Normal Cognitive Decline Research Articles

Longitudinal Variations in Retinal and Neuronal Degeneration in Cognitively Normal Older Adults using Peripapillary Optical Coherence Tomography Angiography

AbstractBackgroundDespite an aging population, it remains challenging to reliably differentiate between loss of cognitive function associated with normal aging and cognitive decline associated with pathologic processes. With growing interest in using retinal and optic nerve biomarkers to diagnose neurodegenerative diseases, characterization of the velocity of normal retinal age‐related changes will further our understanding. We evaluated longitudinal microvascular changes in cognitively normal older adults using optical coherence tomography (OCT) and OCT angiography (OCTA).MethodsParticipants over 50 years old without history of neurodegenerative disease or cognitive impairment were enrolled. Exclusion criteria included retinal/optic nerve pathology, glaucoma, and diabetes, among others. The Zeiss Cirrus HD‐OCT 5000 with AngioPlex was used to obtain OCT and OCTA images at baseline and two years later. OCTA parameters measured were optic nerve head‐centered capillary perfusion density (CPD) and capillary flux index (CFI). OCT was used to measure retinal nerve fiber layer (RNFL) thickness. Generalized estimating equations were used to account for measurements obtained from two eyes of the same subject.Results189 eyes of 111 cognitively normal older adults were analyzed (average age at baseline, 69.3 ± 5.8; average Mini‐Mental State Examination score, 29.54 ± 0.71; 86 women [77.5%]). Average follow up was 2.1 ± 0.5 years. After controlling for sex, CPD (p<.001), CFI (p<.001), and RNFL thickness (p=0.005) decreased with increasing age at both cross‐sectional time points. Over the follow‐up period, rate of change in CPD, CFI, and RNFL thickness was not significantly correlated with age; however, rate of change in CPD (p=.038) and RNFL thickness (p=0.008) was slower in females compared to males. Average CPD was higher among females at both time points compared to males (p=.002), with no significant differences in CFI and RNFL thickness.ConclusionsIn cognitively normal adults, there is a significant reduction in peripapillary CPD, CFI, and RNFL thickness associated with aging beyond 50 years old. Females had higher CPD values with slower rates of change in CPD and RNFL thickness. With prior studies documenting microvascular alterations associated with Alzheimer’s disease, these values provide benchmarks of normal aging and help detect accelerated rates of decline in neurodegenerative diseases.

Novel microglial markers that are specifically increased in early clinical AD stages

AbstractBackgroundTranscriptomic and pathological studies indicate that microglia play a key role in the progression of Alzheimer’s disease (AD). Throughout the stages of the AD continuum, there may be varying microglia phenotypes, such as the disease‐associated microglia (DAM). Microglia proteins have been detected in cerebrospinal‐fluid (CSF), providing a quantifiable avenue for potential stage‐detection. This study aims to find CSF microglial biomarkers to stage early‐ versus late‐AD.MethodIn total, 637 proteins were measured with proximity extension assay in 564 samples from the Amsterdam Dementia Cohort and from University of Pennsylvania. We defined four clinical groups spanning the AD continuum, as follows: 1) cognitively normal or subjective cognitive decline with negative AD‐ratio of CSF t‐tau/amyloid‐beta42 as controls, and positive AD‐ratio 2) subjective cognitive decline, 3) mild cognitive impairment, and 4) AD‐dementia. We selected 176 microglia‐enriched proteins based on human‐derived single‐cell RNA‐sequencing data and compared the groups by ANCOVA and Tukey’s HSD. Functional characterisation was done by associating proteins of interest to a list of microglial markers per state, such as DAM‐like proteins, that were identified through single‐cell Hierarchical Poisson Factorization.ResultsOverall, proteins showed distinct wave‐like patterns of dysregulation, presented in figure 1. 21 of the 176 microglial proteins were specifically upregulated in the early stages, while 20 were specific to the dementia stage. The proteins increased specifically in early stages consisted of receptors, possibly reflecting increased cellular recruitment, with an increase in DAM‐like proteins, particularly ones associated to MHC class II binding, such as CD4 and CD74, which are related to adaptive innate immune response.ConclusionIn conclusion, we identify varying microglial protein signatures spanning the AD stages, which may provide a basis for early‐staging biomarkers. Independent cohort and cross‐method validations are ongoing, and are necessary for the understanding of the hypothesized dynamicity of AD inflammation driven by microglia.

Post-COVID cognitive impairments: targets of neuropsychological rehabilitation

BACKGROUND: At the moment, a large number of scientific studies are devoted to the topic of post-COVID cognitive disorders, as well as to the study of the neurological and psychiatric consequences of COVID-19. However, the issues of describing the cognitive profile that is pathognomonic for a post-COVID patient, as well as the treatment and neurocorrection of emerging disorders are considered extremely rarely. AIM: The aim of this study is to compile a cognitive profile of a post-COVID patient and identify targets for neuropsychological rehabilitation. MATERIALS AND METHODS: A complete neuropsychological examination was carried out on 50 patients who had suffered moderate or mild COVID-19 no more than six months ago from the time of research. Used: MoCA test, clock drawing test, verbal association technique, FAB, G. Head test, test for understanding comparative constructions, “barrel and box” test, symbol-numeric coding test, asthenia rating scale (MFI-20), Hospital scale anxiety and depression. RESULTS: According to the results of screening scales, patients scored borderline between normal and mild (subjective) cognitive decline. No impairments in operational auditory-verbal and visual memory were detected. Low performance in the symbolic-numeric coding technique was revealed, combined with a deterioration in the understanding of logical-grammatical structures. These same scales have a direct correlation with the general level of cognitive integrity. High rates of anxiety and asthenia and low rates of depression were revealed. CONCLUSIONS: This cohort of patients was found to have mild cognitive deficits. A decrease in neurodynamic parameters and a violation of quasi-spatial concepts come to the fore. There are high rates of anxiety and asthenia with the leading mental component of asthenia, against the background of preserved motivation and low rates of depression. The targets of neurocorrection for these patients are: stability of attention, fluency of speech, speed of thinking, quasi-spatial concepts.

Correlations between plasma markers and brain Aβ deposition across the AD continuum: Evidence from SILCODE.

Previous studies have found that Alzheimer's disease (AD)-related plasma markers are associated with amyloid beta (Aβ) deposition, but the change of this association in different Aβ pathological stages remains unclear. Data were obtained from the SILCODE. According to the standardized uptake value ratio (SUVR) and Aβ stage classification, correlation analysis was performed among plasma biomarkers, and voxel/SUVR values in the regions of interest (ROI) and clinical scale information, respectively. Mediation analysis was used to study the possible pathways. The proportion of cognitively normal (CN) and subjective cognitive decline (SCD) was the highest in stages A0 to 1, while in stages A2 to 4, the proportion of mild cognitive impairment (MCI) and AD increased. Plasma phosphorylated tau (p-tau)181 and glial fibrillary acidic protein (GFAP) levels were significantly lower in stage A0 compared to the later phases. Two pathways demonstrated fully mediated effects: positron emission tomography (PET) SUVR-plasma p-tau181-Mini-Mental State Examination (MMSE) and PET SUVR-plasma GFAP-MMSE. This study demonstrated the role of plasma biomarkers in the early stage of AD, especially in SCD, from both the clinical diagnosis and Aβ stage dimensions. Plasma ptau181 and GFAP level serve as indicators of early Alzheimer's disease and the pathologic Aβ staging classification. A possible ceiling effect of GFAP was observed in the mid-to-late stages of the AD course. This study confirms the role of AD plasma markers in promoting Aβ deposition at an early stage, particularly in females with subjective cognitive decline(SCD). The overlapping brain regions of plasma p-tau181, GFAP, and neurofilament light for Aβ deposition in the brain in early AD were distributed across various regions, including the posterior cingulate gyrus, rectus gyrus, and inferior temporal gyrus.

Large-scale coupling of prefrontal activity patterns as a mechanism for cognitive control in health and disease: evidence from rodent models.

Cognitive control of behavior is crucial for well-being, as allows subject to adapt to changing environments in a goal-directed way. Changes in cognitive control of behavior is observed during cognitive decline in elderly and in pathological mental conditions. Therefore, the recovery of cognitive control may provide a reliable preventive and therapeutic strategy. However, its neural basis is not completely understood. Cognitive control is supported by the prefrontal cortex, structure that integrates relevant information for the appropriate organization of behavior. At neurophysiological level, it is suggested that cognitive control is supported by local and large-scale synchronization of oscillatory activity patterns and neural spiking activity between the prefrontal cortex and distributed neural networks. In this review, we focus mainly on rodent models approaching the neuronal origin of these prefrontal patterns, and the cognitive and behavioral relevance of its coordination with distributed brain systems. We also examine the relationship between cognitive control and neural activity patterns in the prefrontal cortex, and its role in normal cognitive decline and pathological mental conditions. Finally, based on these body of evidence, we propose a common mechanism that may underlie the impaired cognitive control of behavior.

Bartonella spp. infection in people with Mild Cognitive Impairment: A pilot study.

Mild Cognitive Impairment (MCI) is a neurological disorder at the transition between normal cognitive decline and dementia. Despite the potential role of neuroinflammation in the pathogenesis of MCI, infectious triggers remain mostly unknown. Infection with Bartonella spp., a zoonotic bacterium, has recently been associated with diffuse neurological and psychiatric symptoms. Given the preferential endothelial localization of Bartonella spp. and the role of vascular changes in neurocognitive decline, we hypothesized that there is an association between Bartonella spp. infection and pathologically accelerated decline in cognitive function in aging. To test this hypothesis, we collected serological and molecular markers of past and present Bartonella spp. infection in a sample of older people with and without MCI. Samples were processed in a blinded way to exclude laboratory biases. Contrary to our hypothesis, people with MCI were not more likely than people without MCI to have an active Bartonella spp. infection as measured by droplet digital PCR (p = 0.735) and quantitative PCR (p = 1). In addition, there was no significant difference in positive serological results between cases and controls (p = 0.461). Overall, higher-than-expected active Bartonella spp. infection (37% by ddPCR) and seroreactivity (71% by indirect fluorescent antibody assay) were found in people without MCI. Conclusions require caution, as our study was limited by the small number of cases with MCI. Overall, our results identified a higher than previously recognized rate of exposure and infection with Bartonella spp. in this older study population but does not support a specific role for such infection in MCI.

NMR analysis seeking for cognitive decline and dementia metabolic markers in plasma from aged individuals.

BackgroundBlood biomarkers can improve the ability to diagnose dementia, providing new information to better understand the pathophysiology and causes of the disease. Some studies with patients have already shown changes in metabolic profiles among patients with pathological cognitive decline or Alzheimer's disease, when compared to individuals with normal cognition. MethodsTo search for new metabolic biomarkers of dementia, we analyzed serum levels of several metabolites, measured by nuclear magnetic resonance spectroscopy, in elderly individuals, a group with normal cognitive decline (control), and three other groups with cognitive decline. pathological (low, moderate, and severe). ResultsDecreased plasma levels of tyrosine, glutamate, valine, leucine, and isoleucine are associated with worsening of pathological cognitive decline. However, the area under analysis of receptor operating characteristics suggests that tyrosine and glutamate have low specificity and sensitivity. Valine, leucine, and isoleucine are influenced by blood glucose or diabetes, but these conditions do not seem to be of great influence in the differences observed. Isobutyrate, histidine, acetone and unknown-1 metabolite also decrease their plasma levels with increasing CD. Isobutyrate ad histidine could have neuroprotective and antioxidant actions, respectively. To elucidate the role of decreased unknown metabolite-1 as a CD biomarker, it will be necessary to previously investigate its identity. To define and elucidate the role of acetone in pathological CD, additional laboratory and clinical studies must be performed. All these metabolites together may constitute a set of biomarkers with capability to identify pathological CD or dementia. Significance and noveltyDecrease of glutamate, tyrosine, valine, leucine, isoleucine, histidine, isobutyrate, acetone and unknown-1 metabolite together are a set of biomarkers able to identify pathological CD or dementia. Histidine, isobutyrate, acetone and unknown-1 metabolite are more specific biomarkers of CD.

Analysis of Mobile Device Dual Tasking on the Move: Normal Cognitive Decline of Aging as Ground Truth for Mild Cognitive Impairment

The widespread use of mobile phones in daily life makes them a fundamental tool for the study of human behavior. In particular, they can be used as a source of additional information to help to diagnose diseases. This work is based on contrasted dual-tasking tests where cognitive performance is studied by performing tasks of high cognitive load while walking. In this case, we study significant differences in mobile device use among groups of people of different ages and examine whether they are more characteristic when the interaction takes place on the move. A study is conducted by monitoring the interaction with the mobile device for one consecutive week and analyzing the correlations between these interactions and the participants’ ages. Additionally, a user profiling model is designed to help to use this ground truth in future works focused on the early diagnosis of cognitive deficits. The results obtained contribute to preliminarily characterizing how age-related normotypical cognitive decline affects interactions with mobile devices. In addition, the pilot study generates a dataset with monitored events and interactions of 45 users that includes more than 4.5 million records.

Cognitive training based on functional near-infrared spectroscopy neurofeedback for the elderly with mild cognitive impairment: a preliminary study.

Mild cognitive impairment (MCI) is often described as an intermediate stage of the normal cognitive decline associated with aging and dementia. There is a growing interest in various non-pharmacological interventions for MCI to delay the onset and inhibit the progressive deterioration of daily life functions. Previous studies suggest that cognitive training (CT) contributes to the restoration of working memory and that the brain-computer-interface technique can be applied to elicit a more effective treatment response. However, these techniques have certain limitations. Thus, in this preliminary study, we applied the neurofeedback paradigm during CT to increase the working memory function of patients with MCI. Near-infrared spectroscopy (NIRS) was used to provide neurofeedback by measuring the changes in oxygenated hemoglobin in the prefrontal cortex. Thirteen elderly MCI patients who received CT-neurofeedback sessions four times on the left dorsolateral prefrontal cortex (dlPFC) once a week were recruited as participants. Compared with pre-intervention, the activity of the targeted brain region increased when the participants first engaged in the training; after 4 weeks of training, oxygen saturation was significantly decreased in the left dlPFC. The participants demonstrated significantly improved working memory compared with pre-intervention and decreased activity significantly correlated with improved cognitive performance. Our results suggest that the applications for evaluating brain-computer interfaces can aid in elucidation of the subjective mental workload that may create additional or decreased task workloads due to CT.

Glymphatic function plays a protective role in ageing-related cognitive decline

Abstract Objective The glymphatic pathway, characterised as a cerebral drainage system, influences cognitive function in neurodegenerative diseases; however, evidence is limited in a normal ageing population. The aim of this study was to investigate the effect of glymphatic function on ageing-related cognitive decline. Methods We retrospectively reviewed the Cognitive Impairment, Retinopathy, and Cerebrovascular Lesions in the Elderly (CIRCLE) study, and participants with multi-model magnetic resonance imaging (MRI) scans and Mini-Mental State Examinations (MMSE) were enrolled. Glymphatic function was evaluated via the diffusion tensor imaging along the perivascular space (DTI-ALPS) index. Regression models were used to estimate the impact of the DTI-ALPS index on cognitive decline cross-sectionally and longitudinally. We further analysed the mediation effect of the DTI-ALPS on age and cognitive function. Results A total of 633 participants were included in this study (48.2% female; mean age, 62.8 ± 8.9 years). The DTI-ALPS index was positively associated with cognitive function cross-sectionally (β = 0.108, P = 0.003), and was an independent protective factor for cognitive decline longitudinally (odds ratio (OR) = 0.029, P = 0.007). The DTI-ALPS index declined progressively with ageing (r = −0.319, P <0.001), and the decrease was more pronounced after 65 years of age. Furthermore, the DTI-ALPS index mediated the relationship between age and MMSE score (β = −0.016, P <0.001). The mediation effect accounted for 21.3%, which was higher in subjects aged over 65 years (25.3%) compared with those aged under 65 years (5.3%). Conclusion Glymphatic function played a protective role in normal ageing-related cognitive decline, which may serve as a potential therapeutic target against cognitive decline in future.

Association of N-nitrosodimethylamine exposure with cognitive impairment based on the clues of mice and humans.

N-nitrosodimethylamine (NDMA) is an environmental and food contaminant, but limited data to concern whether NDMA has adverse effects on the brain. This study first determined the concentration of NDMA in foods from aquaculture markets in Shenzhen, then analyzed the effects on C57BL/6 mice and further evaluated on the urine samples of elderly Chinese residents with normal cognition (NC, n = 144), cognitive decline (CD, n = 116) and mild cognitive impairment (MCI, n = 123). The excessive rate of NDMA in foods was 3.32% (27/813), with a exceeding range of 4.78-131.00 μg/kg. Behavioral tests showed that 60 days treatment of mice with 3 mg/kg NDMA reduced cognitive performance. Cognitive impairment in human was significantly associated with sex, educational levels, length of residence in Shenzhen, household registration, passive smoking, rice, fresh vegetables, bacon products. NDMA was detected in 55.4% (212/383) of urine samples, with a median concentration of 0.23 μg/L (1.20 × 10 -7-157.39 μg/L). The median concentration for NC, CD and MCI were 0.32, 0.27, and 0 μg/L, respectively. The urinary NDMA concentration had a strong negative correlation with cognitive impairment (Kendall's Tau-b = -0.89, P = 0.024). The median estimated daily intake (EDI) of NDMA was determined to be 6.63 ng/kg-bw/day. Taken together, there appears to be an association between NDMA and human and murine cognition, which provides a new clue to Alzheimer's disease (AD).

COGNITIVE FUNCTION AND INDEPENDENCE IN THE OLDEST-OLD: REVIEW STUDY BASED ON AGING IN PLACE

Some older adults desire to continue living in the community in which they reside. The concept of Aging in Place (AIP) is appropriate for this idea. For AIP to be successful, the oldest-old need to demonstrate their abilities and live safely, independently, and comfortably in their homes and communities. Conversely, AIP in an inappropriate manner, without a safe environment, and without support provided, comprising dangerous situations caused by declining cognitive and physical function, lead to reduced quality of life for older people. Therefore, this study aimed to examine cognitive function in the oldest-old to understand differences between normal aging and cognitive decline due to dementia. Cognitive decline due to normal aging in the oldest-old is caused by impaired frontal lobe function, while decline due to Alzheimer’s disease is caused by impaired temporal-parietal lobe function, suggesting that this impairment may be useful for achieving independence for AIP.

Analysis of Dual-Tasking Effect on Gait Variability While Interacting with Mobile Devices

Cognitive deficits are very difficult to diagnose during the initial stages; tests typically consist of a patient performing punctual dual-task activities, which are subjectively analyzed to determine the cognitive decline impact on gait. This work supports novel and objective diagnosis methods by stating a baseline on how neurotypical aging affects dual tasks while using a smartphone on the move. With this aim, we propose a twofold research question: Which mobile device tasks performed on the move (dual tasking) have characteristic changes in gait parameters, and which are especially characteristic at older ages? An experiment was conducted with 30 healthy participants where they performed 15 activities (1 single task, 2 traditional dual-tasks and 12 mobile-based dual-tasks) while walking about 50 m. Participants wore a wireless motion tracker (15 sensors) that made the concise analysis of gait possible. The results obtained characterized the gait parameters affected by mobile-based dual-tasking and the impact of normal cognitive decline due to aging. The statistical analysis shows that using smartphone-based dual-tasking produces more significant results than traditional dual-tasking. In the study, 3 out of 10 gait parameters were very significantly affected (p < 0.001) when using the traditional dual tasks, while 5 out of 10 parameters were very significantly affected (p < 0.001) in mobile-based dual-tasking. Moreover, the most characteristic tasks and gait parameters were identified through the obtained results. Future work will focus on applying this knowledge to improve the early diagnosis of MCI.

Validation of the ki:e SB‐C a Novel Digital Speech Biomarker for Cognition in a Dutch Memory Clinic Population

AbstractBackgroundProgressive cognitive decline is the cardinal behavioral symptom in most dementia‐causing diseases such as Alzheimer’s disease. Whereas classic neuropsychological tests often have excellent psychometric properties to measure cognitive decline in dementia, there are scenarios in which they are less suitable. Speech‐based digital biomarkers can be deployed remotely and extracted in a highly automated fashion allowing solutions to scale. We present the validation of a novel digital Speech Biomarker for Cognition (SB‐C) in a Dutch memory clinic population containing patients with Mild Cognitive Impairment (MCI) and age‐ as well as education‐matched participants with Subjective Cognitive Decline (SCD).MethodThe ki:e SB‐C is a novel speech‐based cognitive composite score. The presented validation results are based on a sample that was not used when developing the SB‐C. Validation data has been collected from two age‐ and education‐matched groups: Normal Cognition but subjective cognitive decline (SCD; n = 48, 15 F), MCI (n = 48, 18 F). We automatically extract the SB‐C from SVF and AVLT speech recordings using our proprietary speech analysis pipeline including automatic speech recognition and feature extraction. Recordings were collected from a Dutch memory clinic population containing MCI and SCD participants. We performed (1) analytical and (2) clinical validation. For (1) we performed Spearman rank correlation between SB‐C score and anchor score Mini Mental State Examination (MMSE) to show that the algorithm is correctly measuring the concept of interest cognition. For (2) we performed a non‐parametric Kruskal‐Wallis test to compare SB‐C scores of both NC and MCI groups.ResultThe biomarker score SB‐C and MMSE were strongly correlated (r = 0.61, p < 0.001), such that lower MMSE scores are reflected in lower biomarker scores (compare also figure 1). Additionally, there was a very significant group difference for the SB‐C biomarker score between the NC and MCI group (NC > MCI; χ2 = 26.461 (1), p < 0.001).ConclusionThe ki:e SB‐C is a reliable score for cognition, showing convergent validity with the MMSE and separating well between MCI and SCD populations. The availability of valid digital speech biomarkers for cognition has great potential for decentralized clinical trials in dementia aetiologies and beyond.

Long-covid cognitive impairment: Cognitive assessment and apolipoprotein E (APOE) genotyping correlation in a Brazilian cohort.

IntroductionFew studies have objectively evaluated cognitive deficits after the acute phase of COVID-19 disease. Moreover, the role of apolipoprotein E (APOE) genotypes in cognitive decline in patients with COVID-19 has not been evaluated yet.MethodsThis cross-sectional study was conducted in confirmed cases of COVID-19 patients with neurological symptoms that persisted for more than 3 months from the onset. We determined APOE genotypes.ResultsThe final sample consisted of 141 patients. The most frequent APOE genotype was E3/E3 (N = 95; 67.3%). In total, 93 patients (65.9%) had memory impairment symptoms as the main complaint, objectively confirmed through screening tests in 25 patients (17.7%). Patients with cognitive impairment had a lower frequency of anosmia than the normal and subjective cognitive decline (SCD) groups (p = 0.005). In addition, depression was recurrent in the cognitive impairment group and the SCD group (p = 0.046). Cognitive impairment was significantly more frequent in hospitalized patients and those with a lower education level. Cognitive status was not associated with APOE genotypes.DiscussionHospitalized patients had more severe infection with a greater possibility of systemic complications, greater inflammatory response, and prolonged hospitalization, which could impact cognitive performance. Cognitive impairment in patients with COVID-19 does not necessarily involve specific APOE polymorphisms. However, psychiatric disorders may also be responsible for cognitive complaints. Cognitive complaints are frequent in patients with COVID-19, even after the acute phase of the disease and in mild cases. Hospitalized participants and depressed patients may have a higher risk of cognitive impairment. APOE genotypes or haplotypes may not significantly play a role in COVID-19 cognitive impairment.

Electromyographic Patterns of Paratonia in Normal Subjects and in Patients with Mild Cognitive Impairment or Alzheimer's Disease.

Information on prevalence, pathophysiology, and clinical assessment of paratonia are scarce. In a previous study, we suggested that surface electromyography (EMG) can be used to assess paratonia. To assess clinical and EMG features of paratonia in both patients with cognitive impairment and healthy subjects. We examined 18 patients with Alzheimer's disease (AD), 21 patients with mild cognitive impairment (MCI), 30 healthy seniors (seniors), and 30 healthy juniors (juniors). Paratonia was assessed using the "Paratonia Scale". EMG bursts were recorded from biceps and triceps during manually applied passive movements of elbow joint. Continuous (sinusoidal) and discontinuous (linear) movements were applied at 2 different velocities (fast and slow). In comparison to juniors, seniors had higher clinical scores. In comparison to seniors, AD had higher oppositional scores, while MCI had higher facilitatory scores. EMG activity during passive movements correlated with paratonia clinical scores, was velocity-dependent and increased with movement repetition, most effectively for sinusoidal movements. Similar EMG activity was detected in not paratonic muscles. Paratonia increases with normal aging and cognitive decline progression. While facilitatory paratonia is due to involuntary contraction of the shortening muscle, oppositional paratonia is due, at least partially, to involuntary contraction of the lengthening muscle. Most characteristic feature of this muscle contraction is the progressive increase with movement repetition, that helps distinguish oppositional paratonia from spasticity and rigidity. A similar EMG activity is detected in not paratonic muscles, showing that, during tone assessment, the descending motor system is incompletely inactivated also in normotonic muscles.

A Feasibility Study of Two Cognitive Training Programs for Urban Community-Dwelling Older Adults

Cognitive training approaches are promising to manage the effects of normal cognitive decline for the aging adult, especially with the development and integration of computerized cognitive training. Supportive community models for older adults, such as senior centers, may provide engagement opportunities for occupation-based cognitive training programming. Fourteen older adults (n = 13 Black) from an urban older adult community center participated. This feasibility trial used a two-group, pretest-posttest design to examine differences between an occupation-based computerized cognitive training (CCT) program (n = 7) and a traditional cognitive training (TCT) program (n = 7), as assessed by participants’ perceptions of the perceived benefits, tolerance of time of sessions, and on executive functioning measures. There were no significant differences in the tolerance of time of sessions (p = 0.81) between CCT (average session time = 43.64 min) and TCT (average session time = 44.27 min). Additionally, there were no significant differences in how the two program groups perceived the training based on helpfulness (p = 1.00), positive opinions (p = 0.46), and executive functioning measurement changes. All participants reported “enjoyment” of the training. Including occupation-based CCT and TCT programming is feasible and positive within community-based programming focusing on a diverse population. Short-term improvements in executive functioning should not be expected but are worthy of longer-term observation, considering a socialization component, telehealth integrations, and expansion of supportive technology-based models.

Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum

One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design. To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates. This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria. Alzheimer disease biomarkers detected on PET or in CSF. Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations. Among the 19 097 participants (mean [SD] age, 69.1 [9.8] years; 10 148 women [53.1%]) included, 10 139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P = .04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P = .004), subjective cognitive decline (9%; 95% CI, 3%-15%; P = .005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P = .004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P = .18). This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.

Dissecting Digital Card Games to Yield Digital Biomarkers for the Assessment of Mild Cognitive Impairment: Methodological Approach and Exploratory Study.

BackgroundMild cognitive impairment (MCI), the intermediate cognitive status between normal cognitive decline and pathological decline, is an important clinical construct for signaling possible prodromes of dementia. However, this condition is underdiagnosed. To assist monitoring and screening, digital biomarkers derived from commercial off-the-shelf video games may be of interest. These games maintain player engagement over a longer period of time and support longitudinal measurements of cognitive performance.ObjectiveThis paper aims to explore how the player actions of Klondike Solitaire relate to cognitive functions and to what extent the digital biomarkers derived from these player actions are indicative of MCI.MethodsFirst, 11 experts in the domain of cognitive impairments were asked to correlate 21 player actions to 11 cognitive functions. Expert agreement was verified through intraclass correlation, based on a 2-way, fully crossed design with type consistency. On the basis of these player actions, 23 potential digital biomarkers of performance for Klondike Solitaire were defined. Next, 23 healthy participants and 23 participants living with MCI were asked to play 3 rounds of Klondike Solitaire, which took 17 minutes on average to complete. A generalized linear mixed model analysis was conducted to explore the differences in digital biomarkers between the healthy participants and those living with MCI, while controlling for age, tablet experience, and Klondike Solitaire experience.ResultsAll intraclass correlations for player actions and cognitive functions scored higher than 0.75, indicating good to excellent reliability. Furthermore, all player actions had, according to the experts, at least one cognitive function that was on average moderately to strongly correlated to a cognitive function. Of the 23 potential digital biomarkers, 12 (52%) were revealed by the generalized linear mixed model analysis to have sizeable effects and significance levels. The analysis indicates sensitivity of the derived digital biomarkers to MCI.ConclusionsCommercial off-the-shelf games such as digital card games show potential as a complementary tool for screening and monitoring cognition.Trial RegistrationClinicalTrials.gov NCT02971124; https://clinicaltrials.gov/ct2/show/NCT02971124

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.