Cognitive Progression Research Articles

Serum metabolites associated with brain amyloid beta deposition, cognition and dementia progression.

Metabolomics in the Alzheimer’s Disease Neuroimaging Initiative cohort provides a powerful tool for mapping biochemical changes in Alzheimer’s disease, and a unique opportunity to learn about the association between circulating blood metabolites and brain amyloid-β deposition in Alzheimer’s disease. We examined 140 serum metabolites and their associations with brain amyloid-β deposition, cognition and conversion from mild cognitive impairment to Alzheimer’s disease in the Alzheimer’s Disease Neuroimaging Initiative. Processed [18F] Florbetapir PET images were used to perform a voxel-wise statistical analysis of the effect of metabolite levels on amyloid-β accumulation across the whole brain. We performed a multivariable regression analysis using age, sex, body mass index, apolipoprotein E ε4 status and study phase as covariates. We identified nine metabolites as significantly associated with amyloid-β deposition after multiple comparison correction. Higher levels of one acylcarnitine (C3; propionylcarnitine) and one biogenic amine (kynurenine) were associated with decreased amyloid-β accumulation and higher memory scores. However, higher levels of seven phosphatidylcholines (lysoPC a C18:2, PC aa C42:0, PC ae C42:3, PC ae C44:3, PC ae C44:4, PC ae C44:5 and PC ae C44:6) were associated with increased brain amyloid-β deposition. In addition, higher levels of PC ae C44:4 were significantly associated with lower memory and executive function scores and conversion from mild cognitive impairment to Alzheimer’s disease dementia. Our findings suggest that dysregulation of peripheral phosphatidylcholine metabolism is associated with earlier pathological changes noted in Alzheimer’s disease as measured by brain amyloid-β deposition as well as later clinical features including changes in memory and executive functioning. Perturbations in phosphatidylcholine metabolism may point to issues with membrane restructuring leading to the accumulation of amyloid-β in the brain. Additional studies are needed to explore whether these metabolites play a causal role in the pathogenesis of Alzheimer’s disease or if they are biomarkers for systemic changes during preclinical phases of the disease.

Clinical progression of progressive supranuclear palsy: impact of trials bias and phenotype variants.

Progressive supranuclear palsy causes diverse clinical presentations, including classical Richardson’s syndrome and several variant phenotypes. Clinical trials of disease-modifying therapies have recently been completed, with more planned for the next 2 years. However, many people with progressive supranuclear palsy do not meet eligibility criteria for these clinical trials. Understanding clinical progression with different phenotypes would improve trial design and enhance the accuracy of risk–benefit and cost–benefit assessments of new treatments for progressive supranuclear palsy. We set out to determine rates of motor and cognitive progression of possible, probable and definite progressive supranuclear palsy, with different phenotypes, from a representative cohort in a regional UK healthcare service. Longitudinal clinical data from people with Richardson’s syndrome and variant phenotypes were analysed using linear mixed-modelling, using both the full and modified versions of the Progressive Supranuclear Palsy Rating Scale, Mini-Mental State Examination and the revised Addenbrooke’s Cognitive Examination. Subgroup analyses considered patients meeting recent Phase II trial entry criteria and patients with neuropathological confirmation. Two hundred and twenty-seven patients [male = 59%, mean age (±standard deviation), 71.8 (±7.0) years] were followed for a mean 21.6 (±15.6) months. One hundred and seventy-four (77%) had Richardson’s syndrome at the outset, 25 had cortical variant presentations (13%, frontal, corticobasal, speech and language variants) and 28 had subcortical variant presentations (14%, parkinsonism, postural instability and gait freezing variants). Across all participants, annual progression in Richardson’s syndrome was faster than variant phenotypes on the Mini-Mental State Examination (−1.8 versus −0.9/year, P = 0.005) and revised Addenbrooke’s Cognitive Examination (−5.3 versus −3.0/year, P = 0.01) but not the Progressive Supranuclear Palsy Rating Scale (9.0 versus 7.1/year, P = 0.2) nor the modified Progressive Supranuclear Palsy Rating Scale (2.7 versus 2.3/year, P = 0.4). However, for those with more than 1 years’ follow-up, a significant difference was observed between Richardson’s syndrome and variant phenotypes in Progressive Supranuclear Palsy Rating Scale (8.7 versus 6.3/year, P = 0.04). Survival was longer in variant phenotypes than Richardson’s syndrome [7.3 (±3.9) versus 5.6 (±2.0) years, P = 0.02]. Pathologically confirmed cases (n = 49) supported these findings. Patients meeting basic trial-eligibility criteria (n = 129) progressed faster on the Progressive Supranuclear Palsy Rating Scale than trial-not-eligible patients (10.1 versus 6.1/year, P = 0.001). In conclusion, phenotypes other than Richardson’s syndrome show slower progression and longer survival. Trial criteria do not select representative progressive supranuclear palsy cases. This has implications for trial design, and application of trial results to clinically more diverse patient populations.

Asymmetric Dopamine Transporter Loss Affects Cognitive and Motor Progression in Parkinson's Disease.

ABSTRACTBackgroundAsymmetric hemispheric loss of dopaminergic neurons is one of the characteristic features of Parkinson's disease (PD). However, it is still debated if right or left asymmetry differently affects cognitive and motor progression.ObjectivesThe objective of this study was to investigate, for the first time, the relevance of dopamine transporter (DAT) asymmetry on cognitive and motor manifestations at onset and at 4‐year progression in drug‐naïve PD.MethodsFrom the Parkinson's Progression Markers Initiative multicenter cohort, we identified 249 right‐handed patients with PD with baseline asymmetry greater than 20% in putamen DAT binding at single‐photon emission computed tomography. A predominant putamen asymmetry was found on the left in 143 patients (PD‐left), and on the right side in 106 patients (PD‐right); we compared them with 196 healthy controls. Patients were followed longitudinally (2‐year and 4‐year visits), examining their clinical, cognitive, and imaging data.ResultsAt baseline, the PD‐left group showed worse performance on the Symbol Digit Modality Test, an attention and processing‐speed test, and lower cerebrospinal fluid β‐amyloid levels than the PD‐right group. These differences were maintained at follow‐up, declining over time in both groups. By contrast, the PD‐right group showed greater motor impairment at baseline, which increased over 4 years. Striatal DAT binding decreased over time in both groups, but the PD‐right group showed a steeper decline, particularly during the first 2‐year follow‐up. Putaminal asymmetry assessed at baseline was maintained over time.ConclusionsThese findings suggest that hemispheric asymmetric dopaminergic denervation influences PD cognitive and motor performance as well as progression. Predominant right hemisphere nigrostriatal dopaminergic loss is associated with greater motor severity, whereas more pronounced left hemisphere denervation affects cognitive manifestations at onset and their progression. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson's disease.

A key driver of patients’ well-being and clinical trials for Parkinson’s disease (PD) is the course disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia (PDD), a major determinant for quality of life, we performed a genome-wide survival study (GWSS) of 11.2 million variants in 3,821 PD patients over 31,053 longitudinal visits. We discover and replicate RIMS2 as a progression locus (P = 2.78 × 10−11; hazard ratio (HR) = 4.77), identify suggestive evidence for TMEM108 (HR = 2.86, P = 2.09 × 10−8) and WWOX (HR = 2.12, P = 2.37 × 10−8), and confirm associations for GBA (HR = 1.93, P = 0.0002) and APOE (HR = 1.48, P = 0.001). Polygenic progression scores exhibit a substantial aggregate association with dementia risk, while polygenic susceptibility scores are not predictive. This study identifies a novel synaptic locus and polygenic score for cognitive disease progression in PD and proposes diverging genetic architectures of progression and susceptibility.

Progranulin Enhances Memory in Normal Aging and Alzheimer's Disease Mice

Progranulin is a lysosomal and secreted protein that has neurotrophic properties and promotes neurite outgrowth in vitro. Mutations in the progranulin gene have been found to cause frontotemporal dementia. Additionally, reduced progranulin levels may be a risk factor for the development of Alzheimer's disease (AD). Studies in mouse models of AD support this notion: reducing progranulin exacerbates disease progression whereas increasing progranulin confers protection. However, the physiologic function of progranulin in the CNS is not known. We tested the effects of CNS-administered progranulin in the cognition in young male CD-1 mice, (3-months of age), old C57/BL male mice (24 months of age), 3xTG-AD male and female mice (13 months of age) and SAMP8 mice (12 months of age). Immediately following T maze foot shock avoidance training, CD-1 mice (n = 10 per group) were injected intracerebroventricularly (ICV) with progranulin (0, 0.005, 0.1 or 1.0 ug/2 ul). C57/BL 24 month old (n= 8~9/group) and the 13 month old 3xTG-AD mice (n = 8~9/group), were given either 0 or 1.0 ug/2 ul immediately after training. The 12 month old SAMP8 mice (n = 10~11/group) were given 0, 0.1 or 1.0 ug/2ul. Retention was assessed one week after training. The number of trails to reach a criterion of 5 avoidances in 6 consecutive trails was determined. Following behavioral testing, cortex, hippocampus, and plasma were harvested. CD-1 mice that received and an ICV injection of progranulin 0.1 and 1.0 ug/2 ul had significantly improved retention in T-maze than the mice which receive vehicle. These mice took significantly fewer trials to make an avoidance than the mice which received 0 ug/2 ul. Progranulin at 1.0 ug/2 ul improved retention in the 24 month old C57/BL mice, the 13 month old 3xTG-AD mice Progranulin at 0.1 and 1.0 ug/2ul improve retention in the 12 month old SAMP8 mice. It is becoming increasingly apparent that progranulin is involved in memory dysfunction. We found that progranulin has a direct influence on memory consolidation as its administration following foot shock avoidance training leads to improved memory retention. Our studies suggest that progranulin can directly modulate memory in both cognitively normal and AD mice, indicating that is has an important role not only in the pathogenesis of frontotemporal dementia, but in normal aged-related cognitive decline and AD progression as well.

Serum Neurofilament Dynamics Predicts Cognitive Progression in de novo Parkinson's Disease.

Neurofilament light (NfL) can reflect the extent of neuron/axon damage, thus providing an opportunity to examine the severity and progression of the diseases with such damage. Whether serum NfL can be used as an indicator to monitor the cognitive progress of de novo Parkinson's disease (PD) remains unclear. In this research, 144 healthy controls and 301 de novo PD patients from Parkinson's Progression Markers Initiative (PPMI) were recruited. Linear mixed effects models were used to examine the associations of baseline/longitudinal serum NfL with cognitive decline. Cox regression was used to detect cognitive progression in PD participants. We found PD patients had higher serum NfL than controls at baseline (p = 0.031), and NfL increase was faster in PD group (p < 0.001). Both baseline serum NfL and its rate of change predicted measurable cognitive decline in early PD (MoCA, β= -0.014, p < 0.001; β= -0.002, p < 0.001, respectively). Additionally, we observed that NfL levels were also able to predict progression in different diagnostic groups and Amyloid- PD and Amyloid+PD groups. After an average follow-up of 6.37±1.84 years, the baseline NfL of the third tertile of high concentrations was associated with a future high risk of PD dementia (adjusted HR 6.33, 95% CI 2.62-15.29, p < 0.001). In conclusion, our results indicated that the serum NfL concentration could function as an easily accessible biomarker to monitor the severity and progression of cognitive decline in PD.

Progression to Dementia in Mild Cognitive Impairment With Lewy Bodies or Alzheimer Disease.

ObjectiveTo determine whether mild cognitive impairment with Lewy bodies or mild cognitive impairment with Alzheimer disease differ in their rates of clinical progression to dementia, we undertook longitudinal observation of mild cognitive impairment cases with detailed clinical assessment of Lewy body diagnostic characteristics.MethodsTwo prospective longitudinal cohorts including 111 individuals ≥60 years of age with mild cognitive impairment were assessed annually to track cognitive and clinical progression, including the presence or absence of core clinical features and proposed biomarkers of dementia with Lewy bodies. Multistate modeling was used to assess the associations of diagnostic characteristics of dementia with Lewy bodies with clinical progression from mild cognitive impairment to dementia, with death as a competing outcome.ResultsAfter a mean follow-up of 2.2 years (range 1–6.7 years), 38 of the 111 (34%) participants progressed to dementia: 10 with AD, 3 with possible dementia with Lewy bodies, and 25 with probable dementia with Lewy bodies. The presence of any Lewy body disease characteristic was associated with an increased hazard of transition to dementia; this risk further increased as more diagnostic characteristics were observed (hazard ratio 1.33 per characteristic, 95% confidence interval [CI] 1.11–1.60) and was especially high for those experiencing complex visual hallucinations (hazard ratio 1.98, 95% CI 0.92–4.29) or cognitive fluctuations (hazard ratio 3.99, 95% CI 2.03–7.84).ConclusionsDiagnostic characteristics of Lewy body disease are associated with an increased risk of transition from mild cognitive impairment to dementia.

The role of APOE in cognitive trajectories and motor decline in Parkinson\u2019s disease

We aimed to investigate the role of the APOE genotype in cognitive and motor trajectories in Parkinson’s disease (PD). Using PD registry data, we retrospectively investigated a total of 253 patients with PD who underwent the Mini-Mental State Exam (MMSE) two or more times at least 5 years apart, were aged over 40 years, and free of dementia at the time of enrollment. We performed group-based trajectory modeling to identify patterns of cognitive change using the MMSE. Kaplan–Meier survival analysis was used to investigate the role of the APOE genotype in cognitive and motor progression. Trajectory analysis divided patients into four groups: early fast decline, fast decline, gradual decline, and stable groups with annual MMSE scores decline of − 2.8, − 1.8, − 0.6, and − 0.1 points per year, respectively. The frequency of APOE ε4 was higher in patients in the early fast decline and fast decline groups (50.0%) than those in the stable group (20.1%) (p = 0.007). APOE ε4, in addition to older age at onset, depressive mood, and higher H&Y stage, was associated with the cognitive decline rate, but no APOE genotype was associated with motor progression. APOE genotype could be used to predict the cognitive trajectory in PD.

Psychiatric symptoms in huntington’s disease

Introduction Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder, that typically manifests in adulthood, clinically characterized by progressive motor, cognitive and psychiatric/behavioural symptoms. Psychiatric symptoms are common in HD. The presentation of these symptoms is highly variable, and their course does not correlate with motor or cognitive disease progression. Psychiatric symptoms often precede motor onset by many years.ObjectivesThe authors intend to review the literature the most frequent psychiatric disorders in patients with HD.MethodsNon-systematic review of the literature.ResultsPsychiatric symptoms have been a core feature of HD. Pre-symptomatic HD patients exhibit a greater prevalence of psychiatric symptoms, particularly affective disorders. This symptoms are presenting symptoms of HD in up to half of all people. In symptomatic HD patients, it is estimated that up to 73–98% of patients will have a major psychiatric disorder or psychiatric symptoms. Psychiatric manifestations in HD include depression, irritability, apathy, anxiety, mania, perseverations, obsessions and psychosis. Cognitive changes include progressive deficits in attention, learning, executive and sensory functions, resulting in dementia. Depression, diagnosed in half of patients with HD, is the most common and earliest symptoms prior to the motor onset. There are likely multiple causes of the psychiatric symptoms, with underlying factors including a combination of neurobiological, cognitive, psychological, social and environmental factors.ConclusionsPatients with HD have high psychiatric comorbidity, that causes significant functional impairment and affect quality of life. Thus, they require a multidisciplinary approach in the recognition and treatment of psychiatric symptoms.

Reshaping the path of vascular cognitive impairment with resistance training: a study protocol for a randomized controlled trial

BackgroundSubcortical ischemic vascular cognitive impairment (SIVCI) is the most common form of vascular cognitive impairment. Importantly, SIVCI is considered the most treatable form of cognitive impairment in older adults, due to its modifiable risk factors such as hypertension, diabetes mellitus, and hypercholesterolemia. Exercise training is a promising intervention to delay the progression of SIVCI, as it actively targets these cardiometabolic risk factors. Despite the demonstrated benefits of resistance training on cognitive function and emerging evidence suggesting resistance training may reduce the progression of white matter hyperintensities (WMHs), research on SIVCI has predominantly focused on the use of aerobic exercise. Thus, the primary aim of this proof-of-concept randomized controlled trial is to investigate the efficacy of a 12-month, twice-weekly progressive resistance training program on cognitive function and WMH progression in adults with SIVCI. We will also assess the efficiency of the intervention.MethodsEighty-eight community-dwelling adults, aged > 55 years, with SIVCI from metropolitan Vancouver will be recruited to participate in this study. SIVCI will be determined by the presence of cognitive impairment (Montreal Cognitive Assessment < 26) and cerebral small vessel disease using computed tomography or magnetic resonance imaging. Participants will be randomly allocated to a twice-weekly exercise program of (1) progressive resistance training or (2) balance and tone training (i.e., active control). The primary outcomes are cognitive function measured by the Alzheimer’s Disease Assessment Scale-Cognitive-Plus (ADAS-Cog-13 with additional cognitive tests) and WMH progression.DiscussionThe burden of SIVCI is immense, and to our knowledge, this will be the first study to quantify the effect of progressive resistance training on cognitive function and WMH progression among adults with SIVCI. Slowing the rate of cognitive decline and WMH progression could preserve functional independence and quality of life. This could lead to reduced health care costs and avoidance of early institutional care.Trial registrationClinicalTrials.gov NCT02669394. Registered on February 1, 2016

Advances in computerized MRI‐based biomarkers in Alzheimer’s disease

The use of neuroimaging examinations is crucial in Alzheimer’s disease (AD), in both research and clinical settings. Over the years, magnetic resonance imaging (MRI)–based computer‐aided diagnosis has been shown to be helpful for early screening and predicting cognitive decline. Meanwhile, an increasing number of studies have adopted machine learning for the classification of AD, with promising results. In this review article, we focus on computerized MRI‐based biomarkers of AD by reviewing representative studies that used computerized techniques to identify AD patients and predict cognitive progression. We categorized these studies based on the following applications: (1) identifying AD from normal control; (2) identifying AD from other dementia types, including vascular dementia, dementia with Lewy bodies, and frontotemporal dementia; and (3) predicting conversion from NC to mild cognitive impairment (MCI) and from MCI to AD. This systematic review could act as a state‐of‐the‐art overview of this emerging field as well as a basis for designing future studies.

Functional Connectomics and Disease Progression in Drug-Naïve Parkinson's Disease Patients.

Functional brain connectivity alterations may be detectable even before the occurrence of brain atrophy, indicating their potential as early markers of pathological processes. We aimed to determine the whole-brain network topologic organization of the functional connectome in a large cohort of drug-naïve Parkinson's disease (PD) patients using resting-state functional magnetic resonance imaging and to explore whether baseline connectivity changes may predict clinical progression. One hundred and forty-seven drug-naïve, cognitively unimpaired PD patients were enrolled in the study at baseline and compared to 38 age- and gender-matched controls. Non-hierarchical cluster analysis using motor and non-motor data was applied to stratify PD patients into two subtypes: 77 early/mild and 70 early/severe. Graph theory analysis and connectomics were used to assess global and local topological network properties and regional functional connectivity at baseline. Stepwise multivariate regression analysis investigated whether baseline functional imaging data were predictors of clinical progression over 2 years. At baseline, widespread functional connectivity abnormalities were detected in the basal ganglia, sensorimotor, frontal, and occipital networks in PD patients compared to controls. Decreased regional functional connectivity involving mostly striato-frontal, temporal, occipital, and limbic connections differentiated early/mild from early/severe PD patients. Connectivity changes were found to be independent predictors of cognitive progression at 2-year follow-up. Our findings revealed that functional reorganization of the brain connectome occurs early in PD and underlies crucial involvement of striatal projections. Connectomic measures may be helpful to identify a specific PD patient subtype, characterized by severe motor and non-motor clinical burden as well as widespread functional connectivity abnormalities. © 2021 International Parkinson and Movement Disorder Society.

Euglycemia Indicates Favorable Motor Outcome in Parkinson's Disease

The interplay between glycemic control and Parkinson's disease (PD) has long been recognized but not fully understood. To investigate the association of glycated hemoglobin (HbA1c) levels with motor and cognitive symptom progression in a prospective PD cohort. Of 244 PD patients, 17 had low HbA1c (≤30 mmol/mol), 184 were euglycemic (HbA1c 31-41 mmol/mol), 18 had high HbA1c (HbA1 ≥42 mmol/mol), and 25 had diabetes mellitus (DM). Survival analysis was applied on time until Hoehn and Yahr stage ≥3 (motor outcome) and until mild cognitive impairment. Low HbA1c (HR 2.7; 95% CI 1.3-6; P = 0.01) as well as high HbA1c (HR 3.6; 95% CI 1.5-8.9; P = 0.005) but not DM were independent predictors of unfavorable motor outcome. Both high and low HbA1c levels may be associated with motor symptom progression in PD; however, further studies are needed to confirm these findings and increase understanding regarding causality. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

CSF dynamics as a predictor of cognitive progression

Disproportionately enlarged subarachnoid-space hydrocephalus (DESH), characterized by tight high convexity CSF spaces, ventriculomegaly, and enlarged Sylvian fissures, is thought to be an indirect marker of a CSF dynamics disorder. The clinical significance of DESH with regard to cognitive decline in a community setting is not yet well defined. The goal of this work is to determine if DESH is associated with cognitive decline. Participants in the population-based Mayo Clinic Study of Aging (MCSA) who met the following criteria were included: age ≥ 65 years, 3T MRI, and diagnosis of cognitively unimpaired or mild cognitive impairment at enrollment as well as at least one follow-up visit with cognitive testing. A support vector machine based method to detect the DESH imaging features on T1-weighted MRI was used to calculate a “DESH score”, with positive scores indicating a more DESH-like imaging pattern. For the participants who were cognitively unimpaired at enrollment, a Cox proportional hazards model was fit with time defined as years from enrollment to first diagnosis of mild cognitive impairment or dementia, or as years to last known cognitively unimpaired diagnosis for those who did not progress. Linear mixed effects models were fit among all participants to estimate annual change in cognitive z scores for each domain (memory, attention, language, and visuospatial) and a global z score. For all models, covariates included age, sex, education, APOE genotype, cortical thickness, white matter hyperintensity volume, and total intracranial volume. The hazard of progression to cognitive impairment was an estimated 12% greater for a DESH score of +1 versus −1 (HR 1.12, 95% CI 0.97–1.31, p = 0.11). Global and attention cognition declined 0.015 (95% CI 0.005–0.025) and 0.016 (95% CI 0.005–0.028) z/year more, respectively, for a DESH score of +1 vs −1 (p = 0.01 and p = 0.02), with similar, though not statistically significant DESH effects in the other cognitive domains. Imaging features of disordered CSF dynamics are an independent predictor of subsequent cognitive decline in the MCSA, among other well-known factors including age, cortical thickness, and APOE status. Therefore, since DESH contributes to cognitive decline and is present in the general population, identifying individuals with DESH features may be important clinically as well as for selection in clinical trials.

Data-driven FDG-PET subtypes of Alzheimer\u2019s disease-related neurodegeneration

BackgroundPrevious research has described distinct subtypes of Alzheimer’s disease (AD) based on the differences in regional patterns of brain atrophy on MRI. We conducted a data-driven exploration of distinct AD neurodegeneration subtypes using FDG-PET as a sensitive molecular imaging marker of neurodegenerative processes.MethodsHierarchical clustering of voxel-wise FDG-PET data from 177 amyloid-positive patients with AD dementia enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) was used to identify distinct hypometabolic subtypes of AD, which were then further characterized with respect to clinical and biomarker characteristics. We then classified FDG-PET scans of 217 amyloid-positive patients with mild cognitive impairment (“prodromal AD”) according to the identified subtypes and studied their domain-specific cognitive trajectories and progression to dementia over a follow-up interval of up to 72 months.ResultsThree main hypometabolic subtypes were identified: (i) “typical” (48.6%), showing a classic posterior temporo-parietal hypometabolic pattern; (ii) “limbic-predominant” (44.6%), characterized by old age and a memory-predominant cognitive profile; and (iii) a relatively rare “cortical-predominant” subtype (6.8%) characterized by younger age and more severe executive dysfunction. Subtypes classified in the prodromal AD sample demonstrated similar subtype characteristics as in the AD dementia sample and further showed differential courses of cognitive decline.ConclusionsThese findings complement recent research efforts on MRI-based identification of distinct AD atrophy subtypes and may provide a potentially more sensitive molecular imaging tool for early detection and characterization of AD-related neurodegeneration variants at prodromal disease stages.

Association of lipid levels with motor and cognitive function and decline in advanced Parkinson's disease in the Mark-PD study

ObjectivesIn prospective cohort studies different blood lipid fractions have been identified as risk factors of Parkinson's disease (PD). However, data relating lipoproteins to disease phenotypes and progression in advanced PD patients are sparse. Therefore, we assessed the most common lipoproteins in a case-control design and evaluated their associations with motor and cognitive function and decline in PD patients. MethodsTriglycerides, LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), and lipoprotein a (Lp(a)) were analyzed in 294 PD patients of the MARK-PD study cohort and 588 controls matched for age, sex and cardiovascular risk factors. In PD patients, motor (MDS-UPDRS III, Hoehn-Yahr stage) and cognitive function (MoCA) were examined. In a sub-cohort (n = 98 patients), baseline lipid levels were correlated with motor and cognitive disease progression during a follow-up period of 523 ± 199 days. ResultsAt baseline, HDL-C levels were lower in PD patients compared to matched controls after adjustment. We observed a very weak association of Lp(a) levels with UDPRS III scores. In cross-sectional analyses, no other lipid fraction revealed a significant and consistent association with motor or cognitive function. During follow-up, no lipid fraction level was associated with motor or cognitive progression. ConclusionIn advanced PD, there is no strong and consistent association of lipid levels with motor or cognitive function and decline.

Embelin ameliorates cognitive dysfunction and progression of kindling in pentylenetetrazol-induced kindling in mice by attenuating brain inflammation

ObjectiveThis study was conducted to evaluate the effect of embelin (EMB) on various epileptic models and related brain inflammation. MethodsMale Swiss albino mice were administered EMB (5, 10, and 20 mg/kg/p.o.) in acute and chronic study for 7 days and 35 days, respectively. Acute study included increasing current electroshock (ICES) and pentylenetetrazol (PTZ)-induced seizure test. Step-down latency (SDL) and forced swim test (FST) were performed to evaluate cognitive functions and depression-like behavior, respectively. Chronic study included PTZ-induced kindling. Levels of inflammatory biomarkers, namely interleukin-1 beta (IL-1β), interleukin-1 receptor antagonist (IL-1Ra), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), were estimated in the hippocampus and cortex of the kindled brains by ELISA technique. Further, neurotransmitters (NTs), namely gamma aminobutyric acid (GABA), glutamate, and dopamine, were estimated by using validated liquid chromatography–mass spectrometry (LC–MS) method followed by ultra-high-performance liquid chromatography (UHPLC). ResultsEmbelin (EMB) treatment increased the seizure threshold to hind limb extension (HLE) in the ICES test and decreased the seizure scores in the kindling experiment. Significantly low levels of IL-1β, IL-1Ra, IL-6, and TNF-α were observed in the hippocampus of PTZ + EMB (10 and 20 mg/kg)-treated groups compared with PTZ+ vehicle-treated group. Significantly lower levels of IL-1Ra, IL-6, and TNF-α compared with PTZ+ vehicle-treated group were observed in the cortex of PTZ + EMB (10 and 20 mg/kg)-treated groups, while IL-1β levels were found to be significantly lower only in the cortex of PTZ + EMB (20 mg/kg)-treated group. Increased levels of dopamine and GABA and decreased levels of glutamate in both hippocampus and cortex were observed in EMB + PTZ-treated groups compared with vehicle + PTZ-treated group. Latency of step down was found to be increased and immobility time in FST was decreased in EMB + PTZ groups compared with vehicle + PTZ group. ConclusionEmbelin suppressed epileptogenesis in the kindled mice via neurochemical modulation of neurotransmitters and inhibiting the inflammatory pathway. Further, EMB was also observed to be protecting the kindled animals from cognition and depression-like behavior.

Associations of Vascular Risk with Cognition, Brain Glucose Metabolism, and Clinical Progression in Cognitively Intact Elders.

Increasing evidence supports an important role of vascular risk in cognitive decline and dementia. This study aimed to examine whether vascular risk was associated with cognitive decline, cerebral hypometabolism, and clinical progression in cognitively intact elders. Vascular risk was assessed by the Framingham Heart Study general Cardiovascular disease (FHS-CVD) risk score. The cross-sectional and longitudinal associations of FHS-CVD risk score with cognition and brain glucose metabolism were explored using multivariate linear regression and linear mixed effects models, respectively. The risk of clinical progression conversion was assessed using Kaplan-Meier survival curves and multivariate Cox proportional hazard models. A total of 491 cognitively intact elders were included from Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Participants with high FHS-CVD risk scores had lower baseline Mini-Mental State Examination (MMSE) (p = 0.009), executive function (EF) (p < 0.001), memory function (MEM) (p < 0.001) scores, and F18-fluorodeoxyglucose positron emission tomography (FDG-PET) uptake (p < 0.001) than those with low FHS-CVD risk scores. In longitudinal analyses, individuals with higher FHS-CVD risk scores had greater longitudinal declines in MMSE (p = 0.043), EF (p = 0.029) scores, and FDG-PET uptake (p = 0.035). Besides, individuals with a higher vascular risk had an increased risk of clinical progression (p = 0.004). These findings indicated effects of vascular risk on cognitive decline, cerebral hypometabolism, and clinical progression. Early detection and management of vascular risk factors might be useful in the prevention of dementia.

Olfactory-cognitive index distinguishes involvement of frontal lobe shrinkage, as in sarcopenia from shrinkage of medial temporal areas, and global brain, as in Kihon Checklist frailty/dependence, in older adults with progression of normal cognition to Alzheimer's disease.

AimOlfactory impairment as a prodromal symptom, as well as sarcopenia, frailty and dependence as geriatric syndromes, is often associated with cognitive decline in older adults with progression of Alzheimer's disease. The present study aimed to evaluate the associations of olfactory and cognitive decline with these geriatric syndromes, and with structural changes of the brain in older adults.MethodsThe participants were 135 older adults (47 men and 88 women, mean age 79.5 years), consisting of 64 with normal cognition, 23 with mild cognitive impairment and 48 with Alzheimer's disease. Olfactory function was evaluated by the Open Essence odor identification test. Shrinkage of the regional brain was determined by magnetic resonance imaging.ResultsLogistic regression analysis with Open Essence, Mini‐Mental State Examination, age and sex as covariates showed higher olfactory‐cognitive index (|coefficient for Open Essence (a) / coefficient for Mini‐Mental State Examination (b)|) in participants with sarcopenia (Asia Working Group for Sarcopenia), and lower values of (|a/b|) in participants with Barthel Index dependence, Kihon Checklist frailty, Lawton Index dependence and support/care‐need certification as objective variables. Logistic regression analysis adjusted by age and sex also showed significant shrinkage of the frontal lobe in participants with AWGS sarcopenia, especially in women, and shrinkage of the medial temporal areas and global brain in participants with Kihon Checklist frailty/dependence.ConclusionsOlfactory‐cognitive index (|a/b|) might be a useful tool to distinguish involvement of frontal lobe shrinkage, as in sarcopenia from shrinkage of the medial temporal areas, and global brain, as in frailty/dependence, in older adults with progression of normal cognition to Alzheimer's disease. Geriatr Gerontol Int 2021; ••: ••–••.

Modifiable, Non-Modifiable, and Clinical Factors Associated with Progression of Alzheimer's Disease.

There is an extensive literature relating to factors associated with the development of Alzheimer's disease (AD), but less is known about factors which may contribute to its progression. This review examined the literature with regard to 15 factors which were suggested by PubMed search to be positively associated with the cognitive and/or neuropathological progression of AD. The factors were grouped as potentially modifiable (vascular risk factors, comorbidities, malnutrition, educational level, inflammation, and oxidative stress), non-modifiable (age at clinical onset, family history of dementia, gender, Apolipoprotein E ɛ4, genetic variants, and altered gene regulation), and clinical (baseline cognitive level, neuropsychiatric symptoms, and extrapyramidal signs). Although conflicting results were found for the majority of factors, a positive association was found in nearly all studies which investigated the relationship of six factors to AD progression: malnutrition, genetic variants, altered gene regulation, baseline cognitive level, neuropsychiatric symptoms, and extrapyramidal signs. Whether these or other factors which have been suggested to be associated with AD progression actually influence the rate of decline of AD patients is unclear. Therapeutic approaches which include addressing of modifiable factors associated with AD progression should be considered.