Tipton, Philip W.

AbstractBackgroundRapidly progressive dementia (RPD) is variably defined across published cohorts. A standardized definition is needed to support multicenter studies required to inform the causes of RPD and optimize recognition and management of treatment‐responsive causes. An optimal definition will capture the broad spectrum of causes of RPD, adequately differentiate patients with rapid and typically progressive presentations of neurodegenerative disease, and be reliably implemented across healthcare settings and centers.MethodThe Clinical Dementia Rating® (CDR) is a validated dementia staging tool that is widely used in clinical trials and observational studies. We applied the CDR to diagnose RPD in patients who developed dementia (CDR ≥1) within 1 year or incapacitation (CDR ≥2) within 2 years of symptom onset. This definition was prospectively applied to patients with suspected RPD at Mayo Clinic in Florida (MCF: Jacksonville, FL; Jan 2020 – Oct 2023) and Washington University in St. Louis (WU: Saint Louis, MO; Jun 2016 – Dec 2019), and retrospectively applied to individuals within the National Alzheimer’s Coordinating Center (NACC) dataset. Criteria performance was compared across cohorts.ResultTwo‐hundred twenty‐six patients were referred with suspected RPD at MCF‐WU. Of these, 155/226 (68.6%) met our proposed RPD criteria, including patients with Alzheimer disease and related dementias (ADRD; 34/155, 21.9%), Creutzfeldt Jacob disease (CJD; 25/155, 16.1%), autoimmune encephalitis (52/155, 33.5%), vascular pathologies (14/155, 9.0%), toxic/metabolic disruptions (7/155, 4.5%) and primary psychiatric disorders (4/155, 2.6%). A small subset of NACC participants met our proposed RPD criteria (836/20,418; 0.04%), emphasizing the unique nature of RPD. Causes of RPD in NACC included ADRD (676/836, 80.1%), CJD (72/836, 8.6%), and vascular pathologies (24/836, 2.9%). Rates of progression (∆CDR sum‐of‐boxes/year) clearly distinguished patients with RPD from non‐RPD in both cohorts (MCF‐WU, 13.6±5.8 vs 4.7±5.9, p<0.001; NACC, 6.7±3.1 vs. 1.7±1.4, p<0.001).ConclusionOur CDR‐based definition of RPD distinguished patients with a broad spectrum of causes of RPD from those with typically progressive dementia across multiple cohorts. Broad application of this criteria would standardize diagnosis of RPD and support the design and implementation of multicenter studies RPD.

AbstractBackgroundPatients with the precipitous onset of cognitive symptoms (i.e., suspected rapid progressive dementia [RPD]) may continue to decline (true RPD) or may stabilize or improve (non‐RPD). Recognizing patients with RPD early in the disease course is important to support clinical care and enrollment in research.MethodPatients referred for the evaluation of suspected RPD were prospectively enrolled and followed for up to 2 years at Mayo Clinic in Florida (Jacksonville, FL; Jan‐2020 – Oct‐2023) and Washington University in St. Louis (Saint Louis, MO; Jun‐2016 – Dec‐2019). Clinical data were independently reviewed by two dementia specialists who established clinical diagnoses, referencing published criteria. Patients were diagnosed with RPD if they progressed to dementia (global Clinical Dementia Rating® [CDR] ≥1) within 1 year or incapacitation (CDR ≥2) within 2 years of symptom onset. Univariate statistics compared demographics, clinical details, and test results between patients with RPD and non‐RPD. Variables with p<0.1 were entered into a multivariate logistic regression model to identify factors associated with RPD.ResultOf 248 patients referred for suspected RPD, 187 (75.4%) met stated criteria for RPD. Patients with RPD were older (62.6±14.4 years vs 55.0±18.3 years; p<0.001), and more likely to be diagnosed with Alzheimer disease or related dementias (28.3% vs 9.8%; p = 0.003) or Creutzfeldt‐Jakob (19.1% vs 4.6%; p = 0.008). Non‐RPD cases were more often attributed to autoimmune/inflammatory disease (42.6% vs 29.4%, p = 0.061) or other causes (e.g., psychiatric, neoplasms, toxic/metabolic; 34.4% vs 16.6%, p = 0.006). After controlling for age, hallucinations (OR, 2.81; 95%CI: 1.21‐6.52), elevated CSF protein (OR, 2.43; 95%CI: 1.17‐5.03), and CSF white blood cell count <5 cells/mm3 (OR, 2.77; 95%CI: 1.32‐5.85) were independently associated with RPD. Cortical visual loss (15/183, 8.2%) and substantial brain atrophy on MRI (27/184, 14.7%) were specific to patients with RPD, representing additional distinguishing features.ConclusionHallucinations, cortical visual loss, substantial atrophy on MRI, elevated CSF protein, and normal CSF white blood cell count were independently associated with RPD. Early detection of these features in patients with suspected RPD may inform clinical care and enrollment in research studies of RPD.

Abstract Purpose This study examined occupational histories in neuropathologically confirmed cases of multiple system atrophy to identify environmental associations of potential relevance to disease causation. Methods 270 neuropathologically confirmed cases of multiple system atrophy obtained from the Mayo Clinic brain bank for neurodegenerative disorders in Jacksonville, Florida, were included in this case-control study. Demographic and disease information was collected from medical records. Information regarding occupational history was collected retrospectively from medical records and published obituaries. Proportions of employment by occupational sector were compared to United States census data. Results The most common prior occupations in patients were healthcare (15.2%), education (15.2%), administration (14.8%), clerical (10.7%), petroleum industry (8.9%), business ownership (8.5%), and metal industry (7.8%). When comparing patients to United States census data, significant differences were identified for electrical (5.6% vs. 0.4%, P < 0.001), education (15.2% vs. 2.3%, P < 0.001), real estate (4.4% vs. 0.7%, P < 0.001), metal industry (7.8% vs. 3.0%, P < 0.001), information technology (4.1% vs. 1.8%, P = 0.011), clerical (10.7% vs. 5.5%, P = 0.001), and petroleum industry (8.9% vs. 5.6%, P = 0.024). Conclusions Electrical engineers and electricians, educators, real estate agents, workers in the metal industry, information technologists, clerical staff, and workers in the petroleum industry were significantly overrepresented in our series of multiple system atrophy patients as compared to population data. We hypothesize that these occupational associations may signify environmental exposures increasing disease risk in genetically susceptible individuals. We cannot exclude a potential selection bias in patients willing to donate their brains to an academic center in order to contribute to scientific knowledge.

OBJECTIVE The aim of this study was to compare outcomes of direct targeting in deep brain stimulation (DBS) for essential tremor using 7T MRI versus 3T MRI. The authors hypothesized that 7T MRI direct targeting would be noninferior to 3T MRI in early tremor outcomes. METHODS A retrospective study was conducted on patients undergoing unilateral thalamic DBS for essential tremor between 2021 and 2023. Two matched cohorts were assessed, one using 7T MRI and the other using 3T MRI for surgical planning. The primary endpoint was the percentage improvement in the Fahn-Tolosa-Marin Tremor Rating Scale (TRS) scores. Additionally, the authors assessed optimized programming settings and variance in electrode position on postoperative imaging. Demographic and clinical data were compared using the nonparametric Mann-Whitney U-test. The squared Euclidean distance of each contact from the group mean centroid was calculated and averaged across the entire cohort to provide the variance (i.e., the mean squared distance) of electrode contact position. RESULTS A total of 34 patients were analyzed, with 17 in each cohort. There were no significant differences in demographic information or mean surgical dates between the groups. There were no differences in intraoperative target repositioning or adverse events. The 7T group had a significantly greater TRS improvement than the 3T group (64.9% ± 11.4% vs 50.9% ± 16.4%, p = 0.004). Patients in the 7T cohort also had a lower mean stimulation current compared with those in the 3T cohort (2.0 ± 0.8 mA vs 2.7 ± 0.9 mA, p = 0.01). Image evaluation revealed that although the mean electrode position was comparable between 7T and 3T, the 7T electrode positioning was more clustered, indicating a lower variance in the final electrode location. The mean Euclidean distance between the individual electrode tips and the group centroid was significantly less at 7T than at 3T (1.82 ± 0.68 mm vs 2.75 ± 0.81 mm, p = 0.001). CONCLUSIONS Despite concerns for increased artifacts and distortions at 7T, the authors show that these effects can be mitigated with an appropriate workflow, leading to improved surgical outcomes with direct targeting using 7T MRI. Their results suggest similar accuracy but greater precision in targeting with 7T MRI compared with 3T MRI, resulting in lower stimulation currents and improved tremor reduction. Future studies are needed to assess outcomes related to 7T MRI in targeting other subcortical structures.