Megha Vasavada

Olfactory cortex degeneration in Alzheimer's disease and mild cognitive impairment.

BACKGROUND Olfactory deficits are prevalent in patients with Alzheimers disease (AD) and mild cognitive impairment (MCI). These symptoms precede clinical onset of cognitive and memory deficits and coincide with AD pathology preferentially in the central olfactory structures, suggesting a potential biomarker for AD early detection and progression. OBJECTIVE Therefore, we tested the hypothesis that structural degeneration of the primary olfactory cortex (POC) could be detected in AD as well as in MCI patients and would be correlated with olfactory functional magnetic resonance imaging (fMRI) alterations, reflecting loss of olfactory cortex activity. METHODS Total structural volumes and fMRI activation volumes of the POC and hippocampus were measured along with olfactory and cognitive behavioral tests in 27 cognitively normal (CN), 21 MCI, and 15 AD subjects. RESULTS Prominent atrophy in the POC and hippocampus was found in both AD and MCI subjects and correlated with behavioral measurements. While behavioral and volumetric measurements showed a gradual decline from CN to MCI to AD, olfactory activation volume in the POC and hippocampus showed a steeper decline in the MCI group compared to corresponding tissue volume, resembling the AD group. CONCLUSIONS Decline in olfactory activity was correlated with the AD structural degeneration in the POC. A more prominent olfactory activity deficit than that of behavioral and tissue volume measurements was shown in the MCI stage. Olfactory fMRI may thus provide an earlier and more sensitive measure of functional neurodegeneration in AD and MCI patients.

MRI evaluation of asymmetry of nigrostriatal damage in the early stage of early-onset Parkinson's disease.

INTRODUCTION The motor symptoms and signs of early-onset idiopathic Parkinsons disease (PD) in Hoehn and Yahr (H&Y) stage-1 are generally unilateral. We hypothesized that there would be detectable differences in the quantitative MRI parameters in these PD patients between the hemispheres contralateral to the clinically symptomatic and non-symptomatic body side. METHODS We tested this hypothesis by comparing transverse relaxation rates and diffusion tensor imaging (DTI) parameters in the substantia nigra and putamen between the two hemispheres contralateral to the symptomatic and non-symptomatic side in H&Y stage-1 PD patients who had onset of symptoms between ages of 40-59 years. RESULTS There were quantifiable hemispheric asymmetries in transverse relaxation rates in the substantia nigra, as well as fractional anisotropy and mean diffusivity in the putamen in early PD, which correlated with the unilaterality of motor symptoms as evaluated using the motor portion of the Unified Parkinsons Disease Rating Scale. CONCLUSION Transverse relaxation mapping and DTI demonstrated significant differences between the symptomatic and non-symptomatic hemispheres at the early stage of early-onset PD. These findings support the hypothesis of asymmetric neurodegeneration in the bilateral nigrostriatal pathways in the early stage of the disease.

Effect of Electroconvulsive Therapy on Striatal Morphometry in Major Depressive Disorder

Patients with major depression show reductions in striatal and paleostriatal volumes. The functional integrity and connectivity of these regions are also shown to change with antidepressant response. Electroconvulsive therapy (ECT) is a robust and rapidly acting treatment for severe depression. However, whether morphological changes in the dorsal and ventral striatum/pallidum relate to or predict therapeutic response to ECT is unknown. Using structural MRI, we assessed cross-sectional effects of diagnosis and longitudinal effects of ECT for volume and surface-based shape metrics of the caudate, putamen, pallidum, and nucleus accumbens in 53 depressed patients (mean age: 44.1 years, 13.8 SD; 52% female) and 33 healthy controls (mean age: 39.3 years, 12.4 SD; 57% female). Patients were assessed before ECT, after their second ECT, and after completing an ECT treatment index. Controls were evaluated at two time points. Support vector machines determined whether morphometric measures at baseline predicted ECT-related clinical response. Patients showed smaller baseline accumbens and pallidal volumes than controls (P<0.05). Increases in left putamen volume (P<0.03) occurred with ECT. Global increases in accumbens volume and local changes in pallidum and caudate volume occurred in patients defined as treatment responders. Morphometric changes were absent across time in controls. Baseline volume and shape metrics predicted overall response to ECT with up to 89% accuracy. Results support that ECT elicits structural plasticity in the dorsal and ventral striatum/pallidum. The morphometry of these structures, forming key components of limbic-cortical-striatal-pallidal-thalamic circuitry involved in mood and emotional regulation, may determine patients likely to benefit from treatment.

Neurochemical correlates of rapid treatment response to electroconvulsive therapy in patients with major depression

Background Electroconvulsive therapy (ECT) is a highly effective brain stimulation treatment for severe depression. Identifying neurochemical changes linked with ECT may point to biomarkers and predictors of successful treatment response. Methods We used proton magnetic resonance spectroscopy (1H-MRS) to measure longitudinal changes in glutamate/glutamine (Glx), creatine (Cre), choline (Cho) and N-acetylaspartate (NAA) in the dorsal (dACC) and subgenual anterior cingulate cortex (sgACC) and bilateral hippocampus in patients receiving ECT scanned at baseline, after the second ECT session and after the ECT treatment series. Patients were compared with demographically similar controls at baseline. Controls were assessed twice to establish normative values and variance. Results We included 50 patients (mean age 43.78 ± 14 yr) and 33 controls (mean age 39.33 ± 12 yr) in our study. Patients underwent a mean of 9 ± 4.1 sessions of ECT. At baseline, patients showed reduced Glx in the sgACC, reduced NAA in the left hippocampus and increased Glx in the left hippocampus relative to controls. ECT was associated with significant increases in Cre in the dACC and sgACC and decreases in NAA in the dACC and right hippocampus. Lower NAA levels in the dACC at baseline predicted reductions in depressive symptoms. Both ECT and symptom improvement were associated with decreased Glx in the left hippocampus and increased Glx in the sgACC. Limitations Attrition and clinical heterogeneity may have masked more subtle findings. Conclusion ECT elicits robust effects on brain chemistry, impacting Cre, NAA and Glx, which suggests restorative and neurotrophic processes. Differential effects of Glx in the sgACC and hippocampus, which approach control values with treatment, may reflect previously implicated underactive cortical and overactive subcortical limbic circuitry in patients with major depression. NAA levels at baseline are predictive of therapeutic outcome and could inform future treatment strategies.

Electroconvulsive therapy and structural neuroplasticity in neocortical, limbic and paralimbic cortex

Electroconvulsive therapy (ECT) is a highly effective and rapidly acting treatment for severe depression. To understand the biological bases of therapeutic response, we examined variations in cortical thickness from magnetic resonance imaging (MRI) data in 29 patients scanned at three time points during an ECT treatment index series and in 29 controls at two time points. Changes in thickness across time and with symptom improvement were evaluated at high spatial resolution across the cortex and within discrete cortical regions of interest. Patients showed increased thickness over the course of ECT in the bilateral anterior cingulate cortex (ACC), inferior and superior temporal, parahippocampal, entorhinal and fusiform cortex and in distributed prefrontal areas. No changes across time occurred in controls. In temporal and fusiform regions showing significant ECT effects, thickness differed between patients and controls at baseline and change in thickness related to therapeutic response in patients. In the ACC, these relationships occurred in treatment responders only, and thickness measured soon after treatment initiation predicted the overall ECT response. ECT leads to widespread neuroplasticity in neocortical, limbic and paralimbic regions and changes relate to the extent of antidepressant response. Variations in ACC thickness, which discriminate treatment responders and predict response early in the course of ECT, may represent a biomarker of overall clinical outcome. Because post-mortem studies show focal reductions in glial density and neuronal size in patients with severe depression, ECT-related increases in thickness may be attributable to neuroplastic processes affecting the size and/or density of neurons and glia and their connections.

Rapidly acquired multisensory association in the olfactory cortex

The formation of an odor percept in humans is strongly associated with visual information. However, much less is known about the roles of learning and memory in shaping the multisensory nature of odor representations in the brain.

Structural connectivity and response to ketamine therapy in major depression: A preliminary study

BACKGROUND Ketamine elicits an acute antidepressant effect in patients with major depressive disorder (MDD). Here, we used diffusion imaging to explore whether regional differences in white matter microstructure prior to treatment may predict clinical response 24h following ketamine infusion in 10 MDD patients. METHODS FSLs Tract-Based Spatial Statistics (TBSS) established voxel-level differences in fractional anisotropy (FA) between responders (patients showing >50% improvement in symptoms 24h post-infusion) and non-responders in major white matter pathways. Follow-up regions-of-interest (ROI) analyses examined differences in FA and radial (RD), axial (AD) and mean diffusivity (MD) between responders and non-responders and 15 age- and sex-matched controls, with groups compared pairwise. RESULTS Whole brain TBSS (p<0.05, corrected) and confirmatory tract-based regions-of-interest analyses showed larger FA values in the cingulum and forceps minor in responders compared to non-responders; complementary decreases in RD occurred in the cingulum (p<0.05). Only non-responders differed from controls showing decreased FA in the forceps minor, increased RD in the cingulum and forceps minor, and increased MD in the forceps minor (p<0.05). LIMITATIONS Non-responders showed an earlier age of onset and longer current depressive episode than responders. Though these factors did not interact with diffusion metrics, results may be impacted by the limited sample size. CONCLUSIONS Though findings are considered preliminary, significant differences in FA, RD and MD shown in non-responders compared to responders and controls in fronto-limbic and ventral striatal pathways suggest that the structural architecture of specific functional networks mediating emotion may predict ketamine response in MDD.

Short- and Long-term Cognitive Outcomes in Patients with Major Depression Treated with Electroconvulsive Therapy

Objectives The risk of cognitive impairment is a concern for patients with major depressive disorder receiving electroconvulsive therapy (ECT). Here, we evaluate the acute, short-term and long-term effects of ECT on tests of processing speed, executive function, memory, and attention. Methods Forty-four patients with major depressive disorder receiving ECT (61% right unilateral, 39% mixed right unilateral–bitemporal, left unilateral, and/or bitemporal lead placement) underwent a cognitive battery prior to ECT (T1), after 2 sessions (T2), and at the end of the index (T3). Thirty-two patients returned for a 6-month follow-up (T4). Thirty-three control subjects were assessed at 2 times approximately 4 weeks apart (C1 and C2). Results At baseline, patients showed deficits in processing speed, executive function, and memory compared with control subjects. Including depression severity and lead placement covariates, linear mixed-model analysis showed significant improvement in only processing speed between T1 and T3 and between T1 and T4 in patients. An acute decline in attention and verbal memory was observed at T2, but performance returned to baseline levels at T3. Longitudinal cognitive outcomes did not differ in patients defined as ECT responders/nonresponders. Limitations Episodic memory was not measured, and medications were not controlled between T3 and T4. Control subjects also showed improvements in processing speed, suggesting practice effects for some measures. Conclusions In this naturalistic ECT treatment study, results show that the initiation of ECT may transiently affect memory and executive function, but cognition is largely unaffected during and after ECT. Whereas some functions might improve, others will at least remain stable up to 6 months following the ECT index.

Central Olfactory Dysfunction in Alzheimer’s Disease and Mild Cognitive Impairment: A Functional MRI Study

BACKGROUND Olfactory deficits are present in early Alzheimers disease (AD) and mild cognitively impaired (MCI) patients. However, whether these deficits are due to dysfunction of the central or peripheral olfactory nervous system remains uncertain. This question is fundamentally important for developing imaging biomarkers for AD using olfactory testing. OBJECTIVE This study sought to use olfactory functional magnetic resonance imaging (fMRI) to further demonstrate the involvement of the central olfactory system in olfactory deficits in MCI and AD. METHODS We investigated the central olfactory system in 27 cognitively normal controls (CN), 21 MCI, and 15 AD subjects using olfactory fMRI with an odor-visual association paradigm during which a visual cue was paired with lavender odorant (odor condition) or odorless air (no-odor condition). RESULTS The CN subjects had significantly greater activated volume in the primary olfactory cortex during both the odor and no-odor conditions compared to either the MCI or AD groups (p < 0.05). No significant differences were observed between the odor and no-odor conditions within each group. No-odor condition activation in AD and MCI correlated with the cognitive and olfactory assessments. CONCLUSION The no-odor condition, allowing investigation of activation patterns when the peripheral olfactory system was not directly involved, elicited the same functional response as the odor condition for each of the three groups. Thus, the olfactory activation deficits present in AD and MCI patients are most likely caused by degeneration of the central olfactory nervous system.

Reduced white matter MRI transverse relaxation rate in cognitively normal H63D-HFE human carriers and H67D-HFE mice

Mutations within the HFE protein gene sequence have been associated with increased risk of developing a number of neurodegenerative disorders. To this effect, an animal model has been created which incorporates the mouse homologue to the human H63D-HFE mutation: the H67D-HFE knock-in mouse. These mice exhibit alterations in iron management proteins, have increased neuronal oxidative stress, and a disruption in cholesterol regulation. However, it remains undetermined how these differences translate to human H63D carriers in regards to white matter (WM) integrity. To this endeavor, MRI transverse relaxation rate (R2) parametrics were employed to test the hypothesis that WM alterations are present in H63D human carriers and are recapitulated in the H67D mice. H63D carriers exhibit widespread reductions in brain R2 compared to non-carriers within white matter association fibers in the brain. Similar R2 decreases within white matter tracts were observed in the H67D mouse brain. Additionally, an exacerbation of age-related R2 decrease is found in the H67D animal model in white matter regions of interest. The decrease in R2 within white matter tracts of both species is speculated to be multifaceted. The R2 changes are hypothesized to be due to alterations in axonal biochemical tissue composition. The R2 changes observed in both the human-H63D and mouse-H67D data suggest that modified white matter myelination is occurring in subjects with HFE mutations, potentially increasing vulnerability to neurodegenerative disorders.