RESUMEN
Objective: Cognitive decline in Parkinson disease (PD) is a disabling and highly variable non-motor feature. While cholinergic systems degeneration is linked to cognitive impairments in PD, most prior research reported cross-sectional associations. We aimed to fill this gap by investigating whether baseline regional cerebral vesicular acetylcholine transporter ligand [ 18 F]-fluoroethoxybenzovesamicol ([ 18 F]-FEOBV) binding predicts longitudinal cognitive changes in mild to moderate, non-demented PD subjects. Methods: Seventy-five non-demented, mild-moderate PD subjects received baseline standardized cognitive evaluations and [ 18 F]-FEOBV PET imaging with repeat cognitive evaluations 2 years later. Participants were classified into four cognitive classes based on stability or change in cognition: Persistent normal (no MCI at baseline and follow-up), Persistent MCI, MCI conversion, and MCI reversion. Whole-brain voxel comparisons with normal controls, and voxel-based and cluster volume-of-interest correlation analyses with longitudinal cognitive changes were performed. Results: Whole-brain voxel comparisons of each class with a matched control group revealed unique bi-directional differences in baseline regional [ 18 F]-FEOBV binding. Increased regional [ 18 F]-FEOBV binding in predominantly anterior cortical and sub-cortical regions was found in the persistent normal and MCI reversion groups. Whole-brain voxel correlation analysis between baseline [ 18 F]-FEOBV binding and two-year longitudinal percent changes in cognition identified a specific regional pattern of reduced posterior cortical, limbic and paralimbic [ 18 F]-FEOBV binding predictive of global cognitive declines and across five cognitive domains at two-year follow-ups. Interpretation: Cholinergic system changes correlate with varying cognitive trajectories in mild-moderate PD. Upregulation of cholinergic neurotransmission may be an important compensatory process in mild-moderate PD.
RESUMEN
INTRODUCTION: A recently developed mild behavioral impairment (MBI) diagnostic framework standardizes the early characterization of neuropsychiatric symptoms in older adults. However, the links between MBI, brain function, and Alzheimer's disease (AD) biomarkers are unclear. METHODS: Using data from 128 participants with diagnosis of amnestic mild cognitive impairment and mild dementia - Alzheimer's type, we test a novel model assessing direct relationships between AD biomarker status and MBI symptoms, as well as mediated effects through segregation of the salience and default-mode networks. RESULTS: We identified a mediated effect of tau positivity on MBI through functional segregation of the salience network from the other high-level, association networks. There were no direct effects of AD biomarkers status on MBI. DISCUSSION: Our findings suggest an indirect role of tau pathology in MBI through brain network dysfunction and emphasize the role of the salience network in mediating relationships between neuropathological changes and behavioral manifestations.
RESUMEN
We review the epidemiologic literature on potential protective and risk factors in Parkinson's Disease (PD). Prior research identified numerous possible protective and risk factors. Potential protective factors include tobacco abuse, physical activity, urate levels, NSAID use, calcium channel blocker use, statin use, and use of some α1-adrenergic antagonists. Some potential protective factors could be products of reverse causation, including increased serum urate, tobacco abuse, and coffee-tea-caffeine consumption. Potential risk factors include traumatic brain injury, pesticide exposure, organic solvent exposure, lead exposure, air pollution, Type 2 Diabetes, some dairy products, cardiovascular disease, and some infections including Hepatitis C, H. pylori, and COVID-19. Potential non-environmental risk factors include bipolar disorder, essential tremor, bullous pemphigoid, and inflammatory bowel disease. There is an inverse relationship with PD and risk of most cancers. Though many potential protective and risk factors for PD were identified, research has not yet led to unique, rigorous prevention trials or successful disease-modifying interventions. While efforts to reduce exposure to some industrial toxicants are well justified, PD incidence might be most effectively reduced by mitigation of risks, such as Type 2 Diabetes, air pollution, traumatic brain injury, or physical inactivity, that are general public health intervention targets.
Asunto(s)
Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/prevención & control , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/epidemiología , Factores de Riesgo , Factores Protectores , COVID-19/prevención & controlRESUMEN
Background: Social engagement has beneficial effects during cognitive aging. Large-scale cognitive brain network functions are implicated in both social behaviors and cognition. Objective: We evaluated associations between functional connectivity (FC) of large-scale brain cognitive networks and social engagement, characterized by self-reported social network size and contact frequency. We subsequently tested large-scale brain network FC as a potential mediator of the beneficial relationship between social engagement and cognitive performance. Methods: 112 older adults (70.7±7.3 years, range 54.6-89.7; 84 women) completed the Lubben Social Network Scale 6 (LSNS-6), National Alzheimer's Coordinating Center (NACC) Uniform Data Set 3 (UDS-3) cognitive battery, and resting state fMRI. We completed seed-based correlational analysis in the default mode and salience networks. Significant associations between social engagement scores and cognitive performance, as well as between social engagement and FC of brain networks, informed the construction of mediation models. Results: Social engagement was significantly associated with executive function and global cognition, with greater social engagement associated with better cognitive performance. Social engagement was significantly associated with salience network FC, with greater social engagement associated with higher connectivity. Salience network FC partially mediated associations between social engagement and both executive function and global cognition. Conclusions: Our results suggest that the salience network is a key mediator of the beneficial relationship between social engagement and cognition in older adults.
RESUMEN
We review the descriptive epidemiology of Parkinson disease (PD). PD is a prevalent neurologic disorder in high Socio-Demographic Index (SDI) nations with rising prevalence in low and middle SDI nations. PD became a prevalent disorder in high SDI nations during the 20th century. Population growth, population aging, and increased disease duration are major drivers of rising PD prevalence. Exposure to industrial toxicants may also be a contributor to rising PD prevalence. PD is an age-related disorder with incidence likely peaking in the 8th decade of life and prevalence in the 9th decade of life. PD is notable for significant sex difference in PD risk with greater risk in men. There may be ancestral differences in PD prevalence and risk. PD is associated with moderately increased mortality though this may be underestimated. Despite significant research, there is considerable uncertainty about basic features of PD epidemiology.
Asunto(s)
Enfermedad de Parkinson , Humanos , Masculino , Femenino , Enfermedad de Parkinson/epidemiología , Prevalencia , Incidencia , Caracteres SexualesRESUMEN
The most common genetic risk factors for Parkinson's disease are GBA1 mutations, encoding the lysosomal enzyme glucocerebrosidase. Patients with GBA1 mutations (GBA-PD) exhibit earlier age of onset and faster disease progression with more severe cognitive impairments, postural instability and gait problems. These GBA-PD features suggest more severe cholinergic system pathologies. PET imaging with the vesicular acetylcholine transporter ligand 18F-F-fluoroethoxybenzovesamicol (18F-FEOBV PET) provides the opportunity to investigate cholinergic changes and their relationship to clinical features in GBA-PD. The study investigated 123 newly diagnosed, treatment-naïve Parkinson's disease subjects-with confirmed presynaptic dopaminergic deficits on PET imaging. Whole-gene GBA1 sequencing of saliva samples was performed to evaluate GBA1 variants. Patients underwent extensive neuropsychological assessment of all cognitive domains, motor evaluation with the Unified Parkinson's Disease Rating Scale, brain MRI, dopaminergic PET to measure striatal-to-occipital ratios of the putamen and 18F-FEOBV PET. We investigated differences in regional cholinergic innervation between GBA-PD carriers and non-GBA1 mutation carriers (non-GBA-PD), using voxel-wise and volume of interest-based approaches. The degree of overlap between t-maps from two-sample t-test models was quantified using the Dice similarity coefficient. Seventeen (13.8%) subjects had a GBA1 mutation. No significant differences were found in clinical features and dopaminergic ratios between GBA-PD and non-GBA-PD at diagnosis. Lower 18F-FEOBV binding was found in both the GBA-PD and non-GBA-PD groups compared to controls. Dice (P < 0.05, cluster size 100) showed good overlap (0.7326) between the GBA-PD and non-GBA-PD maps. GBA-PD patients showed more widespread reduction in 18F-FEOBV binding than non-GBA-PD when compared to controls in occipital, parietal, temporal and frontal cortices (P < 0.05, FDR-corrected). In volume of interest analyses (Bonferroni corrected), the left parahippocampal gyrus was more affected in GBA-PD. De novo GBA-PD show a distinct topography of regional cholinergic terminal ligand binding. Although the Parkinson's disease groups were not distinguishable clinically, in comparison to healthy controls, GBA-PD showed more extensive cholinergic denervation compared to non-GBA-PD. A larger group is needed to validate these findings. Our results suggest that de novo GBA-PD and non-GBA-PD show differential patterns of cholinergic system changes before clinical phenotypic differences between carriers versus non-carrier groups are observable.
Asunto(s)
Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/genética , Glucosilceramidasa/genética , Ligandos , Marcha , Cuerpo Estriado , DopaminaRESUMEN
BACKGROUND AND OBJECTIVES: Social isolation is a risk factor for cognitive decline and dementia. We conducted a randomized controlled clinical trial (RCT) of enhanced social interactions, hypothesizing that conversational interactions can stimulate brain functions among socially isolated older adults without dementia. We report topline results of this multisite RCT (Internet-based conversational engagement clinical trial [I-CONECT]; NCT02871921). RESEARCH DESIGN AND METHODS: The experimental group received cognitively stimulating semistructured conversations with trained interviewers via internet/webcam 4 times per week for 6 months (induction) and twice per week for an additional 6 months (maintenance). The experimental and control groups both received weekly 10 minutes telephone check-ins. Protocol modifications were required due to the coronavirus disease 2019 pandemic. RESULTS: A total of 186 participants were randomized. After the induction period, the experimental group had higher global cognitive test scores (Montreal Cognitive Assessment [primary outcome]; 1.75 points [pâ =â .03]) compared with the control group. After induction, experimental group participants with normal cognition had higher language-based executive function (semantic fluency test [secondary outcome]; 2.56 points [pâ =â .03]). At the end of the maintenance period, the experimental group of mild cognitive impairment subjects had higher encoding function (Craft Story immediate recall test [secondary outcome]; 2.19 points [pâ =â .04]). Measure of emotional well-being improved in both control and experimental groups. Resting-state functional magnetic resonance imaging showed that the experimental group had increased connectivity within the dorsal attention network relative to the control group (pâ =â .02), but the sample size was limited. DISCUSSION AND IMPLICATIONS: Providing frequent stimulating conversational interactions via the internet could be an effective home-based dementia risk-reduction strategy against social isolation and cognitive decline. CLINICAL TRIALS REGISTRATION NUMBER: NCT02871921.
Asunto(s)
Disfunción Cognitiva , Demencia , Humanos , Anciano , Disfunción Cognitiva/psicología , Cognición , Función EjecutivaRESUMEN
BACKGROUND: Impaired movement vigor (bradykinesia) is a cardinal feature of Parkinson's disease (PD) and hypothesized to result from abnormal motivational processes-impaired motivation-vigor coupling. Dopamine replacement therapy (DRT) improves bradykinesia, but the response to DRT is multifaceted, comprising a short-duration response (SDR) and a long-duration response (LDR) only manifesting with chronic treatment. Prior experiments assessing motivation-vigor coupling in PD used chronically treated subjects, obscuring the roles of the SDR and LDR. METHODS: To disambiguate the SDR and LDR, 11 de novo PD subjects (6 male [M]:5 female [F]; mean age, 67) were studied before treatment, after an acute levodopa (l-dopa) dose, and in both the practical "off" (LDR) and "on" (LDR + SDR) states after chronic stable treatment. At each visit, subjects were characterized with a standard battery including the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and an incentivized joystick task to assess motor performance in response to varying rewards. RESULTS: l-Dopa induced a robust SDR and LDR, with further improvement in the combined SDR + LDR state. At baseline, after acute treatment (SDR), and after LDR induction, subjects did not exhibit the normal increase in movement speed with increasing reward. Only in the combined SDR + LDR state was there restoration of motivation-vigor coupling. CONCLUSIONS: Although consistent with prior results in chronically treated PD subjects, the significant improvement in motor performance observed with the SDR and LDR suggests that bradykinesia is not solely secondary to deficient modulation of motivational processes. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Asunto(s)
Levodopa , Enfermedad de Parkinson , Masculino , Humanos , Femenino , Anciano , Levodopa/farmacología , Levodopa/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Hipocinesia , Motivación , Movimiento , Dopamina/farmacología , Antiparkinsonianos/uso terapéutico , Antiparkinsonianos/farmacologíaRESUMEN
INTRODUCTION: We investigated associations of Alzheimer's disease (AD) serum biomarkers with longitudinal changes in cognitive function from mid- to late life among women. METHODS: The study population included 192 women with the median age of 53.3 years at baseline, from the Study of Women's Health Across the Nation Michigan Cohort, followed up over 14 years. Associations between baseline serum amyloid ß (Aß)42, the Aß42/40 ratio, phosphorylated tau181 (p-tau181), and total tau with longitudinal changes in cognition were evaluated using linear mixed effects models. RESULTS: After adjusting for confounders, lower Aß42/40 ratios were associated with faster declines in the Digit Span Backward Test. Higher p-tau181 also showed a borderline statistically significant association with more rapid decline in the Symbol Digit Modalities Test. DISCUSSION: Our findings suggest that mid-life serum AD biomarkers could be associated with accelerated cognitive decline from mid- to late life in women. Future studies with larger samples are needed to validate and extend our findings. HIGHLIGHTS: This study investigates midlife serum AD biomarkers on longitudinal cognitive function changes in women. Mid-life serum AD biomarkers are associated with accelerated cognitive decline. A decrease in the Aß42/40 ratio was associated with a faster decline in the DSB score. A higher p-tau181 concentration was associated with a faster decline in the SDMT score.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Femenino , Persona de Mediana Edad , Enfermedad de Alzheimer/epidemiología , Péptidos beta-Amiloides , Proteínas tau , Cognición , BiomarcadoresRESUMEN
Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in non-European ancestry groups in genome-wide association studies (GWAS). We constructed and analyzed a multi-ancestry GWAS dataset in the Alzheimer's Disease (AD) Genetics Consortium (ADGC) to test for novel shared and ancestry-specific AD susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6,728 African American, 8,899 Hispanic (HIS), and 3,232 East Asian individuals, performing within-ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. We identified 13 loci with cross-ancestry associations including known loci at/near CR1 , BIN1 , TREM2 , CD2AP , PTK2B , CLU , SHARPIN , MS4A6A , PICALM , ABCA7 , APOE and two novel loci not previously reported at 11p12 ( LRRC4C ) and 12q24.13 ( LHX5-AS1 ). Reflecting the power of diverse ancestry in GWAS, we observed the SHARPIN locus using 7.1% the sample size of the original discovering single-ancestry GWAS (n=788,989). We additionally identified three GWS ancestry-specific loci at/near ( PTPRK ( P =2.4×10 -8 ) and GRB14 ( P =1.7×10 -8 ) in HIS), and KIAA0825 ( P =2.9×10 -8 in NHW). Pathway analysis implicated multiple amyloid regulation pathways (strongest with P adjusted =1.6×10 -4 ) and the classical complement pathway ( P adjusted =1.3×10 -3 ). Genes at/near our novel loci have known roles in neuronal development ( LRRC4C, LHX5-AS1 , and PTPRK ) and insulin receptor activity regulation ( GRB14 ). These findings provide compelling support for using traditionally-underrepresented populations for gene discovery, even with smaller sample sizes.
RESUMEN
Lecanemab, a novel amyloid-sequestering agent, recently received accelerated Food and Drug Administration approval for the treatment of mild dementia due to Alzheimer disease (AD) and mild cognitive impairment (MCI). Approval was based on a large phase 3 trial, Clarity, which demonstrated reductions in amyloid plaque burden and cognitive decline with lecanemab. Three major concerns should give us pause before adopting this medication: Its beneficial effects are small, its harms are substantial, and its potential costs are unprecedented. Although lecanemab has a clear and statistically significant effect on cognition, its effect size is small and may not be clinically significant. The magnitude of lecanemab's cognitive effect is smaller than independent estimates of the minimally important clinical difference, implying that the effect may be imperceptible to a majority of patients and caregivers. Lecanemab's cognitive effects were numerically smaller than the effect of cholinesterase inhibitors and may be much smaller. The main argument in lecanemab's favor is that it may lead to greater cognitive benefit over time. Although plausible, there is a lack of evidence to support this conclusion. Lecanemab's harms are substantial. In Clarity, it caused symptomatic brain edema in 11% and symptomatic intracranial bleeding in 0.5% of participants. These estimates likely significantly underestimate these risks in general practice for 3 reasons: (1) Lecanemab likely interacts with other medications that increase bleeding, an effect minimized in Clarity. (2) The Clarity population is much younger than the real-world population with mild AD dementia and MCI (age 71 years vs 85 years) and bleeding risk increases with age. (3) Bleeding rates in trials are typically much lower than in clinical practice. Lecanemab's costs are unprecedented. Its proposed price of $26,500 is based on cost-effectiveness analyses with tenuous assumptions. However, even if cost-effective, it is likely to result in higher expenditures than any other medication. If its entire target population were treated, the aggregate medication expenditures would be $120 billion US dollars per year-more than is currently spent on all medications in Medicare Part D. Before adopting lecanemab, we need to know that lecanemab is not less effective, vastly more harmful, and 100× more costly than donepezil.
Asunto(s)
Enfermedad de Alzheimer , Anticuerpos Monoclonales Humanizados , Demencia , Anciano , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/epidemiología , Donepezilo/uso terapéutico , Medicare , Estados Unidos , Anticuerpos Monoclonales Humanizados/uso terapéuticoRESUMEN
There are conflicting results regarding regional age-related changes in serotonin terminal density in human brain. Some imaging studies suggest age-related declines in serotoninergic terminals and perikarya. Other human imaging studies and post-mortem biochemical studies suggest stable brain regional serotoninergic terminal densities across the adult lifespan. In this cross-sectional study, we used [11C]3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile positron emission tomography to quantify brain regional serotonin transporter density in 46 normal subjects, ranging from 25 to 84 years of age. Both voxel-based analyses, using sex as a covariate, and volume-of-interest-based analyses were performed. Both analyses revealed age-related declines in [11C]3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile binding in numerous brain regions, including several neocortical regions, striatum, amygdala, thalamus, dorsal raphe, and other subcortical regions. Similar to some other neurotransmitter systems of subcortical origin, we found evidence of age-related declines in regional serotonin terminal density in both cortical and subcortical regions.
RESUMEN
We investigated the complex relations of socioeconomic status (SES) and healthy lifestyles with cognitive functions among older adults in 1313 participants, aged 60 years and older, from the National Health and Nutrition Examination Survey 2011-2014. Cognitive function was measured using an average of the standardized z-scores of the Consortium to Establish a Registry for Alzheimer's Disease Word Learning and delayed recall tests, the Animal Fluency Test, and the Digit Symbol Substitution Test. Latent class analysis of family income, education, occupation, health insurance, and food security was used to define composite SES (low, medium, high). A healthy lifestyle score was calculated based on smoking, alcohol consumption, physical activity, and the Healthy-Eating-Index-2015. In survey-weighted multivariable linear regressions, participants with 3 or 4 healthy behaviors had 0.07 (95% CI 0.005, 0.14) standard deviation higher composite cognitive z-score, relative to those with one or no healthy behavior. Participants with high SES had 0.37 (95% CI 0.29, 0.46) standard deviation higher composite cognitive z-score than those with low SES. No statistically significant interaction was observed between healthy lifestyle score and SES. Our findings suggested that higher healthy lifestyle scores and higher SES were associated with better cognitive function among older adults in the United States.
Asunto(s)
Cognición , Conductas Relacionadas con la Salud , Animales , Encuestas Nutricionales , Estatus Socioeconómico Bajo , Consumo de Bebidas AlcohólicasRESUMEN
Background: There is increasing interest in therapeutic ketosis as a potential therapy for neurodegenerative disorders-in particular, mild cognitive impairment (MCI), Alzheimer's disease (AD), and Parkinson's disease (PD)-following a proof-of-concept study in Parkinson's disease published in 2005. Methods: To provide an objective assessment of emerging clinical evidence and targeted recommendations for future research, we reviewed clinical trials involving ketogenic interventions in mild cognitive impairment, Alzheimer's disease, and Parkinson's disease reported since 2005. Levels of clinical evidence were systematically reviewed using the American Academy of Neurology criteria for rating therapeutic trials. Results: 10 AD, 3 MCI, and 5 PD therapeutic ketogenic trials were identified. Respective grades of clinical evidence were objectively assessed using the American Academy of Neurology criteria for rating therapeutic trials. We found class "B" evidence (probably effective) for cognitive improvement in subjects with mild cognitive impairment and subjects with mild-to-moderate Alzheimer's disease negative for the apolipoprotein ε4 allele (APOε4-). We found class "U" evidence (unproven) for cognitive stabilization in individuals with mild-to-moderate Alzheimer's disease positive for the apolipoprotein ε4 allele (APOε4+). We found class "C" evidence (possibly effective) for improvement of non-motor features and class "U" evidence (unproven) for motor features in individuals with Parkinson's disease. The number of trials in Parkinson's disease is very small with best evidence that acute supplementation holds promise for improving exercise endurance. Conclusions: Limitations of the literature to date include the range of ketogenic interventions currently assessed in the literature (i.e., primarily diet or medium-chain triglyceride interventions), with fewer studies using more potent formulations (e.g., exogenous ketone esters). Collectively, the strongest evidence to date exists for cognitive improvement in individuals with mild cognitive impairment and in individuals with mild-to-moderate Alzheimer's disease negative for the apolipoprotein ε4 allele. Larger-scale, pivotal trials are justified in these populations. Further research is required to optimize the utilization of ketogenic interventions in differing clinical contexts and to better characterize the response to therapeutic ketosis in patients who are positive for the apolipoprotein ε4 allele, as modified interventions may be necessary.