Plasma p-tau217 predicts cognitive impairments up to ten years before onset in normal older adults.

Importance: Positron emission tomography (PET) biomarkers are the gold standard for detection of Alzheimer amyloid and tau in vivo . Such imaging can identify cognitively unimpaired (CU) individuals who will subsequently develop cognitive impartment (CI). Plasma biomarkers would be more practical than PET or even cerebrospinal fluid (CSF) assays in clinical settings. Objective: Assess the prognostic accuracy of plasma p-tau217 in comparison to CSF and PET biomarkers for predicting the clinical progression from CU to CI. Design: In a cohort of elderly at high risk of developing Alzheimer's dementia (AD), we measured the proportion of CU individuals who developed CI, as predicted by Aß (A+) and/or tau (T+) biomarker assessment from plasma, CSF, and PET. Results from each method were compared with (A-T-) reference individuals. Data were analyzed from June 2023 to April 2024. Setting: Longitudinal observational cohort. Participants: Some 228 participants from the PREVENT-AD cohort were CU at the time of biomarker assessment and had 1 - 10 years of follow-up. Plasma was available from 215 participants, CSF from 159, and amyloid- and tau-PET from 155. Ninety-three participants had assessment using all three methods (main group of interest). Progression to CI was determined by clinical consensus among physicians and neuropsychologists who were blind to plasma, CSF, PET, and MRI findings, as well as APOE genotype. Exposures: Plasma Aß 42/40 was measured using IP-MS; CSF Aß 42/40 using Lumipulse; plasma and CSF p-tau217 using UGOT assay. Aß-PET employed the 18 F-NAV4694 ligand, and tau-PET used 18 F-flortaucipir. Main Outcome: Prognostic accuracy of plasma, CSF, and PET biomarkers for predicting the development of CI in CU individuals. Results: Cox proportional hazard models indicated a greater progression rate in all A+T+ groups compared to A-T-groups (HR = 6.61 [95% CI = 2.06 - 21.17] for plasma, 3.62 [1.49 - 8.81] for CSF and 9.24 [2.34 - 36.43] for PET). The A-T+ groups were small, but also characterized with individuals who developed CI. Plasma biomarkers identified about five times more T+ than PET. Conclusion and relevance: Plasma p-tau217 assessment is a practical method for identification of persons who will develop cognitive impairment up to 10 years later. Key Points: Question: Can plasma p-tau217 serve as a prognostic indicator for identifying cognitively unimpaired (CU) individuals at risk of developing cognitive impairments (CI)?Findings: In a longitudinal cohort of CU individuals with a family history of sporadic AD, almost all individuals with abnormal plasma p-tau217 concentrations developed CI within 10 years, regardless of plasma amyloid levels. Similar findings were obtained with CSF p-tau217 and tau-PET. Fluid p-tau217 biomarkers had the main advantage over PET of identifying five times more participants with elevated tau.Meaning: Elevated plasma p-tau217 levels in CU individuals strongly indicate future clinical progression.

Neurobehavioral Mechanisms Influencing the Association Between Generativity, the Desire to Promote Well-Being of Younger Generations, and Purpose in Life in Older Adults at Risk for Alzheimer's Disease.

OBJECTIVES: Generativity, the desire and action to improve the well-being of younger generations, is associated with purpose in life among older adults. However, the neurobehavioral factors supporting the relationship between generativity and purpose in life remain unknown. This study aims to identify the functional neuroanatomy of generativity and mechanisms linking generativity with purpose in life in at-risk older adults. METHODS: Fifty-eight older adults (mean age = 70.8, SD = 5.03, 45 females) with a family history of Alzheimer's disease (AD) were recruited from the PREVENT-AD cohort. Participants underwent brain imaging and completed questionnaires assessing generativity, social support, and purpose in life. Mediation models examined whether social support mediated the association between generativity and purpose in life. Seed-to-voxel analyses investigated the association between generativity and resting-state functional connectivity (rsFC) to the ventromedial prefrontal cortex (vmPFC) and ventral striatum (VS), and whether this rsFC moderated the relationship between generativity and purpose in life. RESULTS: Affectionate social support mediated the association between generative desire and purpose in life. Generative desire was associated with rsFC between VS and precuneus, and, vmPFC and right dorsolateral prefrontal cortex (rdlPFC). The vmPFC-rdlPFC rsFC moderated the association between generative desire and purpose in life. DISCUSSION: These findings provide insight into how the brain supports complex social behavior and, separately, purpose in life in at-risk aging. Affectionate social support may be a putative target process to enhance purpose in life in older adults. This knowledge contributes to future developments of personalized interventions that promote healthy aging.

Midlife physical activity engagement is associated with later-life brain health.

The relationship between midlife physical activity (PA), and cognition and brain health in later life is poorly understood with conflicting results from previous research. Investigating the contribution of midlife PA to later-life cognition and brain health in high-risk populations will propel the development of health guidance for those most in need. The current study examined the association between midlife PA engagement and later-life cognition, grey matter characteristics and resting-state functional connectivity in older individuals at high-risk for Alzheimer's disease. The association between midlife PA and later-life cognitive function was not significant but was moderated by later-life PA. Meanwhile, greater midlife moderate-to-vigorous PA was associated with greater grey matter surface area in the left middle frontal gyrus. Moreover, greater midlife total PA was associated with diminished functional connectivity between bilateral middle frontal gyri and middle cingulum, supplementary motor areas, and greater functional connectivity between bilateral hippocampi and right cerebellum, Crus II. These results indicate the potentially independent contribution of midlife PA to later-life brain health.

Resting-state MRI functional connectivity as a neural correlate of multidomain lifestyle adherence in older adults at risk for Alzheimer's disease.

Prior research has demonstrated the importance of a healthy lifestyle to protect brain health and diminish dementia risk in later life. While a multidomain lifestyle provides an ecological perspective to voluntary engagement, its association with brain health is still under-investigated. Therefore, understanding the neural mechanisms underlying multidomain lifestyle engagement, particularly in older adults at risk for Alzheimer's disease (AD), gives valuable insights into providing lifestyle advice and intervention for those in need. The current study included 139 healthy older adults with familial risk for AD from the Prevent-AD longitudinal aging cohort. Self-reported exercise engagement, cognitive activity engagement, healthy diet adherence, and social activity engagement were included to examine potential phenotypes of an individual's lifestyle adherence. Two adherence profiles were discovered using data-driven clustering methodology [i.e., Adherence to healthy lifestyle (AL) group and Non-adherence to healthy lifestyle group]. Resting-state functional connectivity matrices and grey matter brain features obtained from magnetic resonance imaging were used to classify the two groups using a support vector machine (SVM). The SVM classifier was 75% accurate in separating groups. The features that show consistently high importance to the classification model were functional connectivity mainly between nodes located in different prior-defined functional networks. Most nodes were located in the default mode network, dorsal attention network, and visual network. Our results provide preliminary evidence of neurobiological characteristics underlying multidomain healthy lifestyle choices.

The influence of generativity on purpose in life is mediated by social support and moderated by prefrontal functional connectivity in at-risk older adults.

Objectives: Generativity, the desire and action to improve the well-being of younger generations, is positively associated with purpose in life among older adults. However, the neural basis of generativity and the neurobehavioral factors supporting the relationship between generativity and purpose in life remain unknown. This study aims to identify the functional neuroanatomy of generativity and mechanisms linking generativity with purpose in life in at-risk older adults. Methods: Fifty-eight cognitively healthy older adults (mean age = 70.78, 45 females) with a family history of Alzheimer's disease were recruited from the PREVENT-AD aging cohort. Participants underwent brain imaging and completed questionnaires assessing generativity, social support, and purpose in life. Mediation models examined whether social support mediated the association between generativity and purpose in life. Seed-to-voxel analyses investigated the association between resting-state functional connectivity (rsFC) to the ventromedial prefrontal cortex (vmPFC) and ventral striatum (VS) and whether this rsFC moderated the relationship between generativity and purpose in life. Results: Affectionate social support mediated the association between generative desire and purpose in life. Generative desire was associated with rsFC between VS and precuneus and vmPFC and right dorsolateral prefrontal cortex (rdlPFC). The vmPFC-rdlPFC connectivity moderated the association between generative desire and purpose in life. Discussion: These findings provide insight into how the brain supports social behavior and, separately, purpose in life in at-risk aging. Affectionate social support may be a putative target process to enhance purpose and life in older adults. This knowledge contributes to future developments of personalized interventions that promote healthy aging.

Characterization of structural and functional network organization after focal prefrontal lesions in humans in proof of principle study.

Lesion research classically maps behavioral effects of focal damage to the directly injured brain region. However, such damage can also have distant effects that can be assessed with modern imaging methods. Furthermore, the combination and comparison of imaging methods in a lesion model may shed light on the biological basis of structural and functional networks in the healthy brain. We characterized network organization assessed with multiple MRI imaging modalities in 13 patients with chronic focal damage affecting either superior or inferior frontal gyrus (SFG, IFG) and 18 demographically matched healthy Controls. We first defined structural and functional network parameters in Controls and then investigated grey matter (GM) and white matter (WM) differences between patients and Controls. Finally, we examined the differences in functional coupling to large-scale resting state networks (RSNs). The results suggest lesions are associated with widespread within-network GM loss at distal sites, yet leave WM and RSNs relatively preserved. Lesions to either prefrontal region also had a similar relative level of impact on structural and functional networks. The findings provide initial evidence for causal contributions of specific prefrontal regions to brain networks in humans that will ultimately help to refine models of the human brain.

Remote cognitive and behavioral assessment: Report of the Alzheimer Society of Canada Task Force on dementia care best practices for COVID-19.

INTRODUCTION: Despite the urgent need for remote neurobehavioral assessment of individuals with cognitive impairment, guidance is lacking. Our goal is to provide a multi-dimensional framework for remotely assessing cognitive, functional, behavioral, and physical aspects of people with cognitive impairment, along with ethical and technical considerations. METHODS: Literature review on remote cognitive assessment and multidisciplinary expert opinion from behavioral neurologists, neuropsychiatrists, neuropsychologists, and geriatricians was integrated under the auspices of the Alzheimer Society of Canada Task Force on Dementia Care Best Practices for COVID-19. Telephone and video approaches to assessments were considered. RESULTS: Remote assessment is shown to be acceptable to patients and caregivers. Informed consent, informant history, and attention to privacy and autonomy are paramount. A range of screening and domain-specific instruments are available for telephone or video assessment of cognition, function, and behavior. Some neuropsychological tests administered by videoconferencing show good agreement with in-person assessment but still lack validation and norms. Aspects of the remote dementia-focused neurological examination can be performed reliably. DISCUSSION: Despite challenges, current literature and practice support implementation of telemedicine assessments for patients with cognitive impairment. Convergence of data across the clinical interview, reliable and brief remote cognitive tests, and remote neurological exam increase confidence in clinical interpretation and diagnosis.

Resting-State Connectivity of Auditory and Reward Systems in Alzheimer's Disease and Mild Cognitive Impairment.

Music-based interventions (MBI) have become increasingly widely adopted for dementia and related disorders. Previous research shows that music engages reward-related regions through functional connectivity with the auditory system, but evidence for the effectiveness of MBI is mixed in older adults with mild cognitive impairment (MCI) and Alzheimer's disease (AD). This underscores the need for a unified mechanistic understanding to motivate MBIs. The main objective of the present study is to characterize the intrinsic connectivity of the auditory and reward systems in healthy aging individuals with MCI, and those with AD. Using resting-state fMRI data from the Alzheimer's Database Neuroimaging Initiative, we tested resting-state functional connectivity within and between auditory and reward systems in older adults with MCI, AD, and age-matched healthy controls (N = 105). Seed-based correlations were assessed from regions of interest (ROIs) in the auditory network (i.e., anterior superior temporal gyrus, posterior superior temporal gyrus, Heschl's Gyrus), and the reward network (i.e., nucleus accumbens, caudate, putamen, and orbitofrontal cortex). AD individuals were lower in both within-network and between-network functional connectivity in the auditory network and reward networks compared to MCI and controls. Furthermore, graph theory analyses showed that the MCI group had higher clustering and local efficiency than both AD and control groups, whereas AD individuals had lower betweenness centrality than MCI and control groups. Together, the auditory and reward systems show preserved within- and between-network connectivity in MCI individuals relative to AD. These results motivate future music-based interventions in individuals with MCI due to the preservation of functional connectivity within and between auditory and reward networks at that initial stage of neurodegeneration.

Human aging reduces the neurobehavioral influence of motivation on episodic memory.

The neural circuitry mediating the influence of motivation on long-term declarative or episodic memory formation is delineated in young adults, but its status is unknown in healthy aging. We examined the effect of reward and punishment anticipation on intentional declarative memory formation for words using an event-related functional magnetic resonance imaging (fMRI) monetary incentive encoding task in twenty-one younger and nineteen older adults. At 24-hour memory retrieval testing, younger adults were significantly more likely to remember words associated with motivational cues than neutral cues. Motivational enhancement of memory in younger adults occurred only for recollection ("remember" responses) and not for familiarity ("familiar" responses). Older adults had overall diminished memory and did not show memory gains in association with motivational cues. Memory encoding associated with monetary rewards or punishments activated motivational (substantia nigra/ventral tegmental area) and memory-related (hippocampus) brain regions in younger, but not older, adults during the target word periods. In contrast, older and younger adults showed similar activation of these brain regions during the anticipatory motivational cue interval. In a separate monetary incentive delay task that did not require learning, we found evidence for relatively preserved striatal reward anticipation in older adults. This supports a potential dissociation between incidental and intentional motivational processes in healthy aging. The finding that motivation to obtain rewards and avoid punishments had reduced behavioral and neural influence on intentional episodic memory formation in older compared to younger adults is relevant to life-span theories of cognitive aging including the dopaminergic vulnerability hypothesis.

Resting-State Functional Connectivity of the Subthalamic Nucleus to Limbic, Associative, and Motor Networks.

The subthalamic nucleus (STN) is a small structure situated deep in the midbrain that exhibits wide-ranging functionality. In addition to its role in motor control, the STN is considered a hub for synchronizing aspects of emotion and cognition including attention, inhibitory control, motivation, and working memory. Evidence from neuroanatomical tracer studies suggests that the medial, ventromedial, and dorsolateral parts of the STN correspond to limbic, associative, and motor subdivisions, respectively. Although the extent of STN functional anatomical overlap remains unclear, blood oxygenation level dependent imaging of the STN may provide complementary information about the diverse functions of this structure. Methodological limitations in spatial and temporal resolutions, however, have prevented a comprehensive exploration of temporal correlations from the STN to the whole brain. In this study, we optimize spatial (2 mm isotropic) and temporal (TR = 1 s) resolutions to take full advantage of the time series signal-to-noise ratio capabilities of multichannel array coils and simultaneous multislice imaging. We interrogated STN seed-to-voxel resting-state functional MRI connectivity in a group of 30 healthy participants that included the whole brain at high-temporal and spatial resolutions. This analysis revealed STN functional connectivity to limbic, associative, and motor networks. Our findings contribute to the understanding of STN functional neuroanatomy in humans and are clinically relevant for ongoing research in deep brain stimulation.

Altered functional connectivity in lesional peduncular hallucinosis with REM sleep behavior disorder.

Brainstem lesions causing peduncular hallucinosis (PH) produce vivid visual hallucinations occasionally accompanied by sleep disorders. Overlapping brainstem regions modulate visual pathways and REM sleep functions via gating of thalamocortical networks. A 66-year-old man with paroxysmal atrial fibrillation developed abrupt-onset complex visual hallucinations with preserved insight and violent dream enactment behavior. Brain MRI showed restricted diffusion in the left rostrodorsal pons suggestive of an acute ischemic stroke. REM sleep behavior disorder (RBD) was diagnosed on polysomnography. We investigated the integrity of ponto-geniculate-occipital circuits with seed-based resting-state functional connectivity MRI (rs-fcMRI) in this patient compared to 46 controls. Rs-fcMRI revealed significantly reduced functional connectivity between the lesion and lateral geniculate nuclei (LGN), and between LGN and visual association cortex compared to controls. Conversely, functional connectivity between brainstem and visual association cortex, and between visual association cortex and prefrontal cortex (PFC) was significantly increased in the patient. Focal damage to the rostrodorsal pons is sufficient to cause RBD and PH in humans, suggesting an overlapping mechanism in both syndromes. This lesion produced a pattern of altered functional connectivity consistent with disrupted visual cortex connectivity via de-afferentation of thalamocortical pathways.

Material-specific interference control is dissociable and lateralized in human prefrontal cortex.

The prefrontal cortex (PFC) plays a key role in the ability to pursue a particular goal in the face of competing alternatives, an ability that is fundamental to higher-order human behavior. Whether this region contributes to cognitive control through material-general mechanisms, or through hemispheric specialization of component abilities, remains unclear. Here we show that left or right ventrolateral PFC damage in humans leads to doubly dissociable deficits in two classic tests of interference control. Patients with damage centered on left ventrolateral prefrontal cortex had exaggerated interference effects in the color-word Stroop, but not the Eriksen flanker task, whereas patients with damage affecting right ventrolateral prefrontal cortex showed the opposite pattern. Thus, effective interference resolution requires either right or left lateral PFC, depending on the nature of the task. This finding supports a lateralized, material-specific account of cognitive control in humans.

Increased behavioral responses to ethanol in Lmo3 knockout mice.

LIM-domain-only 3 (LMO3) is a transcriptional regulator involved in central nervous system development and neuroblastoma. Our previous studies implicated a potential role for LMO3 in regulating ethanol sensitivity and consumption. Here, we examined behavioral responses to ethanol in a line of Lmo3 null (Lmo3(Z) ) mice, utilizing the ethanol-induced loss-of-righting-reflex (LORR) test, two-bottle choice ethanol consumption and the drinking in the dark (DID) test, which models binge-like ethanol consumption. We found that Lmo3(Z) mice exhibited increased sedation time in response to ethanol in the LORR test and drank significantly more ethanol in the DID test compared with their wild-type counterparts, but showed no differences in two-bottle choice ethanol consumption. To explore where LMO3 may be acting in the brain to produce an ethanol phenotype, we also examined reporter gene (ß-galactosidase) expression in heterozygous Lmo3(Z) mice and found strong expression in subcortical areas, particularly in those areas implicated in drug abuse, including the nucleus accumbens (Acb), cortex, hippocampus and amygdala. We also examined Lmo3 expression in the brains of wild-type mice who had undergone the DID test and found a negative correlation between Lmo3 expression in the Acb and the amount of ethanol consumed, consistent with the increased binge-like drinking observed in Lmo3(Z) mice. These results support a role for LMO3 in regulating behavioral responses to ethanol, potentially through its actions in the Acb.

Minocycline-induced dermatomyositis.

Minocycline is a semisynthetic tetracycline that causes a spectrum of autoimmune adverse reactions. We report a previously healthy patient who developed a panniculitis and histopathologically proven dermatomyositis during treatment with minocycline for acne vulgaris. Her signs and symptoms resolved completely upon cessation of minocycline. This case illustrates a novel adverse effect of a widely prescribed medication.

Defining the dopamine transporter proteome by convergent biochemical and in silico analyses.

Monoamine transporters play a key role in neuronal signaling by mediating reuptake of neurotransmitters from the synapse. The function of the dopamine transporter (DAT), an important member of this family of transporters, is regulated by multiple signaling mechanisms, which result in altered cell surface trafficking of DAT. Protein-protein interactions are likely critical for this mode of transporter regulation. In this study, we identified proteins associated with DAT by immunoprecipitation (IP) followed by mass spectrometry. We identified 20 proteins with diverse cellular functions that can be classified as trafficking proteins, cytoskeletal proteins, ion channels and extracellular matrix-associated proteins. DAT was found to associate with the voltage-gated potassium channel Kv2.1 and synapsin Ib, a protein involved in regulating neurotransmitter release. An in silico analysis provided evidence for common transcriptional regulation of the DAT proteome genes. In summary, this study identified a network of proteins that are primary candidates for functional regulation of the DAT, an important player in mechanisms of mental disorders and drug addiction.

Ethanol potentiates the function of the human dopamine transporter expressed in Xenopus oocytes.

Ethanol alters a variety of properties of brain dopaminergic neurons including firing rate, synthesis, release, and metabolism. Recent studies suggest that ethanol's action on central dopamine systems may also involve modulation of dopamine transporter (DAT) activity. The human DAT was expressed in Xenopus oocytes to examine directly the effects of ethanol on transporter function. [3H]Dopamine (100 nM) accumulation into DAT-expressing oocytes increased significantly in response to ethanol (10 min; 10-100 mM). In two-electrode voltage-clamp experiments, DAT-mediated currents were also enhanced significantly by ethanol (10-100 mM). The magnitude of the ethanol-induced potentiation of DAT function depended on ethanol exposure time and substrate concentration. Cell surface DAT binding ([3H]WIN 35,428; 4 nM) also increased as a function of ethanol exposure time. Thus, the increase in dopamine uptake was associated with a parallel increase in the number of DAT molecules expressed at the cell surface. These experiments demonstrate that DAT-mediated substrate translocation and substrate-associated ionic conductances are sensitive to intoxicating concentrations of ethanol and suggest that DAT may represent an important site of action for ethanol's effects on central dopaminergic transmission. A potential mechanism by which ethanol acts to enhance DAT function may involve regulation of DAT expression on the cell surface.

Does acetaldehyde mediate ethanol action in the central nervous system?

BACKGROUND: Some of the effects of ethanol in the central nervous system are due to changes in function of ligand-gated ion channels. Production of detectable amounts of acetaldehyde, a primary metabolite of ethanol, has been demonstrated in brain homogenates. The aim of this study was to determine whether central actions that are often attributed to ethanol may actually be mediated by acetaldehyde. METHODS: The effects of acetaldehyde (1-1000 microM) were tested by two-electrode voltage-clamp electrophysiology in Xenopus laevis oocytes expressing 10 different ligand-gated ion channel receptors [alpha1 glycine; alpha1beta2gamma2Sgamma-aminobutyric acid (GABA)A; rho1 GABAc; 5-hydroxytryptamine-3A; NR1a/NR2A NMDA; GluR1/GluR2 AMPA; GluR6/KA2 kainate; and alpha4beta2, alpha4beta4, and alpha2beta4 nicotinic-acetylcholine] and the G-protein-coupled inward rectifying potassium channel GIRK2. We also investigated the effect of acetaldehyde on the dopamine transporter (DAT), performing dopamine uptake assays in oocytes expressing DAT. RESULTS: Acetaldehyde (1 and 10 microM) significantly enhanced alpha1 glycine receptor-mediated currents. Acetaldehyde did not affect the function of any of the other receptors tested or the potassium currents measured in GIRK2 channels. Moreover, acetaldehyde did not alter the DAT-mediated dopamine uptake. CONCLUSIONS: Our results suggest a potential minor role for acetaldehyde in the glycine receptor-mediated effects of ethanol. Otherwise, acetaldehyde does not modulate function of the neuronal receptors tested in this study, in GIRK channels or DAT, when expressed recombinantly in Xenopus laevis oocytes.