Parkinson's Disease Dementia Research Articles

Parkinson's and Lewy Body Dementia: Can It Be Something Else?

ABSTRACTUnexplained psychopathologies, although intriguing for the inquisitive clinician, pose significant diagnostic and treatment challenges. In such cases, looking beyond what is evident and logical might just be the answer. This case report reflects on a patient with a diagnosis of Parkinson's disease and Lewy body dementia, with an unusual set of symptoms and disease progression. It also explores the possibility of an overlap of clinical features associated with recent exposure to gadolinium contrast agent and its possible implications in the brain tissue and the subsequent neuropsychiatric symptoms.

Metallomic analysis of brain tissues distinguishes between cases of dementia with Lewy bodies, Alzheimer's disease, and Parkinson's disease dementia.

Dementia with Lewy bodies (DLB) can be difficult to distinguish from Alzheimer's disease (AD) and Parkinson's disease dementia (PDD) at different stages of its progression due to some overlaps in the clinical and neuropathological presentation of these conditions compared with DLB. Metallomic changes have already been observed in the AD and PDD brain-including widespread decreases in Cu levels and more localised alterations in Na, K, Mn, Fe, Zn, and Se. This study aimed to determine whether these metallomic changes appear in the DLB brain, and how the metallomic profile of the DLB brain appears in comparison to the AD and PDD brain. Brain tissues from ten regions of 20 DLB cases and 19 controls were obtained. The concentrations of Na, Mg, K, Ca, Zn, Fe, Mn, Cu, and Se were determined using inductively coupled plasma-mass spectrometry (ICP-MS). Case-control differences were evaluated using Mann-Whitney U tests. Results were compared with those previously obtained from AD and PDD brain tissue, and principal component analysis (PCA) plots were created to determine whether cerebral metallomic profiles could distinguish DLB from AD or PDD metallomic profiles. Na was increased and Cu decreased in four and five DLB brain regions, respectively. More localised alterations in Mn, Ca, Fe, and Se were also identified. Despite similarities in Cu changes between all three diseases, PCA plots showed that DLB cases could be readily distinguished from AD cases using data from the middle temporal gyrus, primary visual cortex, and cingulate gyrus, whereas DLB and PDD cases could be clearly separated using data from the primary visual cortex alone. Despite shared alterations in Cu levels, the post-mortem DLB brain shows very few other similarities with the metallomic profile of the AD or PDD brain. These findings suggest that while Cu deficiencies appear common to all three conditions, metal alterations otherwise differ between DLB and PDD/AD. These findings can contribute to our understanding of the underlying pathogenesis of these three diseases; if these changes can be observed in the living human brain, they may also contribute to the differential diagnosis of DLB from AD and/or PDD.

Rab27b promotes lysosomal function and alpha-synuclein clearance in neurons.

Alpha-synuclein (αsyn) is the key pathogenic protein implicated in synucleinopathies including Parkinson's Disease (PD) and Dementia with Lewy Bodies (DLB). In these diseases, αsyn is thought to spread between cells where it accumulates and induces pathology; however, mechanisms that drive its propagation or aggregation are poorly understood. We have previously reported that the small GTPase Rab27b is elevated in human PD and DLB and that it can mediate the autophagic clearance and toxicity of αsyn in a paracrine αsyn cell culture neuronal model. Here, we expanded our previous work and further characterized a role for Rab27b in neuronal lysosomal processing and αsyn clearance. We found that Rab27b KD in this αsyn inducible neuronal model resulted in lysosomal dysfunction and increased αsyn levels in lysosomes. Similar lysosomal proteolytic defects and enzymatic dysfunction were observed in both primary neuronal cultures and brain lysates from Rab27b knockout (KO) mice. αSyn aggregation was exacerbated in Rab27b KO neurons upon treatment with αsyn preformed fibrils. We found no changes in lysosomal counts or lysosomal pH in either model, but we did identify defects in acidic vesicle trafficking in Rab27b KO primary neurons which may drive lysosomal dysfunction and promote αsyn aggregation. Rab27b OE enhanced lysosomal activity and reduced insoluble αsyn accumulation. Finally we found elevated Rab27b levels in human postmortem incidental Lewy Body Disease (iLBD) subjects relative to healthy controls. These data suggest a role for Rab27b in neuronal lysosomal activity and identify it as a potential therapeutic target in synucleinopathies.

Sympathetic 123I-metaiodobenzylguanidine index for Lewy body disease: probability-based diagnosis and identifying patients exempt from late imaging

ObjectiveWe aimed to establish a practical diagnostic index for Lewy body diseases (LBD), such as Parkinson’s disease and dementia, with Lewy bodies in outpatient settings and criteria for exempting patients from late imaging.MethodsWe acquired early and late 123I-metaiodobenzylguanidine (MIBG) images from 108 consecutive patients with suspected LBD and standardized heart-to-mediastinum (H/M) ratios for collimator conditions. Exclusions included young-onset Parkinson’s disease (age < 50 years) and genetic transthyretin-type amyloidosis. We developed logistic models incorporating H/M ratios with or without age (n = 92). The sympathetic MIBG index for LBD (SMILe index), categorized LBD likelihood from 0 (lowest) to 1 (highest). Diagnostic accuracy was assessed as the area under the receiver operating characteristic (ROC) curve (AUC). The characteristics of the new index were compared with H/M ratios. The need for late imaging was explored using the SMILe index.ResultsEarly or late SMILe indexes using a single H/M ratio variable discriminated LBD from non-LBD. The AUC values for early and late SMILe indexes were 0.880 and 0.894 (p < 0.0001 for both), identical to those for early and late H/M ratios. The sensitivity and the specificity of early SMILe indexes with a 0.5 threshold were 76% and 90%, achieving accuracy of accuracy 86%. Similarly, the late SMILe index demonstrated a sensitivity of 76% and specificity of 87%, with an accuracy of 84%. Early SMILe indexes < 0.3 or > 0.7 (representing 84% patients) indicated a diagnosis without a late MIBG study.ConclusionThe 123I-MIBG-derived SMILe indexes provide likelihood of LBD, and those with a 50% threshold demonstrated optimal diagnostic accuracy for LBD. The index values of either < 0.3 or > 0.7 accurately selected patients who do not need late imaging.

REM sleep and neurodegeneration.

Several brainstem, subcortical and cortical areas are involved in the generation of rapid eye movement (REM) sleep. The alteration of these structures as a result of a neurodegenerative process may therefore lead to REMsleep anomalies. REM sleep behaviour disorder is associated with nightmares, dream-enacting behaviours and increased electromyographic activity in REM sleep. Its isolated form is a harbinger of synucleinopathies such as Parkinson's disease or dementia with Lewy bodies, and neuroprotective interventions are advocated. This link might also be present in patients taking antidepressants, with post-traumatic stress disorder, or with a history of repeated traumatic head injury. REM sleep likely contributes to normal memory processes. Its alteration has also been proposed to be part of the neuropathological changes occurring in Alzheimer's disease.

A Population-Based Approach to the Argument on Brain-First and Body-First Pathogenesis of Lewy Body Disease.

To explore the clinical progression of the brain-/body-first categories within Lewy body disease (LBD): Parkinson's disease (PD), dementia with Lewy bodies (DLB), and PD dementia. We used of the Rochester Epidemiology Project to establish a population-based cohort of clinically diagnosed LBD. We used two definitions for differentiating between brain- and body-first LBD: a previously hypothesized body-first presentation in patients with rapid eye movement sleep behavior onset before motor symptoms onset; and an expanded definition of body-first LBD when a patient had at least 2 premotor symptoms between constipation, erectile dysfunction, rapid eye movement sleep behavior, anosmia, or neurogenic bladder. Brain-first patients were more likely to be diagnosed with PD (RR = 1.43, p = 0.003), whereas body-first patients were more likely to be diagnosed with DLB (RR = 3.15, p < 0.001). Under the expanded definition, there was no difference in LBD diagnosis between brain-first and body-first patients (PD: RR = 1.03, p = 0.10; DLB: RR = 0.88, p = 0.58) There were no patterns between brain- or body-first presentation, PD dementia under either definition (original: p = 0.09, expanded: p = 0.97), and no significant difference in motor symptoms between brain-first and body-first. Our findings do not support the dichotomous classification of body-first and brain-first LBD with the currently proposed definition. Biological exposures resulting in PD and DLB are unlikely to converge on a binary classification of top-down or bottom-up synuclein pathology. ANN NEUROL 2024;96:551-559.

Comprehensive Analysis of Dementia Types and Risk Factors: A Study From a Tertiary Care Center in India.

Background and objective Dementia is a prevalent clinical syndrome characterized by memory impairment and cognitive dysfunction. Its global burden is expected to rise significantly, particularly in low- and middle-income countries. Understanding the spectrum of dementia types and associated risk factors is crucial for effective management. This study aims to elucidate the demographic profiles, clinical types, and risk factors of newly diagnosed dementia cases at a tertiary care hospital in India. Methods and materials A cross-sectional, hospital-based observational study was conducted on 81 patients at the Department of Medicine, Dr. D. Y. Patil Medical College, Hospital, and Research Centre, Pimpri, Pune, from February 2022 to January 2024. Ethical approval was obtained, and written consent was obtained from participants. Clinical diagnosis was based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) criteria, supported by cognitive assessment tools and laboratory/radiological investigations. Inclusion criteria encompassed individuals aged 18 years or older, presenting with clinical symptoms suggestive of dementia, having a Mini-Mental State Examination (MMSE) score of less than 24 and Montreal Cognitive Assessment (MoCA) score of less than 25, according to DSM-V criteria for dementia. Exclusion criteria included individuals with a history of head trauma or those below 18 years of age. Results Of the 81 participants, the majority (74.1%) were over 60 years old, with females comprising 59.3% of the sample. Alzheimer's disease was the most prevalent dementia subtype (34.5%), followed by vascular dementia (19.7%) and mixed dementia (13.5%). Other causes included Lewy body dementia (2.46%), Parkinson's dementia (4.9%), frontotemporal dementia (4.9%), and Creutzfeldt-Jakob disease (1.2%). Reversible causes accounted for a significant proportion of cases: alcohol-associated dementia (6.1%), hypothyroid-associated dementia (3.7%), HIV-associated dementia (2.46%), herpes simplex dementia (1.2%), neurosyphilis-associated dementia (1.2%), and normal pressure hydrocephalus (NPH)-associated dementia (2.4%). Analysis of risk factors revealed distinct patterns among different dementia types, emphasizing the role of cardiovascular and metabolic health. Conclusion This study provides insights into the demographic profiles, clinical types, and dementia risk factors in India. Addressing causes and managing cardiovascular/metabolic health is crucial for dementia prevention and management. Comprehensive care strategies and ongoing research efforts are essential for improving dementia outcomes and enhancing the quality of life for affected individuals and their families.

Investigation of the genetic aetiology of Lewy body diseases with and without dementia.

Up to 80% of Parkinson's disease patients develop dementia, but time to dementia varies widely from motor symptom onset. Dementia with Lewy bodies presents with clinical features similar to Parkinson's disease dementia, but cognitive impairment precedes or coincides with motor onset. It remains controversial whether dementia with Lewy bodies and Parkinson's disease dementia are distinct conditions or represent part of a disease spectrum. The biological mechanisms underlying disease heterogeneity, in particular the development of dementia, remain poorly understood, but will likely be the key to understanding disease pathways and, ultimately, therapy development. Previous genome-wide association studies in Parkinson's disease and dementia with Lewy bodies/Parkinson's disease dementia have identified risk loci differentiating patients from controls. We collated data for 7804 patients of European ancestry from Tracking Parkinson's, The Oxford Discovery Cohort, and Accelerating Medicine Partnership-Parkinson's Disease Initiative. We conducted a discrete phenotype genome-wide association study comparing Lewy body diseases with and without dementia to decode disease heterogeneity by investigating the genetic drivers of dementia in Lewy body diseases. We found that risk allele rs429358 tagging APOEe4 increases the odds of developing dementia, and that rs7668531 near the MMRN1 and SNCA-AS1 genes and an intronic variant rs17442721 tagging LRRK2 G2019S on chromosome 12 are protective against dementia. These results should be validated in autopsy-confirmed cases in future studies.

Dementia with Lewy bodies: Primary care PAs can make this difficult diagnosis.

Lewy body dementia is an umbrella term for dementia with Lewy bodies (DLB) and Parkinson disease dementia. These progressive, degenerative brain disorders link dementia with psychosis and parkinsonism and are difficult to diagnose. The diagnosis of DLB is challenging, especially in its early phase, because the presentation is variable. Relevant screening tools and a complete physical examination are essential. Making the correct diagnosis lets patients and caregivers make arrangements, have more timely access to services, improve patient quality of life, and lessen the burden on caregivers.

Parkinson's disease with hyposmia and dysautonomia: does it represent a distinct subtype?

Olfactory dysfunction or dysautonomia is one of the earliest prodromal nonmotor symptoms of Parkinson's disease (PD). We aimed to investigate whether PD patients with dysautonomia and hyposmia at the de novo stage present different prognoses regarding PD dementia (PDD) conversion, motor complication development, and change in levodopa-equivalent doses (LED). In this retrograde cohort study, we included 105 patients with newly diagnosed PD patients who underwent cross-cultural smell identification test (CC-SIT), autonomic function tests (AFT), and dopamine transporter (DAT) scan at the de novo stage. PD patients were divided into Hyposmia + /Dysautonomia + (H + /D +) and Hyposmia - /Dysautonomia - (H - /D -) groups depending on the result of AFT and CC-SIT. Baseline clinical, cognitive, imaging characteristics, longitudinal risks of PDD development and motor complication occurrence, and longitudinal LED changes were compared between the two groups. When compared with the H - /D - group, the H + /D + group showed lower standardized uptake value ratios in all subregions, lower asymmetry index, and steeper ventral - dorsal gradient in the DAT scan. The H + /D + group exhibited poorer performance in frontal/executive function and a higher risk of PDD development. The risk of motor complications including levodopa-induced dyskinesia, wearing off, and freezing of gait, was comparable between the two groups. The analysis of longitudinal changes in LED using a linear mixed model showed that the increase of LED in the H + /D + group was more rapid. Our results suggest that PD patients with dysautonomia and hyposmia at the de novo stage show a higher risk of PD dementia conversion and rapid progression of motor symptoms.

A.1 Repurposing Ambroxol as a disease-modifying treatment for Parkinson’s disease dementia: A phase 2, randomized, double blind placebo-controlled trial

Background: Currently there are no disease modifying treatment for Synucleinopathies including Parkinson’s disease Dementia (PDD). Carrying a mutation in the GBA gene (beta-glucocerebrosidase/ GCAse) is a leading risk factor for synucleinopathies. Raising activity GCAse lowers α-synuclein levels in cells and animal models. Ambroxol is a pharmacological chaperone for GCAse and can raise GCAse levels. Our goal is to test Ambroxol as a disease-modifying treatment in PDD. Methods: We randomized fifty-five individuals with PDD to Ambroxol 1050mg/day, 525mg/day, or placebo for 52 weeks. Primary outcome measures included safety, Alzheimer’s disease Assessment Scale-cognitive (ADAS-Cog) subscale and the Clinician’s Global Impression of Change (CGIC). Secondary outcomes included pharmacokinetics, cognitive and motor outcomes and and plasma and CSF biomarkers. Results: Ambroxol was well tolerated. There were 7 serious adverse events (SAEs) none deemed related to Ambroxol. GCase activity was increased in white blood cells by ~1.5 fold. There were no differences between groups on primary outcome measures. Patients receiving high dose Ambroxol appeared better on the Neuropsychiatric Inventory. GBA carriers appeared to improve on some cognitive tests. pTau 181 was reduced in CSF. Conclusions: Ambroxol was safe and well-tolerated in PDD. Ambroxol may improve biomarkers and cognitive outcomes in GBA1 mutation carrie.rs Ambroxol improved some biomarkerss. ClinicalTrials.gov NCT02914366

Localized Pantothenic Acid (Vitamin B5) Reductions Present Throughout the Dementia with Lewy Bodies Brain.

Localized pantothenic acid deficiencies have been observed in several neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease dementia (PDD), and Huntington's disease (HD), indicating downstream energetic pathway perturbations. However, no studies have yet been performed to see whether such deficiencies occur across the dementia with Lewy bodies (DLB) brain, or what the pattern of such dysregulation may be. Firstly, this study aimed to quantify pantothenic acid levels across ten regions of the brain in order to determine the localization of any pantothenic acid dysregulation in DLB. Secondly, the localization of pantothenic acid alterations was compared to that previously in AD, PDD, and HD brains. Pantothenic acid levels were determined in 20 individuals with DLB and 19 controls by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) across ten brain regions. Case-control differences were determined by nonparametric Mann-Whitney U test, with the calculation of S-values, risk ratios, E-values, and effect sizes. The results were compared with those previously obtained in DLB, AD, and HD. Pantothenic acid levels were significantly decreased in six of the ten investigated brain regions: the pons, substantia nigra, motor cortex, middle temporal gyrus, primary visual cortex, and hippocampus. This level of pantothenic acid dysregulation is most similar to that of the AD brain, in which pantothenic acid is also decreased in the motor cortex, middle temporal gyrus, primary visual cortex, and hippocampus. DLB appears to differ from other neurodegenerative diseases in being the only of the four to not show pantothenic acid dysregulation in the cerebellum. Pantothenic acid deficiency appears to be a shared mechanism of several neurodegenerative diseases, although differences in the localization of this dysregulation may contribute to the differing clinical pathways observed in these conditions.

Lower urinary tract dysfunction in the central nervous system neurogenic bladder and the real-life treatment outcome of botulinum toxin A.

Neurogenic lower urinary tract dysfunction (NLUTD) is common in patients with central nervous system (CNS) lesions. Cases of cerebrovascular accidents (CVA), Parkinson's disease, dementia, and other intracranial lesions develop poor bladder control with or without urinary difficulty due to loss of cortical perception of bladder filling sensation and poor coordination of urethral sphincter relaxation during reflex micturition. Patients with CNS lesions usually have overactive bladder (OAB) symptoms, including urgency, frequency, incontinence, voiding symptoms of dysuria, large postvoid residual volume, and retention. In elderly patients with severe CNS disease the OAB symptoms are usually difficult to adequately relieve by medical treatment, and thus, their quality of life is greatly. Botulinum toxin A (BoNT-A) is currently licensed and has been applied in patients with idiopathic and neurogenic OAB due to spinal cord injury or multiple sclerosis. However, the application of BoNT-A in the treatment of urinary incontinence due to NLUTD in chronic CNS lesions has not been well-documented. Although cohort studies and case series support BoNT-A treatment for neurogenic OAB, chronic urine retention after intravesical BoNT-A injection for OAB and exacerbated urinary incontinence after urethral BoNT-A injection for voiding dysfunction have greatly limited its application among patients with NLUTD due to CNS lesions. This article reviews the pathophysiology and clinical characteristics of NLUTD in patients with CNS lesions and the clinical effects and adverse events of BoNT-A injection for patients with NLUTD. A flowchart was created to outline the patient selection and treatment strategy for neurogenic OAB.

Near-Infrared Ratiometric Fluorescent Probe for Detecting Endogenous Cu2+ in the Brain.

Copper participates in a range of critical functions in the nervous system and human brain. Disturbances in brain copper content is strongly associated with neurological diseases. For example, changes in the level and distribution of copper are reported in neuroblastoma, Alzheimer's disease, and Lewy body disorders, such as Parkinson disease and dementia with Lewy bodies (DLB). There is a need for more sensitive techniques to measure intracellular copper levels to have a better understanding of the role of copper homeostasis in neuronal disorders. Here, we report a reaction-based near-infrared (NIR) ratiometric fluorescent probe CyCu1 for imaging Cu2+ in biological samples. High stability and selectivity of CyCu1 enabled the probe to be deployed as a sensor in a range of systems, including SH-SY5Y cells and neuroblastoma tumors. Furthermore, it can be used in plant cells, reporting on copper added to Arabidopsis roots. We also used CyCu1 to explore Cu2+ levels and distribution in post-mortem brain tissues from patients with DLB. We found significant decreases in Cu2+ content in the cytoplasm, neurons, and extraneuronal space in the degenerating substantia nigra in DLB compared with healthy age-matched control tissues. These findings enhance our understanding of Cu2+ dysregulation in Lewy body disorders. Our probe also shows promise as a photoacoustic imaging agent, with potential for applications in bimodal imaging.

A stem cell-based assay platform demonstrates alpha-synuclein dependent synaptic dysfunction in patient-derived cortical neurons

Alpha-synuclein (αS)-rich Lewy bodies and neurites in the cerebral cortex correlate with the presence of dementia in Parkinson disease (PD) and Dementia with Lewy bodies (DLB), but whether αS influences synaptic vesicle dynamics in human cortical neurons is unknown. Using a new iPSC-based assay platform for measuring synaptic vesicle cycling, we found that in human cortical glutamatergic neurons, increased αS from either transgenic expression or triplication of the endogenous locus in patient-derived neurons reduced synaptic vesicle cycling under both stimulated and spontaneous conditions. Thus, using a robust, easily adopted assay platform, we show for the first time αS-induced synaptic dysfunction in human cortical neurons, a key cellular substrate for PD dementia and DLB.

Human dementia with Lewy bodies brain shows widespread urea elevations

IntroductionSeveral recent studies have uncovered the presence of widespread urea elevations in multiple neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease dementia (PDD), vascular dementia (VaD), and Huntington's disease (HD). However, it is currently unknown whether dementia with Lewy bodies also shows these alterations in urea. This study aimed to investigate if and where urea is perturbed in the DLB brain. MethodsTissues from ten brain regions were obtained from 20 diagnosed cases of DLB and 19 controls. Urea concentrations were measured using ultra-high performance liquid chromatography–tandem mass spectrometry (UHPLC–MS/MS). Case–control differences were assessed by nonparametric Mann-Whitney U tests, and s-values, E-values, effect sizes, and risk ratios were determined for each brain region. The results were compared to those previously obtained for AD, PDD, VaD, and HD. ResultsAs with other previously investigated dementia diseases, DLB shows widespread urea elevations, affecting all ten regions investigated in the current study; the degree of these elevations is lower than that seen in AD or PDD, similar to that seen in HD, and higher than that observed in VaD. The highest urea fold-change was observed in the pons and the lowest in the primary visual cortex. ConclusionUrea elevations appear to be a shared alterations across at least five neurodegenerative diseases, despite their many differences in clinical and neuropathological presentation. The cause and effects of this perturbation should be the focus of future studies, for its possible contributions to the pathology of these conditions.

Nuclear aggregates of NONO/SFPQ and A-to-I-edited RNA in Parkinson’s disease and dementia with Lewy bodies

Neurodegenerative diseases are commonly classified as proteinopathies that are defined by the aggregation of a specific protein. Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are classified as synucleinopathies since α-synuclein (α-syn)-containing inclusions histopathologically define these diseases. Unbiased biochemical analysis of PD and DLB patient material unexpectedly revealed novel pathological inclusions in the nucleus comprising adenosine-to-inosine (A-to-I)-edited mRNAs and NONO and SFPQ proteins. These inclusions showed no colocalization with Lewy bodies and accumulated at levels comparable to α-syn. NONO and SFPQ aggregates reduced the expression of the editing inhibitor ADAR3, increasing A-to-I editing mainly within human-specific, Alu-repeat regions of axon, synaptic, and mitochondrial transcripts. Inosine-containing transcripts aberrantly accumulated in the nucleus, bound tighter to recombinant purified SFPQ invitro, and potentiated SFPQ aggregation in human dopamine neurons, resulting in a self-propagating pathological state. Our data offer new insight into the inclusion composition and pathophysiology of PD and DLB.

Polymerase I as a Target for Treating Neurodegenerative Disorders.

Polymerase I (Pol I) is at the epicenter of ribosomal RNA (rRNA) synthesis. Pol I is a target for the treatment of cancer. Given the many cellular commonalities between cancer and neurodegeneration (i.e., different faces of the same coin), it seems rational to consider targeting Pol I or, more generally, rRNA synthesis for the treatment of disorders associated with the death of terminally differentiated neurons. Principally, ribosomes synthesize proteins, and, accordingly, Pol I can be considered the starting point for protein synthesis. Given that cellular accumulation of abnormal proteins such as α-synuclein and tau is an essential feature of neurodegenerative disorders such as Parkinson disease and fronto-temporal dementia, reduction of protein production is now considered a viable target for treatment of these and closely related neurodegenerative disorders. Abnormalities in polymerase I activity and rRNA production may also be associated with nuclear and nucleolar stress, DNA damage, and childhood-onset neuronal death, as is the case for the UBTF E210K neuroregression syndrome. Moreover, restraining the activity of Pol I may be a viable strategy to slow aging. Before starting down the road of Pol I inhibition for treating non-cancerous disorders of the nervous system, many questions must be answered. First, how much Pol I inhibition can neurons tolerate, and for how long? Should inhibition of Pol I be continuous or pulsed? Will cells compensate for Pol I inhibition by upregulating the number of active rDNAs? At present, we have no effective and safe disease modulatory treatments for Alzheimer disease, α-synucleinopathies, or tauopathies, and novel therapeutic targets and approaches must be explored.

Clinical research on neurological and psychiatric diagnosis and monitoring using wearable devices: A literature review

AbstractWearable devices have opened up exciting possibilities for monitoring and managing home health, particularly in the realm of neurological and psychiatric diseases. These devices capture signals related to physiological and behavioral changes, including heart rate, sleep patterns, and motor functions. Their emergence has resulted in significant advancements in the management of such conditions. Traditional clinical diagnosis and assessment methods heavily rely on patient reports and evaluations conducted by healthcare professionals, often leading to a detachment of patients from their home environment and creating additional burdens for both patients and healthcare providers. The increasing popularity of wearable devices offers a potential solution to these challenges. This review focuses on the clinical utility of wearable devices in diagnosing and monitoring neurological and psychiatric diseases. Through research findings and practical examples, we highlight the potential role of wearable devices in diagnosing and monitoring conditions such as autism spectrum disorder, depression, epilepsy, stroke prognosis, Parkinson's disease, dementia, and other diseases. Additionally, the review discusses the benefits and limitations of wearable devices in clinical applications, while highlighting the challenges they face. Finally, it provides prospects for enhancing the value of wearable devices in the monitoring and diagnosis of neurological and psychiatric diseases.

Meta-analysis on the interrelationship between sarcopenia and mild cognitive impairment, Alzheimer's disease and other forms of dementia.

Sarcopenia has been associated with adverse health outcomes, including cognitive dysfunction. However, its specific interrelationship with neurocognitive disorders such as mild cognitive impairment (MCI), Alzheimer's disease (AD) or other types of dementia has not been thoroughly explored. This meta-analysis aims to summarize the existing evidence on this interrelationship. This systematic review was pre-registered on PROSPERO (CRD42022366309) and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. Databases, including PubMed, Embase, CINAHL, Scopus, Web of Science, PEDro, SPORTDiscus and the Cochrane Central Register of Controlled Trials, and the data registry ClinicalTrials.gov were searched from inception to 8 June 2023. Observational studies (cross-sectional and cohort) and interventional studies reporting on the association and prevalence of sarcopenia in MCI, AD or other types of dementia in adults ≥50years were included. For the meta-analysis, pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated for the association of sarcopenia with the neurocognitive disorders using random-effects/fixed-effects models. Subgroup analyses were performed to identify potential sources of heterogeneity. A total of 77 studies consisting of 92058 subjects were finally included in the qualitative analysis (71 cross-sectional, 4 cohort and 2 interventional studies). Studies were heterogeneous, using different diagnostic criteria to define both sarcopenia and cognitive status. The majority of studies (n=38) included Asian community-dwelling older adults. Most studies investigated the association of sarcopenia with AD (33/77) and MCI (32/77). For studies focusing on other forms of dementia, two studies included Lewy body dementia and one study included Parkinson's dementia, whereas the remaining studies did not specify dementia aetiology (n=21). Three cohort studies explored the association between sarcopenia and incident MCI, whereas only one cohort study explored the association between dementia and incident sarcopenia. Two interventional studies investigated whether an exercise programme could prevent the progression of sarcopenia in older adults with dementia or AD. The information for the meta-analysis was extracted from 26 studies. Sarcopenia was significantly associated with MCI (pooled OR=1.58, 95% CI 1.42-1.76) (n=14), AD (pooled OR=2.97, 95% CI 2.15-4.08) (n=3) and non-AD dementia (pooled OR=1.68, 95% CI 1.09-2.58) (n=9). The significance and magnitude of the associations differed in subgroup analyses by study design, population, definition of sarcopenia or used tool to measure cognitive status. This meta-analysis showed that sarcopenia is significantly associated with MCI, AD and other types of dementia. These findings suggest the importance of early screening and prevention of sarcopenia in older people with cognitive dysfunction, although further longitudinal research is needed to clarify the causal relationship.