Evaluating the Effect of Alzheimer's Disease-Related Biomarker Change in Corticobasal Syndrome and Progressive Supranuclear Palsy.

OBJECTIVES: To evaluate the effect of Alzheimer's disease (AD) -related biomarker change on clinical features, brain atrophy and functional connectivity of patients with corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). METHODS: Data from patients with a clinical diagnosis of CBS, PSP, and AD and healthy controls were obtained from the 4-R-Tauopathy Neuroimaging Initiative 1 and 2, the Alzheimer's Disease Neuroimaging Initiative, and a local cohort from the Toronto Western Hospital. Patients with CBS and PSP were divided into AD-positive (CBS/PSP-AD) and AD-negative (CBS/PSP-noAD) groups based on fluid biomarkers and amyloid PET scans. Cognitive, motor, and depression scores; AD fluid biomarkers (cerebrospinal p-tau, t-tau, and amyloid-beta, and plasma ptau-217); and neuroimaging data (amyloid PET, MRI and fMRI) were collected. Clinical features, whole-brain gray matter volume and functional networks connectivity were compared across groups. RESULTS: Data were analyzed from 87 CBS/PSP-noAD and 23 CBS/PSP-AD, 18 AD, and 30 healthy controls. CBS/PSP-noAD showed worse performance in comparison to CBS/PSP-AD in the PSPRS [mean(SD): 34.8(15.8) vs 23.3(11.6)] and the UPDRS scores [mean(SD): 34.2(17.0) vs 21.8(13.3)]. CBS/PSP-AD demonstrated atrophy in AD signature areas and brainstem, while CBS/PSP-noAD patients displayed atrophy in frontal and temporal areas, globus pallidus, and brainstem compared to healthy controls. The default mode network showed greatest disconnection in CBS/PSP-AD compared with CBS/PSP-no AD and controls. The thalamic network connectivity was most affected in CBS/PSP-noAD. INTERPRETATION: AD biomarker positivity may modulate the clinical presentation of CBS/PSP, with evidence of distinctive structural and functional brain changes associated with the AD pathology/co-pathology. ANN NEUROL 2024;96:99-109.

Distinct involvement of the cranial and spinal nerves in progressive supranuclear palsy.

The most frequent neurodegenerative proteinopathies include diseases with deposition of misfolded tau or α-synuclein in the brain. Pathological protein aggregates in the PNS are well-recognized in α-synucleinopathies and have recently attracted attention as a diagnostic biomarker. However, there is a paucity of observations in tauopathies. To characterize the involvement of the PNS in tauopathies, we investigated tau pathology in cranial and spinal nerves (PNS-tau) in 54 tauopathy cases [progressive supranuclear palsy (PSP), n = 15; Alzheimer's disease (AD), n = 18; chronic traumatic encephalopathy (CTE), n = 5; and corticobasal degeneration (CBD), n = 6; Pick's disease, n = 9; limbic-predominant neuronal inclusion body 4-repeat tauopathy (LNT), n = 1] using immunohistochemistry, Gallyas silver staining, biochemistry, and seeding assays. Most PSP cases revealed phosphorylated and 4-repeat tau immunoreactive tau deposits in the PNS as follows: (number of tau-positive cases/available cases) cranial nerves III: 7/8 (88%); IX/X: 10/11 (91%); and XII: 6/6 (100%); anterior spinal roots: 10/10 (100%). The tau-positive inclusions in PSP often showed structures with fibrillary (neurofibrillary tangle-like) morphology in the axon that were also recognized with Gallyas silver staining. CBD cases rarely showed fine granular non-argyrophilic tau deposits. In contrast, tau pathology in the PNS was not evident in AD, CTE and Pick's disease cases. The single LNT case also showed tau pathology in the PNS. In PSP, the severity of PNS-tau involvement correlated with that of the corresponding nuclei, although, occasionally, p-tau deposits were present in the cranial nerves but not in the related brainstem nuclei. Not surprisingly, most of the PSP cases presented with eye movement disorder and bulbar symptoms, and some cases also showed lower-motor neuron signs. Using tau biosensor cells, for the first time we demonstrated seeding capacity of tau in the PNS. In conclusion, prominent PNS-tau distinguishes PSP from other tauopathies. The morphological differences of PNS-tau between PSP and CBD suggest that the tau pathology in PNS could reflect that in the central nervous system. The high frequency and early presence of tau lesions in PSP suggest that PNS-tau may have clinical and biomarker relevance.

Vanadium inhalation induces actin changes in mice testicular cells.

Infertility is becoming a health problem, which has increased mainly in megacities, and several studies have shown its association with environmental pollution. Air pollution has been linked to alterations in sperm parameters, both in humans and animal models. In male humans, it has been associated with reduced semen quality and DNA alterations. Vanadium is a transition element that has increased in recent decades as a component of air suspended matter and has been associated with reprotoxic effects in animal models. Few are the mechanisms described by which the vanadium produces these effects, and cytoskeleton interaction is a possibility. We reported immunohistochemical changes in actin testicular cytoskeleton in a vanadium inhalation experimental mice model. Our findings show that exposure to vanadium pentoxide (0.02 M) results in actin decrease in testicular cells from 3-12 weeks exposure time; this effect was statistically significant and exposure time dependent. Actin cytoskeleton damage is a mechanism that could explain vanadium reprotoxic effects and its association with impaired fertility.

Effect of Motor Interference Therapy on Distress Related to Traumatic Memories: A Randomized, Double-Blind, Controlled Feasibility Trial.

INTRODUCTION: Traumatic memories (TM) are a core feature of stress-related disorders, including posttraumatic stress disorder (PTSD). Treatment is often difficult, and specific pharmacological interventions are lacking. We present a novel non-pharmacological intervention called motor interference therapy (MIT) as a promising alternative for these symptoms. AIMS: To determine the feasibility of MIT, a brief, audio-delivered, and non-pharmacological intervention that uses cognitive and motor tasks to treat TM. METHODS: We designed a randomized, double-blind trial. Twenty-eight participants from an outpatient clinic with at least one TM were included to receive either MIT or progressive muscle relaxation (PMR). Spanish versions of the PTSD symptom severity scale (EGS), visual analog scale for TM (TM-VAS), and quality of life (EQ-VAS) were applied prior to intervention, 1 week, and 1 month following intervention. RESULTS: Mean scores on all measures improved from baseline to posttest for both groups. MIT participants showed significantly more positive scores at 1 week and 1 month (TM-VAS baseline: 9.8 ± 0.4; immediate: 6.0 ± 2.0; 1 week: 3.8 ± 3.1 [d = 1.57]; 1 month 2.9 ± 2.8 [d = 1.93]) than PMR participants on measures of distress due to TM, trauma re-experiencing, anxiety, and a composite measure of PTSD. CONCLUSION: MIT is a simple, effective, and easy-to-use tool for treating TM and other stress-related symptoms. It requires relatively few resources and could be adapted to many contexts. The results provide proof-of-principle support for conducting future research with larger cohorts and controls to improve clinical effectiveness and research on brief interventions. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03627078.

CSF α-Synuclein Seed Amplification Assay in Patients With Atypical Parkinsonian Disorders.

BACKGROUND AND OBJECTIVES: There is no disease-modifying treatment of corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP), 2 disorders characterized by their striking phenotypic, and, in CBS, pathologic heterogeneity. Seed amplification assays (SAAs) could enable the detection of neuropathologic processes, such as α-synuclein (αSyn) copathology, that affect the success of future disease-modifying treatment strategies. The primary objective was to assess possible αSyn copathology in CBS and PSP, as detected in CSF using an αSyn SAA (αSyn-SAA). Secondary objectives were to evaluate the association of αSyn-SAA positivity with other biomarkers including of Alzheimer disease (AD), and with clinical presentation. We hypothesized that αSyn-SAA positivity would be detectable in CBS and PSP and that it would be associated with AD biomarker positivity and ß-amyloid (Aß) 42 levels, neurodegeneration as assessed by neurofilament light chain (NfL) levels, and symptoms associated with synucleinopathies. METHODS: This cross-sectional observational study included patients clinically diagnosed with CBS and PSP who underwent a lumbar puncture between 2012 and 2021 (Toronto Western Hospital, Canada). CSF was tested for αSyn-SAA positivity, AD biomarkers, and NfL levels. Clinical data were derived from medical records. RESULTS: We tested the CSF of 40 patients with CBS (19 female patients, 65.9 ± 8.6 years) and 28 with PSP (13 female patients, 72.5 ± 8.7 years old), mostly White (n = 50) or Asian (n = 14). αSyn-SAA positivity was observed in 35.9% patients with CBS and 28.6% with PSP. In young-onset, but not late-onset patients, αSyn-SAA positivity and AD positivity were associated (odds ratio [OR] 8.8, 95% CI 1.2-82.6, p < 0.05). A multivariable linear regression analysis showed a significant interaction of αSyn-SAA status by age at onset on CSF Aß42 levels (ß = 0.3 ± 0.1, p < 0.05). Indeed, age at onset was positively related to Aß42 levels only in αSyn-SAA-positive patients, as shown by slope comparison. A logistic regression analysis also suggested that REM sleep behavior disorder was associated with αSyn-SAA positivity (OR 60.2, 95% CI 5.2-1,965.8; p < 0.01). DISCUSSION: We detected a frequency of αSyn-SAA positivity in CBS and PSP in line with pathologic studies, highlighting the usefulness of SAAs for in vivo detection of otherwise undetectable neuropathologic processes. Our results also suggest that AD status (specifically low Aß42) and older age at onset may contribute to αSyn-SAA positivity. This opens new perspectives for the stratification of patients in clinical trials.

The effect of motor interference therapy in traumatic memories: A pilot study.

INTRODUCTION: Traumatic memories of events such as a life-threatening incident, serious injury, or sexual violence are a core symptom of stress-related disorders; they might be susceptible to positive modification with interference tasks (reconsolidation-based interventions). Our objective was to test the effect of performing a motor interference task (finger tapping in response to audio cues) on patients who suffer from traumatic memories. METHODS: We designed an uncontrolled pilot prospective clinical trial. Ten participants listened to an audio track that instructed them to tap their fingers in response to specific audio cues while trying to recall the traumatic event. Each patient underwent an assessment including the Spanish version of the PTSD Symptom Severity Scale-Revised (EGS-R), the visual analogue scale (EQ-VAS) from EuroQol 5D (EQ-5D), and a simple visual analogue scale (VAS) before the intervention, immediately after, and a week after the treatment. RESULTS: All measures exhibited a statistically significant improvement 1 week after the study. On the PTSD scale, 1 week later, 30% of the patients did not score high enough for such diagnosis. The VAS measured immediately following the intervention (4.4, SD = 2.22) also improved (p < .001), and 30% of the patients scored zero. One week after the intervention, the VAS improved more than 50% CONCLUSION: The rapid 1-week improvement on the PSTD scale and the VAS after a 30 min intervention support the idea of further research using a double-blind, controlled design powered to demonstrate the efficacy of motor interference, an easy-to-apply therapeutic tool, in the treatment of traumatic memories.

Síntomas depresivos inducidos por el retiro de benzodiacepinas en el trastorno esquizoafectivo. Reporte de un caso / Depressive symptoms induced by benzodiazepine withdrawal in schizoaffective disorder. Case report

Resumen Introducción: Dentro del espectro de las enfermedades psiquiátricas, una de las más complejas es el trastorno esquizoafectivo debido al reto diagnóstico y al manejo psicofarmacológico. Esta enfermedad combina síntomas cardinales de la esquizofrenia con síntomas de trastornos del afecto. El tratamiento se enfoca entonces a mejorar los síntomas psicóticos y regular el estado de ánimo. Dentro de los fármacos que se utilizan se encuentran las benzodiacepinas, que deben retirarse gradualmente para evitar recaídas o síntomas de abstinencia. En este reporte comentamos el caso de una paciente que después del retiro gradual hasta la suspensión de clonazepam presentó síntomas depresivos que remitieron tras la reinstalación del fármaco. Reporte del caso: Mujer de 31 años de edad sin antecedentes de importancia para su padecimiento actual. Inició con síntomas psicóticos que requirieron hospitalización, donde se agregaron síntomas maniatiformes y se integró el diagnostico de episodio maniaco con síntomas psicóticos. Se manejó con un antipsicótico, estabilizador del estado de ánimo y benzodiacepinas, con lo que sus síntomas remitieron. A los dos años presentó un cuadro psicótico sin síntomas afectivos y se diagnosticó como trastorno esquizoafectivo según el DSM V. Por su mejoría se disminuyeron los fármacos de forma gradual. Tras la suspensión del clonazepam, la paciente presentó síntomas depresivos que remitieron al reinstalar el fármaco. Discusión: La aparición súbita de síntomas depresivos se consideró como una posible recaída dada la patología de base. Estrictamente hablando, la paciente no cumplía criterios para diagnosticar un síndrome de abstinencia a benzodiacepinas. En la literatura se reporta que en algunos casos los síntomas depresivos pueden ser parte de este espectro, sin embargo no se especifica ni temporalidad ni alguna otra característica relevante. Tras el reinicio del fármaco a la dosis mínima que utilizaba la paciente, en menos de dos semanas se logró la remisión total de un episodio que cumplía los criterios diagnósticos para un trastorno depresivo mayor. Esto nos permitió establecer una relación directa entre la suspensión del clonazepam y la aparición de dichos síntomas. Conclusiones: A pesar de que el manejo dependerá de las características de cada paciente y las preferencias de su médico, vale la pena tener en mente la aparición de síntomas poco usuales asociados con el uso de los fármacos aun a pesar de seguir los lineamientos establecidos para el cambio y suspensión, en este caso, de las benzodiacepinas.

Abstract Introduction: Within the spectrum of psychiatric illnesses one of the most complex is the schizoaffective disorder due to the fact that both, its diagnosis and pharmacological management are challenging. This disease combines cardinal symptoms of schizophrenia and mood disorders symptoms. The aim of the treatment focuses on improving both psychotic symptoms and mood stabilization. Benzodiazepines are frequently used, and should be gradually reduced in order to prevent either a relapse or withdrawal symptoms. Here, we report the case of a 31-year-old female patient that after a gradual reduction of benzodiazepines and the suspension of clonazepam developed depressive symptoms, which subsided after the drug reinstatement. Case report: A 31-year-old female with no relevant past medical history developed psychotic symptoms that required hospitalization. Maniac symptoms appeared and therefore, the diagnosis was a manic episode with psychotic symptoms. Antipsychotic drugs, a mood stabilizer and benzodiazepines were the treatment used and the patient showed clinical improvement. She was free of clinical manifestations for two years, until the patient presented a psychotic episode without mood symptoms; therefore she was diagnosed with schizoaffective disorder according to the DSM V criteria. After clinical improvement drugs were decreased gradually. Following the suspension of clonazepam the patient had depressive symptoms that disappeared after the reinstatement of the drug. Discussion: The sudden appearance of depressive symptoms was considered as a possible relapse linked to the underlying disease. Strictly speaking, the patient did not meet the criteria for benzodiazepine withdrawal syndrome. The literature reports that in some cases depressive symptoms may be part of this spectrum, however neither a temporality nor any other relevant characteristics were specified. After restarting the drug at the lowest dose that the patient used, total remission of the major depressive disorder was achieved in less than two weeks. This allowed us to establish, at our discretion, a direct link between the suspension of clonazepam and the appearance of these symptoms. Conclusion: Although the management depends on the characteristics of each patient and the physician preferences, it is worth keeping in mind the possibility of unusual symptoms that may appear even by following the correct guidelines established for a correct decrease doses and the suspension of benzodiazepines.