Parkinson's Disease Dementia Research Articles

Biomarker Assessment in Parkinson’s Disease Dementia and Dementia with Lewy Bodies by the Immunomagnetic Reduction Assay and Clinical Measures

Background: Plasma biomarker assays provide an opportunity to reassess whether Alzheimer’s disease, Parkinson’s disease dementia (PDD), and dementia with Lewy bodies (DLB) plasma biomarkers are diagnostically useful. Objective: We hypothesized that immunomagnetic reduction (IMR) of plasma biomarkers could differentiate between patients with PDD and DLB and healthy patients when combined with established clinical testing measures. Methods: Plasma samples from 61 participants (12 PDD, 12 DLB, 37 controls) were analyzed using IMR to quantify amyloid-β 42 (Aβ42), total tau (t-tau), phosphorylated tau at threonine 181 (p-tau181), and α-synuclein (α-syn). Receiver operating characteristic curve (ROC) analysis was used to obtain sensitivity, specificity, and area under the ROC curve. Biomarker results were combined with clinical measures from the Unified Parkinson’s Disease Rating Scale (UPDRS), Montreal Cognitive Assessment, and Hoehn-Yahr stage to optimize diagnostic test performance. Results: Participants with PDD had higher α-syn than those with DLB and healthy participants and were distinguishable by their biomarker products Aβ42×p-tau181 and Aβ42×α-syn. Patients with DLB had higher p-tau181 than those with PDD and healthy participants and were distinguishable by their concentrations of α-syn×p-tau181. Plasma α-syn plus UPDRS versus either test alone increased sensitivity, specificity, and AUC when healthy patients were compared with those with PDD and DLB. Combined clinical examination scores and plasma biomarker products demonstrated utility in differentiating PDD from DLB when p-tau181 was combined with UPDRS, α-syn was combined with UPDRS, and α-syn×p-tau181 was combined with UPDRS. Conclusions: In this pilot study, IMR plasma p-tau181 and α-syn may discriminate between PDD and DLB when used in conjunction with clinical testing.

Mitochondrial Dysfunction in Parkinson’s Disease: A Contribution to Cognitive Impairment?

Among the non-motor symptoms associated with Parkinson’s disease (PD), cognitive impairment is one of the most common and disabling. It can occur either early or late during the disease, and it is heterogeneous in terms of its clinical manifestations, such as Subjective Cognitive Dysfunction (SCD), Mild Cognitive Impairment (MCI), and Parkinson’s Disease Dementia (PDD). The aim of the present review is to delve deeper into the molecular mechanisms underlying cognitive decline in PD. This is extremely important to delineate the guidelines for the differential diagnosis and prognosis of the dysfunction, to identify the molecular and neuronal mechanisms involved, and to plan therapeutic strategies that can halt cognitive impairment progression. Specifically, the present review will discuss the pathogenetic mechanisms involved in the progression of cognitive impairment in PD, with attention to mitochondria and their contribution to synaptic dysfunction and neuronal deterioration in the brain regions responsible for non-motor manifestations of the disease.

CSF d18:1 sphingolipid species in Parkinson disease and dementia with Lewy bodies with and without GBA1 variants

Variants in GBA1 result in dysregulated sphingolipids. We investigated five CSF d18:1 sphingolipid species in a longitudinal multicenter cohort comprising people with Parkinson’s Disease and Dementia with Lewy bodies with and without GBA1 variants and healthy controls. We found no increase of sphingolipid species in heterozygous GBA1 variant participants and no effect on development of cognitive impairment. Thus, CSF d18:1 sphingolipids are not suitable as state markers in Parkinson’s Disease.

Insular monoaminergic deficits in prodromal α-synucleinopathies.

This study assessed data from two cohorts of patients with alpha-synucleinopathies (University of Brescia and University of Rome Tor-Vergata cohorts). Consecutive participants with video-polysomnography-confirmed iRBD, Parkinson's disease (PD), dementia with Lewy bodies (DLB) and controls underwent neurological, clinical and 123I-FP-CIT SPECT imaging assessments. Individuals with iRBD were longitudinally monitored to collect clinical phenoconversion to PD or DLB. The main outcome was to identify whole brain 123 I-FP-CIT SPECT measures reflecting monoaminergic deficits in each clinical group as compared to controls. The cohort (n = 184) included 45 patients with iRBD, 47 PD, 42 DLB and 50 age-matched controls. Individuals with iRBD were categorized as RBD-DAT- (n = 32) and RBD-DAT+ (n = 13), according to nigrostriatal assessment used in clinical practice. Compared to controls, RBD-DAT- showed an early involvement of the left insula, which increased in RBD-DAT+, and was present in patients with Parkinson's disease and dementia with Lewy bodies. Longitudinal cox regression analyses revealed a higher risk of phenoconversion in individuals with iRBD and insular monoaminergic deficits [HR = 3.387; CI 95%: 1.18-10.27]. In this study, altered insular monoaminergic binding in iRBD was associated with phenoconversion to DLB or PD. These findings may provide a helpful stratification approach for future pharmacological or non-pharmacological interventions.

Sex Differences in Neuropsychiatric Symptoms in Alpha-Synucleinopathies: A Systematic Review and Meta-Analysis.

Alpha-synucleinopathies, such as Parkinson's disease (PD), Parkinson's disease dementia (PDD), and dementia with Lewy bodies (DLB), demonstrate sex differences with regard to prevalence, age of onset, and motor manifestations. Neuropsychiatric symptoms (NPS) are common early and late manifestations of these disorders. We aimed to describe sex differences in NPS across alpha-synucleinopathies. We searched Web of Science Core collection databases to identify observational studies published between January 1, 2000, and June 1, 2022, reporting the prevalence or severity of NPS among individuals with a diagnosis of PD, PDD, or DLB. Prevalence and severity were pooled for each NPS according to sex using random-effects models. Two-hundred-and-forty studies, representing 796,026 participants (45% females), were included in the meta-analysis. Female sex was associated with a higher prevalence of anxiety (OR = 1.60 [95% CI: 1.40, 1.82]), depression (OR = 1.56 [1.45, 1.67]), fatigue (OR = 1.21 [1.02, 1.43]), and psychotic symptoms (OR = 1.26 [1.14, 1.40]) and more severe anxiety (g = 1.35 [95% CI: 0.58, 2.13]), depression (g = 1.57 [1.05, 2.08]), and fatigue (g = 0.86 [0.41, 1.32]), while male sex was associated with a higher prevalence of apathy (OR = 0.77 [0.63, 0.93]), impulse control disorders (OR = 0.67 [0.55, 0.82]), REM sleep behavior disorder (OR = 0.54 [0.42, 0.70]), hypersomnolence (OR = 0.67 [0.56, 0.80]), and suicide (OR = 0.30 [0.20, 0.44]). NPS have different prevalences and severities in alpha-synucleinopathies according to sex. These findings support consideration of sex in the elaboration of clinical tools.

Examining Agreement in Psychotic Symptom Assessment: Insights from Parkinson's Disease Dementia Dyads.

Psychosis and cognitive decline often co-occur in Parkinson's Disease (PD), which complicates assessment. We measured agreement between patients with PD and dementia (PDD) and care partners (CPs) in their independent evaluation of PD-related psychotic symptoms. We compared responses to a PD psychosis rating scale (SAPS-PD) in 21 dyads of patients with PDD and cognitively normal CPs. We assessed the concordance of responses using the intraclass correlation coefficient (ICC). Following the psychosis assessment, the clinician used all available information and adjudicated who provided the most reliable responses. Dyads demonstrated poor concordance in summary scores (ICC = 0.464). Six of the nine individual items had poor agreement. The clinician adjudicated the patient's response as the more reliable in 71.4% of cases. Although many psychotic symptoms are internal and not observable, in the context of PDD, both patient and CP inputs are valuable, but final adjudication favors patient responses.

Cholinergic Basal Forebrain Integrity and Cognition in Parkinson's Disease: A Reappraisal of Magnetic Resonance Imaging Evidence.

Cognitive impairment is a well-recognized and debilitating symptom of Parkinson's disease (PD). Degradation in the cortical cholinergic system is thought to be a key contributor. Both postmortem and in vivo cholinergic positron emission tomography (PET) studies have provided valuable evidence of cholinergic system changes in PD, which are pronounced in PD dementia (PDD). A growing body of literature has employed magnetic resonance imaging (MRI), a noninvasive, more cost-effective alternative to PET, to examine cholinergic system structural changes in PD. This review provides a comprehensive discussion of the methodologies and findings of studies that have focused on the relationship between cholinergic basal forebrain (cBF) integrity, based on T1- and diffusion-weighted MRI, and cognitive function in PD. Nucleus basalis of Meynert (Ch4) volume has been consistently reduced in cognitively impaired PD samples and has shown potential utility as a prognostic indicator for future cognitive decline. However, the extent of structural changes in Ch4, especially in early stages of cognitive decline in PD, remains unclear. In addition, evidence for structural change in anterior cBF regions in PD has not been well established. This review underscores the importance of continued cross-sectional and longitudinal research to elucidate the role of cholinergic dysfunction in the cognitive manifestations of PD. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Cholinergic dysfunction in isolated rapid eye movement sleep behaviour disorder links to impending phenoconversion.

Most patients with isolated rapid eye movement sleep behaviour disorder (iRBD) progress to a parkinsonian alpha-synucleinopathy. However, time to phenoconversion shows great variation. The aim of this study was to investigate whether cholinergic and dopaminergic dysfunction in iRBD patients was associated with impending phenoconversion. Twenty-one polysomnography-confirmed iRBD patients underwent baseline 11C-donepezil and 6-Fluoro-(18F)-l-3,4-dihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET). Potential phenoconversion was monitored for up to 8 years. PET images were analysed according to patients' diagnoses after 3 and 8 years using linear regression. Time-to-event analysis was made with Cox regression, dividing patients into low and high tracer uptake groups. Follow-up was accomplished in 17 patients. Eight patients progressed to either Parkinson's disease (n = 4) or dementia with Lewy bodies (n = 4), while nine remained non-phenoconverters. Compared with non-phenoconverters, 8-year phenoconverters had lower mean 11C-donepezil uptake in the parietal (p = 0.032) and frontal cortex (p = 0.042), whereas mean 11C-donepezil uptake in 3-year phenoconverters was lower in the parietal cortex (p = 0.005), frontal cortex (p = 0.025), thalamus (p = 0.043) and putamen (p = 0.049). Phenoconverters within 3 years and 8 years had lower 18F-DOPA uptake in the putamen (p < 0.001). iRBD patients with low parietal 11C-donepezil uptake had a 13.46 (95% confidence interval 1.42;127.21) times higher rate of phenoconversion compared with those with higher uptake (p = 0.023). iRBD patients with low 18F-DOPA uptake in the most affected putamen were all phenoconverters with higher rate of phenoconversion (p = 0.0002). These findings suggest that cortical cholinergic dysfunction, particularly within the parietal cortex, could be a biomarker candidate for predicting short-term phenoconversion in iRBD patients. This study aligns with previous reports suggesting dopaminergic dysfunction is associated with forthcoming phenoconversion.

Genetic variability of incretin receptors affects the occurrence of neurodegenerative diseases and their characteristics

BackgroundAlzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases. Their treatment options are rather limited, and no neuroprotective or disease-modifying treatments are available. Anti-diabetic drugs, such as glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) agonists, have been suggested as a potential therapeutic option. AimsAssess GLP1R and GIPR genetic variability in relation to AD- and PD-related phenotypes. MethodsAD, PD patients and healthy control subjects were included in the study. Cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease were measured in AD patients, while cognitive impairment was evaluated in PD. All participants were genotyped for three SNPs: GLP1R rs10305420, GLP1R rs6923761 and GIPR rs1800437. ResultsGLP1R rs10305420 genotypes were associated with increased odds for AD and PD development. GLP1R rs10305420 and GLP1R rs6923761 genotypes were significantly associated with Aβ42/40 ratio (p = 0.041 and p = 0.050), while GLP1R rs6923761 was also associated with p-tau levels (p = 0.022). Finally, GIPR rs1800437 heterozygotes as well as carriers of at least one GIPR rs1800437 C allele presented with increased odds for the development of dementia in PD (OR = 1.92; 95 % CI = 1.05–3.51; p = 0.034 and OR = 1.95; 95 % CI = 1.08–3.52; p = 0.027, respectively). ConclusionGLP1R and GIPR genetic variability may affect the occurrence of AD and PD and is also associated with AD CSF biomarkers for Alzheimer's disease and dementia in PD. The data on GLP1R and GIPR genetic variability may support the function of incretin receptors in neurodegeneration.

Exploratory Analysis of the Association Between Plasma Ceramide Alterations and Cognitive Dysfunction in Parkinson's Disease.

Prior research has underscored the importance of sphingolipid metabolism in Parkinson's disease (PD) pathogenesis. Our objective was to explore the associations between plasma ceramide levels and PD patients with cognitive dysfunction (PD-CD). We enrolled two study populations from Eastern China and the Parkinson's Progression Markers Initiative (PPMI), comprising 290 (100 HCs, 160 PDs, and 30 MSAs) and 429 (125 HCs and 304 PDs) participants, respectively. The plasma levels of ceramides (Cer 16:0, Cer 18:0, Cer 24:0, and Cer 24:1) were tested via HPLC-MS/MS analysis. Compared with those in the HC group, the plasma levels of Cer 18:0, Cer 24:1, Cer 16:0/Cer 24:0, Cer 18:0/Cer 24:0, and Cer 24:1/Cer 24:0 were higher in both the PD and MSA groups. Significant differences in the plasma levels of Cer 16:0/Cer 24:0, Cer 18:0/Cer 24:0, and Cer 24:1/Cer 24:0 were observed among the PD-NC (PD with normal cognition), PD-MCI (PD with mild cognitive impairment), and PDD (PD dementia) groups, with the PDD group exhibiting the highest levels. PD patients with higher baseline levels of plasma ceramides (specifically, Cer 18:0, Cer 16:0/Cer 24:0, Cer 18:0/Cer 24:0, and Cer 24:1/Cer 24:0) demonstrated accelerated cognitive decline compared with individuals who had lower baseline plasma ceramide levels during the 5-year follow-up period. A biomarker panel including Cer 18:0/Cer 24:0 and Cer 24:1/Cer 24:0 could effectively differentiate PD-CD from PD-NC with notable diagnostic accuracy. Our results indicate that plasma ceramide levels could potentially be used as diagnostic biomarkers for PD-CD.

Comparison of Brain Activity between Patients with Parkinson Disease Dementia and Patients Affected by Dementia with Lewy Body through EEG Analysis

Objective: Parkinson's disease dementia (PDD) and Dementia with Lewy bodies (DLB) are two syndromes categorized under synucleinopathy, sharing comparable symptoms. The identification of biomarkers would offer an accurate approach for improved diagnosis, treatment, and monitoring of treatment efficacy for these distinct forms of dementia. Method: This study utilized spectral analysis and nonlinear dynamic analysis to compare electroencephalogram (EEG) characteristics between PDD and DLB patients. EEG data was collected from 30 PDD patients, 36 DLB patients, and 36 healthy subjects at rest. Following a conditioning phase to minimize noise and eliminate artifacts, we derived spectral and complexity features using Welch's method and sample entropy. Analysis of variance with repeated measures was performed to compare spectral features and nonlinear dynamics of brain activity between the groups. Results: Post hoc comparison showed that in the control group, the power of delta and theta bands was lower and the power of alpha and beta bands was higher than in patients with PDD and DLB. (P &lt; 0.05). In the theta and alpha bands, the PDD group showed greater power than the DLB group (P &lt; 0.05). Furthermore, there was a significant main effect of diagnosis (F = 4.67, P = 0.007), and also the diagnosis by region interaction for complexity values (F = 4.58, P = 0.009). Post hoc analysis showed that the EEG complexity of the control group was significantly higher than that of the PDD and DLB groups in the frontal, central, temporal and parietal regions (P &lt; 0.05). Moreover, the EEG complexity of the PDD group was significantly higher than that of the DLB group in the central, temporal and parietal regions (P &lt; 0.05). Conclusion: Although both PDD and DLB had almost similar patterns compared to the control group, they showed differences in the EEG power spectrum and its nonlinear dynamics. Our findings indicated marked diffuse slowing and lower cortical complexity or activity in DLB patients compared to PDD in all regions, especially in the central, temporal and parietal areas.

SENSE-Cog Lewy: Investigating the Impact of Sensory Loss on the Diagnosis, Clinical Features and Prognosis of Lewy Body Dementia

Abstract Background Lewy Body Dementia (LBD) accounts for 20% of the nearly 65,000 people with dementia in Ireland, but fewer than 5% of those affected receive a formal diagnosis. LBD includes both Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) and can be characterised by fluctuating and progressive cognitive difficulties, vivid visual hallucinations and REM sleep behaviour disturbances. Sensory function such hearing, vision and olfactory function declines with age—but increasing evidence shows that abnormal patterns of sensory dysfunction can be one of the earliest clinical signs and predictors of progression of neurodegenerative diseases such as Lewy body dementia and Parkinson’s disease dementia. Methods A scoping review was undertaken using Embase, CINAHL, PsychINFO and PubMed. Only reports on people with LBD (DLB and PDD) from any stage, prodromal to late stage were considered. Papers primarily addressing other forms of neurocognitive disorders were excluded. Sensory loss was conceptualised as the loss of smell, vision and hearing. Two reviewers independently assessed each study for inclusion, and disagreements were resolved by a third reviewer. Results Reports on sensory loss in LBD were very few and most often were comparing sensory loss across different dementia types. Strong associations were observed between olfactory loss and particular visual impairment patterns and the severity of both cognitive and non-cognitive DLB symptoms. Olfactory impairment is a potential early biomarker of DLB and PDD and severity of olfactory dysfunction can predict cognitive decline. Visual hallucinations, for example, were found to be closely linked to visual impairment patterns such as pareidolia. Conclusion This study highlights a knowledge gap regarding the patterns of sensory loss in LBD and their relationship with cognitive and non-cognitive LBD symptoms. Sensory assessments represent potentially valuable diagnostic and prognosis tool in LBD, with further research required to understand the aetiological mechanisms underlying sensory impairment in LBD and other dementias.

Implementing a Pilot Geriatric Oncology Service at a National Cancer Centre in Dublin

Abstract Background The American Society of Clinical Oncology and International Society of Geriatric Oncology recommend comprehensive geriatric assessment (CGA) for older adults commencing systemic anti-cancer treatments (SACTs) (1, 2). Routine CGA is lacking in cancer centres nationally. Methods A pilot, interdisciplinary geriatric-oncology (GO) clinic comprising a geriatric medicine consultant and specialist registrar, medical oncology fellow, physiotherapist and occupational therapist was established Dec 2023. New oncology patient referrals were screened applying the G8 tool; a score of ≤14 triggering referral. Polypharmacy was defined as ≥5 regular medications. Frailty was assessed using Clinical Frailty Scale (CFS) and cognition using Montreal Cognitive Assessment (MoCA). Results To date, 30 patients have attended the clinic; mean age 77.2 (SD5) years (range 68-85); 73% female, 50% with a CFS score of ≥4. Sixty-percent (n=18) were due to commence chemotherapy, the remainder hormonal or targeted treatment. Polypharmacy was identified in 66.6% (n=20), with 13.3% (n=4) having an anti-cholinergic burden score of ≥3, MoCAs were completed in 60% (n=18), of whom 77.8% (n=14) had an abnormal result (&amp;lt;26/30 MoCA or &amp;lt;18/22 MoCA blind). Twenty-six percent (n=8) reported ≥1 fall in the preceding six-months. Deprescribing interventions were completed in 40% (n=12); 58.3% (n=7) had ≥2 medications stopped. Medications most commonly deprescribed included opioids (n=2), antihypertensives (n=2), statins (n=2). Ambulatory blood pressure monitors were arranged for 33.3% (n=10) and DEXAs for 40% (n=12) and appropriately actioned. Follow up was arranged in the Falls and Syncope Unit for 7%, day hospital 10%, geriatric outpatients 10%, group psycho-oncology sessions 20%, specialist cancer rehabilitation physiotherapy service 17%. Parkinsons disease and dementia were diagnosed in 1 and 1 patients, respectively. Each patient had a detailed assessment and plan forwarded to their treating oncologist. Conclusion The development of a dedicated GO service is in line with international standards. By undergoing CGA, geriatric syndromes amenable to intervention were identified in patients.

Alpha-synuclein modulates the repair of genomic DNA double-strand breaks in a DNA-PKcs-regulated manner

α-synuclein (αSyn) is a presynaptic and nuclear protein that aggregates in important neurodegenerative diseases such as Parkinson's Disease (PD), Parkinson's Disease Dementia (PDD) and Lewy Body Dementia (LBD). Our past work suggests that nuclear αSyn may regulate forms of DNA double-strand break (DSB) repair in HAP1 cells after DNA damage induction with the chemotherapeutic agent bleomycin1. Here, we report that genetic deletion of αSyn specifically impairs the non-homologous end-joining (NHEJ) pathway of DSB repair using an extrachromosomal plasmid-based repair assay in HAP1 cells. Notably, induction of a single DSB at a precise genomic location using a CRISPR/Cas9 lentiviral approach also showed the importance of αSyn in regulating NHEJ in HAP1 cells and primary mouse cortical neuron cultures. This modulation of DSB repair is regulated by the activity of the DNA damage response signaling kinase DNA-PKcs, since the effect of αSyn loss-of-function is reversed by DNA-PKcs inhibition. Together, these findings suggest that αSyn plays an important physiologic role in regulating DSB repair in both a transformed cell line and in primary cortical neurons. Loss of this nuclear function may contribute to the neuronal genomic instability detected in PD, PDD and LBD and points to DNA-PKcs as a potential therapeutic target.

Subjective cognitive and olfactory impairments predict different prospective dementia outcomes.

Self-reported measures emerge as potential indicators for early detection of dementia and mortality. We investigated the predictive value of different self-reported measures, including subjective cognitive decline (SCD), subjective olfactory impairment (SOI), subjective taste impairment (STI), and self-reported poor health (SPH), in order to determine the risk of progressing to Alzheimer's disease (AD) dementia, Parkinson's disease (PD) dementia, or any-other-cause dementia. A total of 6,028 cognitively unimpaired individuals from the 8th wave of the English Longitudinal Study of Ageing (ELSA) were included as the baseline sample and 5,297 individuals from the 9th wave were included as 2-year follow-up sample. Self-rated measures were assessed using questions from the ELSA structured interview. Three logistic regression models were fitted to predict different the dementia outcomes. SCD based on memory complaints (OR = 11.145; P < 0.001), and older age (OR = 1.108, P < 0.001) significantly predicted the progression to AD dementia at follow-up. SOI (OR = 7.440; P < 0.001) and older age (OR = 1.065, P = 0.035) significantly predicted the progression to PD dementia at follow-up. Furthermore, SCD based on memory complaints (OR = 4.448; P < 0.001) jointly with complaints in other (non-memory) mental abilities (OR = 6.662; P < 0.001), and older age (OR = 1.147, P < 0.001) significantly predicted the progression to dementia of any other cause. Different types of complaints are specifically associated with different dementia outcomes. Our study demonstrates that self-reported measures are a useful and accessible tool when screening for individuals at risk of dementia in the general population.

Associations between Thyroid Hormones and Cognitive Impairment in Patients with Parkinson's Disease.

This study aims to explore the correlation of serum thyroid hormone levels to cognitive impairments in Parkinson's disease (PD) patients. In this retrospective study, 106 Chinese patients without cognitive impairments and 94 patients with cognitive impairments, including 55 with mild cognitive impairment (PD-MCI) and 39 with PD dementia (PDD), were analyzed. Clinical data regarding the PD assessments, including disease duration, Unified Parkinson's Disease Rating Scale (UPDRS) Part 3 scores, and Hoehn and Yahr (H-Y) staging, were analyzed. Cognitive functions were evaluated using the Montreal Cognitive Assessment score. Serum levels of thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3), were measured using ELISA. Significantly altered H-Y staging, disease duration, and UPDRS Part 3 scores were observed in PD patients with cognitive impairment compared with those without. Serum levels of FT3 were significantly decreased, while FT4 and TSH levels were significantly elevated in PD patients with cognitive impairment compared with those without. Combined detection of TSH, FT3, and FT4 showed value in distinguishing PD patients with and without cognitive impairment. Furthermore, a comparison of serum levels between PD-MCI and PDD patients revealed significant association between thyroid hormone levels and the degree of cognitive impairment in PD patients. Our findings suggest a relationship between changes in serum thyroid hormone levels and cognitive impairments in PD patients. Thyroid hormone levels, particularly FT3, may serve as potential markers for cognitive dysfunction in PD.

α-Synuclein Conformations in Plasma Distinguish Parkinson's Disease from Dementia with Lewy Bodies.

Aggregation of misfolded α-synuclein (aSyn) within the brain is the pathologic hallmark of Lewy body diseases (LBD), including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Evidence exists for aSyn "strains" - conformations with distinct biological properties. However, biomarkers for PD vs. DLB, including potential aSyn strain differences, are lacking. Here, we used two monoclonal antibodies selective for different in vitro aSyn species - termed Strain A and B - to evaluate human brain tissue, cerebrospinal fluid (CSF), and plasma. Surprisingly, levels of Strain A and B aSyn species differed in plasma from individuals with PD vs. DLB in two independent cohorts. Lower plasma aSyn Strain A species also predicted subsequent PD cognitive decline. Strain A and Strain B aSyn species were undetectable in CSF, but plasma aSyn species could template aSyn fibrillization, particularly in PD. Our findings suggest that aSyn strains may impact LBD clinical presentation and originate outside the brain.

Role of Mitochondrial Dysfunctions in Neurodegenerative Disorders: Advances in Mitochondrial Biology.

Mitochondria, essential organelles responsible for cellular energy production, emerge as a key factor in the pathogenesis of neurodegenerative disorders. This review explores advancements in mitochondrial biology studies that highlight the pivotal connection between mitochondrial dysfunctions and neurological conditions such as Alzheimer's, Parkinson's, Huntington's, ischemic stroke, and vascular dementia. Mitochondrial DNA mutations, impaired dynamics, and disruptions in the ETC contribute to compromised energy production and heightened oxidative stress. These factors, in turn, lead to neuronal damage and cell death. Recent research has unveiled potential therapeutic strategies targeting mitochondrial dysfunction, including mitochondria targeted therapies and antioxidants. Furthermore, the identification of reliable biomarkers for assessing mitochondrial dysfunction opens new avenues for early diagnosis and monitoring of disease progression. By delving into these advancements, this review underscores the significance of understanding mitochondrial biology in unraveling the mechanisms underlying neurodegenerative disorders. It lays the groundwork for developing targeted treatments to combat these devastating neurological conditions.

Long-Term Dementia Risk in Parkinson Disease.

It is widely cited that dementia occurs in up to 80% of patients with Parkinson disease (PD), but studies reporting such high rates were published over two decades ago, had relatively small samples, and had other limitations. We aimed to determine long-term dementia risk in PD using data from two large, ongoing, prospective, observational studies. Participants from the Parkinson's Progression Markers Initiative (PPMI), a multisite international study, and a long-standing PD research cohort at the University of Pennsylvania (Penn), a single site study at a tertiary movement disorders center, were recruited. PPMI enrolled de novo, untreated PD participants and Penn a convenience cohort from a large clinical center. For PPMI, a cognitive battery is administered annually, and a site investigator makes a cognitive diagnosis. At Penn, a comprehensive cognitive battery is administered either annually or biennially, and a cognitive diagnosis is made by expert consensus. Interval-censored survival curves were fit for time from PD diagnosis to stable dementia diagnosis for each cohort, using cognitive diagnosis of dementia as the primary end point and Montreal Cognitive Assessment (MoCA) score <21 and Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I cognition score ≥3 as secondary end points for PPMI. In addition, estimated dementia probability by PD disease duration was tabulated for each study and end point. For the PPMI cohort, 417 participants with PD (mean age 61.6 years, 65% male) were followed, with an estimated probability of dementia at year 10 disease duration of 9% (site investigator diagnosis), 15% (MoCA), or 12% (MDS-UPDRS Part I cognition). For the Penn cohort, 389 participants with PD (mean age 69.3 years, 67% male) were followed, with 184 participants (47% of cohort) eventually diagnosed with dementia. The interval-censored curve for the Penn cohort had a median time to dementia of 15 years (95% CI 13-15); the estimated probability of dementia was 27% at 10 years of disease duration, 50% at 15 years, and 74% at 20 years. Results from two large, prospective studies suggest that dementia in PD occurs less frequently, or later in the disease course, than previous research studies have reported.

A study on possible risk factors for progressive supranuclear palsy in southern part of India.

Background: The etiological factors leading to progressive supranuclear palsy (PSP) are poorly understood. This study aims to evaluate the role of various risk factors in patients with PSP. Methods: A case-control study was conducted over a period of two years from March 2016 to March 2018. The cases were recruited independently by two senior neurologists and a consensus was then reached after discussion for their inclusion. The controls were free of parkinsonian features or dementia and matched by age (± 3 years), sex, and race with the cases. The study population was then interviewed using a standard questionnaire for various possible risk factors. Variables with a significance (P ≤ 0.05) in univariate analysis were considered for bivariate analysis, multivariate analysis, and logistic-regression analysis. Results: A total of 51 cases with an equal number of controls were included in this study. Ten separate variables that included poor educational status, well water, smoking, tapioca, bakery/fast food, tea ≥ 5 cups/day, personality, exposure to pets, exposure to cattle, and family history of stroke were found to show statistical significance after univariate analysis. Among these, tapioca consumption, fast food and bakery items consumption, type A personality, and family history of stroke were found significant after adjusting for the confounding factors. Conclusion: The possible etiological factors that have a relevance in the causation of PSP as borne out in our study include dietary habits such as tapioca, fast food, and bakery items consumption, family history of stroke, and type A personality trait.