Search

ObjectiveMicrotubule-associated protein tau (MAPT) mutations cause frontotemporal lobar degeneration, and novel biomarkers are urgently needed for early disease detection. We used task-free functional magnetic resonance imaging (fMRI) mapping, a promising biomarker, to analyze network connectivity in symptomatic and presymptomatic MAPT mutation carriers.MethodsWe compared cross-sectional fMRI data between 17 symptomatic and 39 presymptomatic carriers and 81 controls with (1) seed-based analyses to examine connectivity within networks associated with the 4 most common MAPT-associated clinical syndromes (ie, salience, corticobasal syndrome, progressive supranuclear palsy syndrome, and default mode networks) and (2) whole-brain connectivity analyses. We applied K-means clustering to explore connectivity heterogeneity in presymptomatic carriers at baseline. Neuropsychological measures, plasma neurofilament light chain, and gray matter volume were compared at baseline and longitudinally between the presymptomatic subgroups defined by their baseline whole-brain connectivity profiles.ResultsSymptomatic and presymptomatic carriers had connectivity disruptions within MAPT-syndromic networks. Compared to controls, presymptomatic carriers showed regions of connectivity alterations with age. Two presymptomatic subgroups were identified by clustering analysis, exhibiting predominantly either whole-brain hypoconnectivity or hyperconnectivity at baseline. At baseline, these two presymptomatic subgroups did not differ in neuropsychological measures, although the hypoconnectivity subgroup had greater plasma neurofilament light chain levels than controls. Longitudinally, both subgroups showed visual memory decline (vs controls), yet the subgroup with baseline hypoconnectivity also had worsening verbal memory and neuropsychiatric symptoms, and extensive bilateral mesial temporal gray matter decline.InterpretationNetwork connectivity alterations arise as early as the presymptomatic phase. Future studies will determine whether presymptomatic carriers' baseline connectivity profiles predict symptomatic conversion. ANN NEUROL 2023;94:632-646.

Rumination is a maladaptive style of regulating thoughts and emotions. It is a common symptom of Major Depressive Disorder (MDD), and more severe rumination is associated with poorer medication and psychotherapy treatment outcomes, particularly among women. It is unclear to what extent rumination may influence the outcomes of, or be responsive to, repetitive Transcranial Magnetic Stimulation (rTMS) treatment of MDD. We retrospectively examined data collected during rTMS treatment of 155 patients (age 42.52 ± 14.22, 79 female) with moderately severe treatment-resistant MDD. The severity of rumination and depression was assessed before and during a course of 30 sessions of measurement-based rTMS treatment using the Ruminative Responses Scale (RSS) and the Patient Health Questionnaire (PHQ-9), respectively. Relationships among baseline levels of rumination, depression, and treatment outcome were assessed using a series of repeated measures linear mixed effects models. Both depression and rumination symptoms significantly improved after treatment, but improvement in depression was not a significant mediator of rumination improvement. Higher baseline rumination (but not depression severity) was associated with poorer depression outcomes independently of depression severity. Female gender was a significant predictor of worse outcomes for all RRS subscales. Both depressive and ruminative symptoms in MDD improved following rTMS treatment. These improvements were correlated, but improvement in rumination was not fully explained by reduction in depressive symptoms. These findings suggest that while improvement in rumination and depression severity during rTMS treatment are correlated, they are partly independent processes. Future studies should examine whether rumination symptoms should be specifically targeted with different rTMS treatment parameters.

We examined the safety and efficacy of repetitive Transcranial Magnetic Stimulation (rTMS) of the right orbitofrontal cortex (OFC) in patients with refractory obsessive-compulsive disorder (OCD) and comorbid Major Depressive Disorder. All participants (n = 26) received excitatory stimulation of the left dorsolateral prefrontal cortex followed by inhibitory stimulation of bilateral supplementary motor area for 10 sessions. In 18 patients with poor early OCD response, treatment was augmented with OFC inhibitory stimulation after the tenth treatment session. Augmentation with OFC stimulation was well-tolerated, and associated with further alleviation of both OCD and depression symptoms, particularly in individuals with more severe illnesses.

Probing naturally-occurring, reciprocal genomic copy number variations (CNVs) may help us understand mechanisms that underlie deviations from typical brain development. Cross-sectional studies have identified prominent reductions in cortical surface area (SA) and increased cortical thickness (CT) in 22q11.2 deletion carriers (22qDel), with the opposite pattern in duplication carriers (22qDup), but the longitudinal trajectories of these anomalies-and their relationship to clinical symptomatology-are unknown. Here, we examined neuroanatomic changes within a longitudinal cohort of 261 22q11.2 CNV carriers and demographically-matched typically developing (TD) controls (84 22qDel, 34 22qDup, and 143 TD; mean age 18.35, ±10.67 years; 50.47% female). A total of 431 magnetic resonance imaging scans (164 22qDel, 59 22qDup, and 208 TD control scans; mean interscan interval = 20.27 months) were examined. Longitudinal FreeSurfer analysis pipelines were used to parcellate the cortex and calculate average CT and SA for each region. First, general additive mixed models (GAMMs) were used to identify regions with between-group differences in developmental trajectories. Secondly, we investigated whether these trajectories were associated with clinical outcomes. Developmental trajectories of CT were more protracted in 22qDel relative to TD and 22qDup. 22qDup failed to show normative age-related SA decreases. 22qDel individuals with psychosis spectrum symptoms showed two distinct periods of altered CT trajectories relative to 22qDel without psychotic symptoms. In contrast, 22q11.2 CNV carriers with autism spectrum diagnoses showed early alterations in SA trajectories. Collectively, these results provide new insights into altered neurodevelopment in 22q11.2 CNV carriers, which may shed light on neural mechanisms underlying distinct clinical outcomes.

ObjectiveMAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach.MethodsWe studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers' clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson's disease (1), and mild cognitive impairment (1). We performed voxel-based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype.ResultsSymptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes emerged in a subset of presymptomatic carriers as early as their thirties. Low white matter volumes arose infrequently among presymptomatic carriers.InterpretationA subset of presymptomatic MAPT mutation carriers showed low volumes in mesial temporal lobe, the region ubiquitously atrophied in all symptomatic carriers. With each decade of age, an increasing percentage of presymptomatic carriers showed low mesial temporal volume, suggestive of early neurodegeneration.

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) have a strong clinical, genetic and pathological overlap. This review focuses on the current understanding of structural, functional and molecular neuroimaging signatures of genetic FTD and ALS. We overview quantitative neuroimaging studies on the most common genes associated with FTD (MAPT, GRN), ALS (SOD1), and both (C9orf72), and summarize visual observations of images reported in the rarer genes (CHMP2B, TARDBP, FUS, OPTN, VCP, UBQLN2, SQSTM1, TREM2, CHCHD10, TBK1).

ObjectiveTo investigate in-vivo cortical gyrification patterns measured by the local gyrification index (lGI) in presymptomatic c9orf72 expansion carriers compared with healthy controls, and investigate relationships between lGI and cortical thickness, an established morphometric measure of neurodegeneration.MethodsWe assessed cortical gyrification and thickness patterns in a cohort of 15 presymptomatic c9orf72 expansion carriers (age 43.7 ± 10.2 years, 9 females) compared with 67 (age 42.4 ± 12.4 years, 36 females) age and sex matched healthy controls using the dedicated Freesurfer pipeline.ResultsCompared with controls, presymptomatic carriers showed significantly lower lGI in left frontal and right parieto-occipital regions. Interestingly, those areas with abnormal gyrification in presymptomatic carriers showed no concomitant cortical thickness abnormality. Overall, for both presymptomatic carriers and healthy controls, gyrification and cortical thickness measures were not correlated, suggesting that gyrification captures a feature distinct from cortical thickness.ConclusionsPresymptomatic c9orf72 expansion carriers show regions of abnormally low gyrification as early as their 30s, decades before expected symptom onset. Cortical gyrification represents a novel grey matter metric distinctive from grey matter thickness or volume and detects differences in presymptomatic carriers at an early age.

Mutations in progranulin (GRN) cause heterogeneous clinical syndromes, including behavioral variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA), corticobasal syndrome (CBS) and Alzheimer-type dementia (AD-type dementia). Human studies have shown that presymptomatic GRN carriers feature reduced connectivity in the salience network, a system targeted in bvFTD. Mice with homozygous deletion of GRN, in contrast, show thalamo-cortical hypersynchrony due to aberrant pruning of inhibitory synapses onto thalamo-cortical projection neurons. No studies have systematically explored the intrinsic connectivity networks (ICNs) targeted by the four GRN-associated clinical syndromes, or have forged clear links between human and mouse model findings. We compared 17 preclinical GRN carriers (14 "presymptomatic" clinically normal and three "prodromal" with mild cognitive symptoms) to healthy controls to assess for differences in cognitive testing and gray matter volume. Using task-free fMRI, we assessed connectivity in the salience network, a non-fluent variant primary progressive aphasia network (nfvPPA), the perirolandic network (CBS), and the default mode network (AD-type dementia). GRN carriers and controls showed similar performance on cognitive testing. Although carriers showed little evidence of brain atrophy, markedly enhanced connectivity emerged in all four networks, and thalamo-cortical hyperconnectivity stood out as a unifying feature. Voxelwise assessment of whole brain degree centrality, an unbiased graph theoretical connectivity metric, confirmed thalamic hyperconnectivity. These results show that human GRN disease and the prevailing GRN mouse model share a thalamo-cortical network hypersynchrony phenotype. Longitudinal studies will determine whether this network physiology represents a compensatory response as carriers approach symptom onset, or an early and sustained preclinical manifestation of lifelong progranulin haploinsufficiency.

Polyamines modulate cellular proliferation and function. Their dysregulation results in inflammatory and oncological repercussions. This study aims to map the current literature and provide an overview of polyamines in dysbiotic oral conditions among older adults. English publications indexed in MEDLINE, Scopus, and Web of Science from January 2000 to May 2024 were screened. Eligibility criteria included clinical and laboratory studies using samples from adults aged 65 or above. This scoping review identified 2725 publications and included 19 publications. Ten studies detected that older adults with oral carcinoma had increased levels of polyamines such as spermidine in saliva and tumour-affected tissues. Eight studies reported older adults suffering from periodontal infection had increased levels of polyamines such as putrescine in saliva, gingival crevicular fluid, and biofilm from the gingival crevice. Two studies showed polyamine levels could reflect the success of periodontal therapy. Three studies found older adults with halitosis had increased levels of polyamines such as cadaverine in saliva and tongue biofilm. Polyamines were suggested as biomarkers for these oral conditions. In conclusion, certain polyamine levels are elevated in older adults with oral cancer, periodontal infections, and halitosis. Polyamines may be used as a simple and non-invasive tool to detect dysbiotic oral conditions and monitor treatment progress in older adults (Open Science Framework registration). [ABSTRACT FROM AUTHOR]

PurposeOur aim was to test the feasibility of a set of quality of care indicators for urinary incontinence and at the same time measure the care provided to women with urinary incontinence in 2 clinical settings.Materials and methodsThis was a pilot test of a set of quality of care indicators. A total of 20 quality of care indicators were previously developed using the RAND Appropriateness Method. These quality of care indicators were used to measure care received for 137 women with a urinary incontinence diagnosis in a 120-physician hospital based multispecialty medical group. We also performed an abstraction of 146 patient records from primary care offices in Southern California. These charts were previously used as part of ACOVE (Assessing Care of Vulnerable Elders Project). As a post-hoc secondary analysis, the 2 populations were compared with respect to quality, as measured by compliance with the quality of care indicators.ResultsIn the ACOVE population, 37.7% of patients with urinary incontinence underwent a pelvic examination vs 97.8% in the multispecialty medical group. Only 15.6% of cases in the multispecialty medical group and 14.2% in ACOVE (p = 0.86) had documentation that pelvic floor exercises were offered. Relatively few women with a body mass index of greater than 25 kg/m(2) were counseled about weight loss in either population (20.9% multispecialty medical group vs 26.1% ACOVE, p = 0.76). For women undergoing sling surgery, documentation of counseling about risks was lacking and only 9.3% of eligible cases (multispecialty medical group only) had documentation of the risks of mesh.ConclusionsQuality of care indicators are a feasible means to measure the care provided to women with urinary incontinence. Care varied by population studied and yet deficiencies in care were prevalent in both patient populations studied.

This comparative case series presents 16 consecutively placed and temporized immediate implants in the maxillary esthetic zone. The implants have a novel, inverted body-shift design, intended to achieve high levels of primary stability via the tapered apical portion. The coronal narrow cylinder provides greater space between the implant platform and facial socket wall and adjacent teeth/ implants, allowing a greater opportunity for augmentation. The restorative platform also features a subcrestal angle correction, which facilitates screw retention. The wider, facial platform-shift thus creates more room for augmentation via dual-zone bone grafting and the application of a dermal allograft, which yields greater soft tissue thickness after initial healing. This case series aimed to evaluate soft tissue thickness and compare the results to two previously published cohorts where implant design served as the only variable between groups. [ABSTRACT FROM AUTHOR]

Introduction: The subepithelial connective tissue graft (S-CTG) is the gold standard in achieving root coverage, but it is not without limitations. The acellular dermal matrix (ADM) is an alternative source that can compensate for the S-CTG's limitations. Body: Severe recession type 1 (RT1) defects were treated with a combined approach of autogenous and allogeneic soft-tissue grafting, optimizing the benefits of both types of materials to achieve maxi- mum root coverage (MRC). Conclusion: Identifying the anatomical limitations of gingival recession as it relates to tooth rotation and its impact on vascular supply will best prepare both the clinician and patient for the expected outcome. [ABSTRACT FROM AUTHOR]

Background: This case report describes a minimally invasive technique to increase the functional resistance of mandibular anterior lingual recession defects to inflammation. There are only a few case reports that describe the soft tissue augmentation of lingual gingival recession, of which none describe a tunneling technique without coronal advancement of the flap to treat a long span of multiple recession defects. Soft tissue augmentation of lingual recession defects is challenging due to the proximity to the tongue, frenum, vital structures, pre‐existing thin phenotype, and limited access during surgery. Methods and Results: A 30‐year‐old male was referred for the treatment of gingival recession on the lingual surfaces of teeth #22–27, with a diagnosis of recession type 2 (RT2). Mucogingival surgery included the preparation of the recipient site with a tunneling protocol, where apical muscular attachment was left undisturbed to isolate the flap from the movement of the tongue during normal function. As the goal was to not coronally advance the tunneled flap, the interdental papillae were not elevated and left intact, further optimizing blood supply. A free gingival graft was harvested, de‐epithelialized extra‐orally, and the resulting connective tissue graft (CTG) was fed through the tunnel and stabilized with sling sutures. Partial root coverage was achieved ranging from 50% to 90% at 4 months, consistent with the initial diagnosis of RT2. There was also a visually appreciable increase in gingival thickness and in the vestibular depth. Conclusion: A de‐epithelialized CTG via tunneling without disturbing the deeper muscular attachment is a conservative method to improve phenotype of lingual recession defects. Key points: Why is this case new information?There are only a few case reports that describe soft tissue augmentation of lingual recession defects, of which none describe a tunneling technique without coronal advancement of the flap to treat a long span of multiple recession defects. This case report introduces a minimally invasive technique to increase the functional resistance of mandibular anterior lingual recession defects to plaque and calculus. What are the keys to successful management of this case?Control of gingival inflammation before and after surgery, with regular maintenance visits and oral hygiene instructions.Precise tunneling, leaving deeper muscular attachment on the floor of the mouth undisturbed.Connective tissue graft of even thickness that is fibrous in quality. What are the primary limitations to success in this case?A shallow lingual vestibule will not allow the clinician to leave deeper muscular attachment apical to tunneling undisturbed. [ABSTRACT FROM AUTHOR]

Discusses constructivism and its integration of theory and practice, especially as it relates to online courses using interactive software. Highlights include situated-learning theory, cognitive-flexibility theory, and the design and implementation of two online courses. (LRW)