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Cognitive impairment is a common non-motor symptom in Parkinson’s Disease (PD) and an important source of patient disability and caregiver burden. The timing, profile and rate of cognitive decline varies widely among individuals with PD and can range from normal cognition to mild cognitive impairment (PD-MCI) and dementia (PDD). Beta-amyloid and tau brain accumulation, oxidative stress and neuroinflammation are reported risk factors for cognitive impairment. Traumatic brain injury and pesticide and tobacco exposure have also been described. Genetic risk factors including genes such as COMT, APOE, MAPT and BDNF may also play a role. Less is known about protective factors, although the Mediterranean diet and exercise may fall in this category. Nonetheless, there is conflicting evidence for most of the factors that have been studied. The use of inconsistent criteria and lack of comprehensive assessment in many studies are important methodological issues. Timing of exposure also plays a crucial role, although identification of the correct time window has been historically difficult in PD. Our understanding of the mechanism behind these factors, as well as the interactions between gene and environment as determinants of disease phenotype and the identification of modifiable risk factors will be paramount, as this will allow for potential interventions even in established PD.

Background Lewy body dementia (LBD) phenotype is associated with the presence and degree of Lewy body, Alzheimer’s pathologies, and substantia nigra neuron loss. Nigral neuron loss is associated with parkinsonism in LBD, and females with LBD are less likely than males to have parkinsonism. As sex differences were reported for clinical correlates of Lewy body and Alzheimer’s pathologies, we aimed to investigate whether there are also sex differences for correlates of nigral neuron loss. Methods Data were obtained from the National Alzheimer’s Coordinating Center for females ( n  = 159) and males ( n  = 263) with brainstem, limbic, and neocortical Lewy body pathology. Sex differences for the nigral neuron loss’ association with Lewy body pathology staging and core clinical LBD features (cognitive fluctuations, visual hallucinations, rapid eye movement sleep behavior disorder, parkinsonism) during follow-up were analyzed with generalized linear models adjusting for age and Alzheimer’s pathology staging. Whether any of the core clinical features at the time of dementia onset can predict underlying nigral neuron loss for females and males were also analyzed with generalized linear models. Results Compared to males, females died older and had higher levels of Braak tau staging, but had similar levels of Lewy body pathology staging and nigral neuron loss. Females were less likely than males to have a clinical Lewy body disease diagnosis during follow-up. More advanced Lewy body pathology staging was associated with more nigral neuron loss, more so for males than females. More nigral neuron loss was associated with parkinsonism and clinical LBD diagnosis during follow-up, more so for males than females. Across the subgroup with dementia (40 females, 58 males), core LBD features at first visit with dementia were not associated with nigral neuron loss. Conclusions Nigral neuron loss’ association with Lewy body pathology staging and core LBD features can differ by sex. Compared to males, females with Lewy body pathology have a higher risk of underdiagnosis. There is a need to elucidate the mechanisms underlying sex differences for pathology and clinicopathological correlations to advance diagnostic and therapeutic efforts in LBD. Highlights Clinical and pathological correlates of nigral loss differ by sex in people with brainstem, limbic and neocortical Lewy body pathology from the NACC. Compared to males with similar age and Alzheimer’s co-pathology, females have less nigral loss at brainstem and limbic Lewy body pathology stages. Compared to males with similar age, Lewy body and Alzheimer’s pathology staging, nigral loss association with parkinsonism and Lewy body dementia phenotype is weaker in females. Clinical features at first visit with dementia may not be associated with underlying nigral loss. Parkinsonism during follow-up may suggest underlying nigral loss for males, but perhaps not as reliably for females. Plain English summary Lewy body dementia (LBD) is the third most common dementia associated with Lewy body pathology, Alzheimer’s pathology, and substantia nigra loss. It is often less recognized in females compared to males, because the typical symptoms are less evident in females. In this study, we investigated whether substantia nigra neuron loss plays a role in the atypical presentation of LBD in females, contributing to the underdiagnosis compared to males. We analyzed data from 159 females and 263 males with pathological Lewy body disease obtained from the National Alzheimer's Coordinating Center. Females tended to be older at the time of death and had more tau buildup, but similar levels of Lewy body pathology and substantia nigra neuron loss compared to males. When we compared males and females of similar age with similar levels of Alzheimer's pathology, we observed that females had less substantia nigra neuron loss at less advanced Lewy body pathology stages. Greater nigral neuron loss was associated with parkinsonism and the typical LBD symptoms in males, but not as strongly in females. The extent of nigral loss could not be predicted based on the clinical features at the time of dementia diagnosis. Thus, the relationship between nigral neuron loss and the LBD symptoms seems to vary by sex. Females with underlying Lewy body disease are more likely to be underdiagnosed compared to males. We need further work to understand why these sex differences exist and how we can better identify and treat LBD.

Introduction Clinicopathological correlations differ by sex in Lewy body dementia (LBD). However, previous studies have focused on pathological staging systems that place less emphasis on regional pathologies. Methods We included 357 people (131 female, 226 male) with a high likelihood of LBD based on pathology from the Brain Bank for Neurodegenerative (Jacksonville, FL). Sex differences for regional Lewy body, senile plaque, and neurofibrillary tangle counts and their associations with clinical LBD diagnosis were assessed. Results Females were less likely to have a clinical LBD diagnosis; they had more Lewy bodies, neurofibrillary tangles, and senile plaques in various regions than males (all p’s < 0.05). A higher likelihood of clinical LBD diagnosis was associated with more middle frontal, cingulate, and entorhinal Lewy body pathology, and more so for males than for females (all p’s < 0.045). Discussion Sex differences for clinicopathological correlations in LBD also occur at the regional pathology level. Females have a higher frequency of clinical misdiagnosis than males. Highlights Females have a higher risk of clinical underdiagnosis for Lewy body dementia (LBD) than males. Regional pathology counts differ by sex for people with a high likelihood of LBD. Regional pathology association with clinical LBD diagnosis differs by sex. Regional Lewy body counts have a stronger association with LBD phenotype for males.

Background People identifying as sexual and gender minorities (SGM) may have higher risk for subjective cognitive decline and Alzheimer’s disease, although the risk for Parkinson’s disease dementia (PDD) has not been investigated. Male sex is associated with a higher risk for PDD, it is unclear whether SGM status impacts the risk. Methods Data were obtained from Fox Insight on April 5th, 2023. The analysis included people (1) with adult‐onset Parkinson’s, (2) responding to questions on sex assigned at birth, gender identity, sexual orientation, (3) with at least one available Penn Parkinson’s Daily Activities Questionnaire‐15 (PDAQ‐15), (4) without dementia at baseline, based on the first PDAQ‐15 (>43). Groups consisted of people identifying as (1) SGM with female sex assigned at birth (SGM‐F, n = 75); (2) cisgender, heterosexual women (CHW, n = 2,046); (3) SGM with male sex assigned at birth (SGM‐M, n = 84); (4) cisgender, heterosexual men (CHM, n = 2,056). Sex assigned at birth and SGM status effects on dementia likelihood during follow‐up were assessed with generalized linear mixed models. Results Out of 159 people identifying as SGM, eight (5.0%) identified as gender minorities, 144 (90.6%) identified as sexual minorities, seven (4.4%) identified as both gender and sexual minorities. At baseline, people with female sex had better PDAQ‐15 scores than people with male sex assigned at birth; SGM‐M had the lowest scores. SGM‐M had a higher dementia likelihood compared to people not identifying as SGM. After adjusting for age, education, employment status, income, perceived discrimination level, age at Parkinson’s diagnosis, baseline PDAQ‐15 scores, that differed across groups at baseline, dementia likelihood was lower for CHW compared to people with male sex assigned at birth. Conclusions For PDD, SGM‐M can be at a higher risk than CHM; people with female sex can have a lower risk than people with male sex assigned at birth. Socioeconomic disadvantages can alter the sex effect on PDD risk, by putting SGM‐M at a higher risk and females at a similar risk level compared to people with male sex assigned at birth, as shown in unadjusted models. Socioeconomic disadvantages should be acknowledged and addressed to support the well‐being of SGM with Parkinson’s.

In people with Lewy body (LB) pathology, Alzheimer's (AD) co-pathology staging has stronger association with cognition for females, and LB pathology staging has stronger association with behavioral and motor symptoms for males. As APOEe4 allele is a risk factor for LB and AD pathologies, in both females and males; we investigated whether APOEe4 association with clinical profile and pathology staging differs by sex in people with LB pathology. Data were obtained from the National Alzheimer's Coordinating Center Uniform Data Set (UDS), Neuropathology and Genetic Data Set for UDS visits conducted between September 2005 and August 2019. 294 females and 490 males with available APOEe4 count data from 33 Alzheimer's Disease Research Centers, with brainstem, limbic or neocortical LB pathology were included, excluding those with other neuropathologic diagnoses. Interactions between sex and APOE ε4 count for pathology staging (LB, AD), clinical diagnosis (LB disease, AD), dementia likelihood and severity (CDR® Dementia Staging Instrument-Sum of Boxes), behavioral symptom severity (Neuropsychiatric Inventory Questionnaire) at last visit were assessed with linear models controlling for age. 40.5% of females, 40.8% of males had one APOEe4; 12.2% of females, 12.9% of males had two APOEe4 alleles (p = .95). Compared to males, females were older at last visit and died older. APOEe4 was not associated with LB pathology staging. Compared to males, APOEe4 was associated with higher level of AD pathology staging (B = 1.48 for females, B = 0.66 for males; p<.001); higher likelihood of AD clinical diagnosis (B = 1.30 for females, B = 0.49 for males; p<.001); lower likelihood of LB disease clinical diagnosis (B = -0.76 for females, B = -0.16, p<.001); higher likelihood for dementia (B = 1.76 for females, B = 1.21 for males; p<.001) and more severe dementia (B = 2.69 for females, B = 1.53 for males; p<.001) for females. Compared to females, APOEe4 was associated with more severe behavioral symptoms for males (B = 0.36 for females, B = 1.34 for males; p<.001). In people with LB pathology, APOEe4 is associated with AD co-pathology staging, clinical diagnosis, dementia likelihood, dementia and behavioral symptom severity. However, these associations can be different for females and males. Clinical and pathological associations of genetic factors can differ by sex in LB disease.

Background In people with Lewy body (LB) pathology, Alzheimer’s (AD) co‐pathology staging has stronger association with cognition for females, and LB pathology staging has stronger association with behavioral and motor symptoms for males. As APOEe4 allele is a risk factor for LB and AD pathologies, in both females and males; we investigated whether APOEe4 association with clinical profile and pathology staging differs by sex in people with LB pathology. Methods Data were obtained from the National Alzheimer’s Coordinating Center Uniform Data Set (UDS), Neuropathology and Genetic Data Set for UDS visits conducted between September 2005 and August 2019. 294 females and 490 males with available APOEe4 count data from 33 Alzheimer’s Disease Research Centers, with brainstem, limbic or neocortical LB pathology were included, excluding those with other neuropathologic diagnoses. Interactions between sex and APOE ε4 count for pathology staging (LB, AD), clinical diagnosis (LB disease, AD), dementia likelihood and severity (CDR® Dementia Staging Instrument‐Sum of Boxes), behavioral symptom severity (Neuropsychiatric Inventory Questionnaire) at last visit were assessed with linear models controlling for age. Results 40.5% of females, 40.8% of males had one APOEe4; 12.2% of females, 12.9% of males had two APOEe4 alleles (p = .95). Compared to males, females were older at last visit and died older. APOEe4 was not associated with LB pathology staging. Compared to males, APOEe4 was associated with higher level of AD pathology staging (B = 1.48 for females, B = 0.66 for males; p<.001); higher likelihood of AD clinical diagnosis (B = 1.30 for females, B = 0.49 for males; p<.001); lower likelihood of LB disease clinical diagnosis (B = ‐0.76 for females, B = ‐0.16, p<.001); higher likelihood for dementia (B = 1.76 for females, B = 1.21 for males; p<.001) and more severe dementia (B = 2.69 for females, B = 1.53 for males; p<.001) for females. Compared to females, APOEe4 was associated with more severe behavioral symptoms for males (B = 0.36 for females, B = 1.34 for males; p<.001). Conclusions In people with LB pathology, APOEe4 is associated with AD co‐pathology staging, clinical diagnosis, dementia likelihood, dementia and behavioral symptom severity. However, these associations can be different for females and males. Clinical and pathological associations of genetic factors can differ by sex in LB disease.

Sex influences the prevalence and symptoms of Lewy body dementia (LBD). However, genome-wide association studies typically focus on autosomal variants and exclude sex-specific risk factors. We addressed this gap by performing an X chromosome-wide association study using whole-genome sequence data from 2591 LBD cases and 4391 controls. We identified a significant risk locus within intron 1 of MAP3K15 (rs141773145, odds ratio = 2.42, 95% confidence interval = 1.65–3.56, p -value = 7.0 × 10 −6 ) in female LBD cases conditioned for APOE ε4 dosage. The locus includes an enhancer region that regulates MAP3K15 expression in ganglionic eminence cells derived from primary cultured neurospheres. Rare variant burden testing showed differential enrichment of missense mutations in TEX13A in female LBD cases, that did not reach significance ( p -value = 1.34 × 10 −4 ). These findings support the sex-specific effects of genetic factors and a potential role of Alzheimer’s-related risk for females with LBD.

Background Pathologic perivascular spaces (PVS), the fluid‐filled compartments surrounding brain vasculature, may underlie cognitive decline in Parkinson's disease (PD). However, whether this impacts specific cognitive domains has not been investigated. Objectives This study examined the relationship of PVS volume at baseline with domain‐specific and global cognitive change over 2 years in PD individuals. Methods A total of 39 individuals with PD underwent 3T T1w magnetic resonance imaging to determine PVS volume fraction (PVS volume normalized to total regional volume) within (i) centrum semiovale, (ii) prefrontal white matter (medial orbitofrontal, rostral middle frontal, and superior frontal), and (iii) basal ganglia. A neuropsychological battery included assessment of cognitive domains and global cognitive function at baseline and after 2 years. Results Higher basal ganglia PVS at baseline was associated with greater decline in attention, executive function, and global cognition scores. Conclusions While previous reports have associated elevated PVS volume in the basal ganglia with decline in global cognition in PD, our findings show such decline may affect the attention and executive function domains. PVS, recently recognized as underlying PD pathophysiology, have not been explored in their contribution to specific aspects of cognitive decline. We found that perivascular spaces in the basal ganglia at baseline are predictive of cognitive decline within the executive function and attention domains in PD individuals over 2 years.

Parkinson’s disease (PD), which is one of the most common neurodegenerative disorders, is a disorder that affects quality of life due to non-motor symptoms in addition to motor symptoms. The non-motor symptoms of this disease vary greatly and affect patients starting from early stages. These symptoms also include language deficits. Besides motor language disorders such as hypophonia and dysarthria, which are common in PD, deficits in morphosyntax, semantics, and understanding metaphors have been reported. Various studies have also shown deficits in action language in PD, in which the ability of action is affected. Although language deficits are thought to be caused by cognitive deficits in this disease, there are studies showing language deficits being independent of cognitive deficits. These language deficits in PD, caused by basal ganglia dysfunctions, may provide valuable information in determining brain areas related to language. In this review, we aimed to assess action language deficits in PD and to evaluate the location of action language in the brain in light of this disorder.

Objective: Akathisia is frequently seen as a drug side-effect. In Parkinson's disease (PD), it is relatively understudied. Moreover, few studies investigating akathisia differ concerning the assessment methods and prevalence rates, indicating a need for an objective approach. Our aim is to determine the prevalence of akathisia with an objective assessment tool and to investigate its relationship with neuropsychiatric symptoms and suicidal tendency. Materials and Methods: One-hundred-one patients with PD and 75 age-and sex-matched control subjects were enrolled. Patients and controls were compared in terms of the presence of akathisia. Further, patients with and without akathisia were compared with regard to disease stage, severity, peak dose dyskinesia, suicide probability, presence of anxiety, and depression using validated tools. Results: Akathisia was more frequent in patients with PD than in controls (6.9 vs. 0% p=0.02). Patients with akathisia scored worse in unified PD rating scalepart II (experiences of daily living) and reported anxiety and dyskinesia more frequently. The probability of suicidality was similar in patients with or without akathisia. Conclusion: Our findings reveal that akathisia is more frequent in patients with PD than controls, and is associated with anxiety.