotropy (FA) values in the pons were calculated to characterize structural damage. The discriminatory power of pontine MD and FA values to differentiate patients with synucleinopathies from healthy controls was examined using receiver operating characteristics (ROC) analyses. Compared to healthy controls, patients with PD, iRBD, and MSA had increased MD values and decreased FA values in the pons, although no correlation was observed between these DTI measures and disease severity. The ROC analyses showed that MD values in the pons had a fair discriminatory power to differentiate healthy controls from patients with PD (area under the curve [AUC], 0.813), iRBD (AUC, 0.779), and MSA (AUC, 0.951). The AUC for pontine FA values was smaller than that for pontine MD values when differentiating healthy controls from patients with PD (AUC, 0.713; p = 0.054) and iRBD (AUC, 0.686; p = 0.045). Our results suggest that MD values in the pons may be a useful marker of brain stem neurodegeneration in patients with synucleinopathies.

Treatment-Specific Hippocampal Subfield Volume Changes With Antidepressant Medication or Cognitive-Behavior Therapy in Treatment-Naive Depression.

Background: Hippocampal atrophy has been consistently reported in major depressive disorder with more recent focus on subfields. However, literature on hippocampal volume changes after antidepressant treatment has been limited. The first-line treatments for depression include antidepressant medication (ADM) or cognitive-behavior therapy (CBT). To understand the differential effects of CBT and ADM on the hippocampus, we investigated the volume alterations of hippocampal subfields with treatment, outcome, and chronicity in treatment-naïve depression patients. Methods: Treatment-naïve depressed patients from the PReDICT study were included in this analysis. A total of 172 patients who completed 12 weeks of randomized treatment with CBT (n = 45) or ADM (n = 127) were included for hippocampal subfield volume analysis. Forty healthy controls were also included for the baseline comparison. Freesurfer 6.0 was used to segment 26 hippocampal substructures and bilateral whole hippocampus from baseline and week 12 structural MRI scans. A generalized linear model with covariates of age and gender was used for group statistical tests. A linear mixed model for the repeated measures with covariates of age and gender was used to examine volumetric changes over time and the contributing effects of treatment type, outcome, and illness chronicity. Results: Of the 172 patients, 85 achieved remission (63/127 ADM, 22/45 CBT). MDD patients showed smaller baseline volumes than healthy controls in CA1, CA3, CA4, parasubiculum, GC-ML-DG, Hippocampal Amygdala Transition Area (HATA), and fimbria. Over 12 weeks of treatment, further declines in the volumes of CA1, fimbria, subiculum, and HATA were observed regardless of treatment type or outcome. CBT remitters, but not ADM remitters, showed volume reduction in the right hippocampal tail. Unlike ADM remitters, ADM non-responders had a decline in volume in the bilateral hippocampal tails. Baseline volume of left presubiculum (regardless of treatment type) and right fimbria and HATA in CBT patients were correlated with a continuous measure of clinical improvement. Chronicity of depression had no effect on any measures of hippocampal subfield volumes. Conclusion: Two first-line antidepressant treatments, CBT and ADM, have different effects on hippocampal tail after 12 weeks. This finding suggests that remission achieved via ADM may protect against progressive hippocampal atrophy by altering neuronal plasticity or supporting neurogenesis. Studies with multimodal neuroimaging, including functional and structural analysis, are needed to assess further the impact of two different antidepressant treatments on hippocampal subfields.

Minimal parkinsonism in the elderly is associated with striatal dopamine loss and pontine structural damage.

INTRODUCTION: To investigate whether neurodegeneration underlying Parkinson's disease (PD) accounts for a substantial proportion of cases of minimal parkinsonism in the elderly. METHODS: We recruited 48 consecutive subjects with minimal parkinsonism who visited the clinic with cognitive complaints. All subjects did not show findings compatible with PD on 18F-FP-CIT PET scans, and had no evidence of other neurodegenerative disorders. Striatal dopamine transporter (DAT) availability was quantified, and mean diffusivity (MD) values in the pons were calculated to characterize structural damage using diffusion tensor imaging. Additionally, 35 patients with PD and 21 healthy controls were included as reference groups. RESULTS: Individuals with minimal parkinsonism (mean age, 73.23 ± 7.03 years) exhibited mild decrease in DAT availability in the posterior putamen, which was at a level between that of healthy controls and patients with PD. DAT availability in the caudate and anterior putamen was also mildly decreased in the minimal parkinsonism group. Individuals with minimal parkinsonism also tended to have higher MD values in the pons compared to healthy controls. CONCLUSIONS: Our results suggest that a substantial proportion of minimal parkinsonism is associated with nigrostriatal dopamine depletion and pontine structural damage, which may be related to the disease process of prodromal PD.

Dysautonomia Is Linked to Striatal Dopamine Deficits and Regional Cerebral Perfusion in Early Parkinson Disease.

PURPOSE: The aim of this study was to investigate the association between autonomic dysfunction and striatal dopamine depletion or metabolic changes in de novo Parkinson disease (PD). METHODS: Based on the Composite Autonomic Severity Score (CASS), patients with de novo PD were classified into PD with (PD-AUT+) and without autonomic dysfunction (PD-AUT-) groups. We compared the dopamine transporter (DAT) availability in the striatum by quantitatively measuring F-FP-CIT PET between both groups. We also assessed the association between DAT availability and the CASS. In addition, we compared regional uptake in early-phase images of F-FP-CIT PET as well as cortical thickness between the PD-AUT+ and PD-AUT- groups. RESULTS: The PD-AUT+ group had significantly lower DAT availability in all striatal subregions than did the PD-AUT- group. The total CASS was significantly correlated with DAT availability in all striatal subregions. In addition, the subscores of the adrenergic component were correlated with DAT availability in all striatal subregions. The subscores of the cardiovagal component were negatively correlated with DAT availability in the caudate and ventral striatum. In early-phase F-FP-CIT PET, the PD-AUT+ group exhibited decreased regional perfusion in the parieto-occipital areas and increased regional perfusion in the pallidothalamic, pontocerebellar, inferior frontal, and primary motor areas compared with the PD-AUT- group. There were no regions of different cortical thickness between the PD groups. CONCLUSIONS: The present study revealed that autonomic dysfunction is closely linked to striatal dopamine depletion and prominent PD-related perfusion patterns in de novo PD, suggesting a greater pathological burden in patients with dysautonomia.

Gender-specific effect of urate on white matter integrity in Parkinson's disease.

OBJECTIVES: To investigate the potential protective influence of serum uric acid (UA) level on white matter (WM) microstructural changes in de novo Parkinson's disease (PD). METHODS: We enrolled a total of 184 patients with drug-naïve de novo PD and 59 age and gender-matched controls that underwent diffusion tensor imaging (DTI). Based on the distribution, serum UA levels were stratified into tertiles in PD patients by gender. Using tract-based spatial statistics (TBSS) analysis, fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were used to compare WM integrity between the groups. RESULTS: Interaction analysis showed that interaction effect on FA values between gender and UA levels in PD was significant in widespread WM areas, including frontal-parieto-temporal, corpus callosum, bilateral internal and external capsule, and thalamic regions. Multiple regression analysis revealed that FA values had a significantly positive correlation with UA levels across widespread WM areas in male patients. However, there was no significant correlation between DTI measures and UA levels in female patients. In a group comparison in male patients, PD with the lowest UA level (PD-L-UA) group showed significantly lower FA and higher MD and RD values in frontal-parieto-temporal WM regions than PD with the highest UA level (PD-H-UA) group. However, female patients did not show significant difference of DTI measures between PD-L-UA and PD-H-UA groups. CONCLUSIONS: The present study demonstrated that the serum UA levels may have the potentially gender-specific close relationship with WM integrity in the early stage of PD.