Subthalamic nucleus-language network connectivity predicts dopaminergic modulation of speech function in Parkinson's disease.

Speech impediments are a prominent yet understudied symptom of Parkinson's disease (PD). While the subthalamic nucleus (STN) is an established clinical target for treating motor symptoms, these interventions can lead to further worsening of speech. The interplay between dopaminergic medication, STN circuitry, and their downstream effects on speech in PD is not yet fully understood. Here, we investigate the effect of dopaminergic medication on STN circuitry and probe its association with speech and cognitive functions in PD patients. We found that changes in intrinsic functional connectivity of the STN were associated with alterations in speech functions in PD. Interestingly, this relationship was characterized by altered functional connectivity of the dorsolateral and ventromedial subdivisions of the STN with the language network. Crucially, medication-induced changes in functional connectivity between the STN's dorsolateral subdivision and key regions in the language network, including the left inferior frontal cortex and the left superior temporal gyrus, correlated with alterations on a standardized neuropsychological test requiring oral responses. This relation was not observed in the written version of the same test. Furthermore, changes in functional connectivity between STN and language regions predicted the medication's downstream effects on speech-related cognitive performance. These findings reveal a previously unidentified brain mechanism through which dopaminergic medication influences speech function in PD. Our study sheds light into the subcortical-cortical circuit mechanisms underlying impaired speech control in PD. The insights gained here could inform treatment strategies aimed at mitigating speech deficits in PD and enhancing the quality of life for affected individuals.

Plasma pTau181 Reveals a Pathological Signature that Predicts Cognitive Outcomes in Lewy Body Disease.

OBJECTIVE: To determine whether plasma phosphorylated-Tau181 (pTau181) could be used as a diagnostic biomarker of concurrent Alzheimer's disease neuropathologic change (ADNC) or amyloidosis alone, as well as a prognostic, monitoring, and susceptibility/risk biomarker for clinical outcomes in Lewy body disease (LBD). METHODS: We studied 565 participants: 94 LBD with normal cognition, 83 LBD with abnormal cognition, 114 with Alzheimer's disease, and 274 cognitively normal. Plasma pTau181 levels were measured with the Lumipulse G platform. Diagnostic accuracy for concurrent ADNC and amyloidosis was assessed with Receiver Operating Characteristic curves in a subset of participants with CSF pTau181/Aß42, and CSF Aß42/Aß40 or amyloid-ß PET, respectively. Linear mixed effects models were used to examine the associations between baseline and longitudinal plasma pTau181 levels and clinical outcomes. RESULTS: Plasma pTau181 predicted concurrent ADNC and amyloidosis in LBD with abnormal cognition with 87% and 72% accuracy, respectively. In LBD patients with abnormal cognition, higher baseline plasma pTau181 was associated with worse baseline MoCA and CDR-SB, as well as accelerated decline in CDR-SB. Additionally, in this group, rapid increases in plasma pTau181 over 3 years predicted a faster decline in CDR-SB and memory. In LBD patients with normal cognition, there was no association between baseline or longitudinal plasma pTau181 levels and clinical outcomes; however, elevated pTau181 at baseline increased the risk of conversion to cognitive impairment. INTERPRETATION: Our findings suggest that plasma pTau181 is a promising biomarker for concurrent ADNC and amyloidosis in LBD. Furthermore, plasma pTau181 holds potential as a prognostic, monitoring, and susceptibility/risk biomarker, predicting disease progression in LBD. ANN NEUROL 2024;96:526-538.

Temporal tau asymmetry spectrum influences divergent behavior and language patterns in Alzheimer's disease.

Understanding the psychiatric symptoms of Alzheimer s disease (AD) is crucial for advancing precision medicine and therapeutic strategies. The relationship between AD behavioral symptoms and asymmetry in spatial tau PET patterns is not well-known. Braak tau progression implicates the temporal lobes early. However, the clinical and pathological implications of temporal tau laterality remain unexplored. This cross-sectional study investigated the correlation between temporal tau PET asymmetry and behavior assessed using the neuropsychiatric inventory and composite scores for memory, executive function, and language, using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. In the entire cohort, continuous right and left temporal tau contributions to behavior and cognition were evaluated, controlling for age, sex, education, and tau burden on the contralateral side. Additionally, a temporal tau laterality index was calculated to define "asymmetry-extreme" groups (individuals with laterality indices greater than two standard deviations from the mean). 695 individuals (age = 73.9 ± 7.6 years, 372 (53.5 %) females) were included, comprising 281 (40%) cognitively unimpaired (CU) amyloid negative, 185 (27%) CU amyloid positive, and 229 (33%) impaired (CI) amyloid positive participants. In the full cohort analysis, right temporal tau was associated with worse behavior (B = 8.14, p-value = 0.007), and left temporal tau was associated with worse language (B = 1.4, p-value < 0.001). Categorization into asymmetry-extreme groups revealed 20 right- and 27 left-asymmetric participants. Within these extreme groups, there was additional heterogeneity along the anterior-posterior dimension. Asymmetrical tau burden is associated with distinct behavioral and cognitive profiles. Wide multi-cultural implementation of social cognition measures is needed to understand right-sided asymmetry in AD.

Tau positron emission tomography in preclinical Alzheimer's disease.

Rates of tau accumulation in cognitively unimpaired older adults are subtle, with magnitude and spatial patterns varying in recent reports. Regional accumulation also likely varies in the degree to which accumulation is amyloid-ß-dependent. Thus, there is a need to evaluate the pattern and consistency of tau accumulation across multiple cognitively unimpaired cohorts and how these patterns relate to amyloid burden, in order to design optimal tau end points for clinical trials. Using three large cohorts of cognitively unimpaired older adults, the Anti-Amyloid Treatment in Asymptomatic Alzheimer's and companion study, Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (n = 447), the Alzheimer's Disease Neuroimaging Initiative (n = 420) and the Harvard Aging Brain Study (n = 190), we attempted to identify regions with high rates of tau accumulation and estimate how these rates evolve over a continuous spectrum of baseline amyloid deposition. Optimal combinations of regions, tailored to multiple ranges of baseline amyloid burden as hypothetical clinical trial inclusion criteria, were tested and validated. The inferior temporal cortex, fusiform gyrus and middle temporal cortex had the largest effect sizes of accumulation in both longitudinal cohorts when considered individually. When tau regions of interest were combined to find composite weights to maximize the effect size of tau change over time, both longitudinal studies exhibited a similar pattern-inferior temporal cortex, almost exclusively, was optimal for participants with mildly elevated amyloid ß levels. For participants with highly elevated baseline amyloid ß levels, combined optimal composite weights were 53% inferior temporal cortex, 31% amygdala and 16% fusiform. At mildly elevated levels of baseline amyloid ß, a sample size of 200/group required a treatment effect of 0.40-0.45 (40-45% slowing of tau accumulation) to power an 18-month trial using the optimized composite. Neither a temporal lobe composite nor a global composite reached 80% power with 200/group with an effect size under 0.5. The focus of early tau accumulation on the medial temporal lobe has resulted from the observation that the entorhinal cortex is the initial site to show abnormal levels of tau with age. However, these abnormal levels do not appear to be the result of a high rate of accumulation in the short term, but possibly a more moderate rate occurring early with respect to age. While the entorhinal cortex plays a central role in the early appearance of tau, it may be the inferior temporal cortex that is the critical region for rapid tau accumulation in preclinical Alzheimer's disease.

Speech patterns during memory recall relates to early tau burden across adulthood.

INTRODUCTION: Early cognitive decline may manifest in subtle differences in speech. METHODS: We examined 238 cognitively unimpaired adults from the Framingham Heart Study (32-75 years) who completed amyloid and tau PET imaging. Speech patterns during delayed recall of a story memory task were quantified via five speech markers, and their associations with global amyloid status and regional tau signal were examined. RESULTS: Total utterance time, number of between-utterance pauses, speech rate, and percentage of unique words significantly correlated with delayed recall score although the shared variance was low (2%-15%). Delayed recall score was not significantly different between ß-amyoid-positive (Aß+) and -negative (Aß-) groups and was not associated with regional tau signal. However, longer and more between-utterance pauses, and slower speech rate were associated with increased tau signal across medial temporal and early neocortical regions. DISCUSSION: Subtle speech changes during memory recall may reflect cognitive impairment associated with early Alzheimer's disease pathology. HIGHLIGHTS: Speech during delayed memory recall relates to tau PET signal across adulthood. Delayed memory recall score was not associated with tau PET signal. Speech shows greater sensitivity to detecting subtle cognitive changes associated with early tau accumulation. Our cohort spans adulthood, while most PET imaging studies focus on older adults.

Loneliness, cerebrovascular and Alzheimer's disease pathology, and cognition.

INTRODUCTION: Loneliness has a rising public health impact, but research involving neuropathology and representative cohorts has been limited. METHODS: Inverse odds of selection weights were generalized from the autopsy sample of Rush Alzheimer's Disease Center cohorts (N = 680; 89 ± 9 years old; 25% dementia) to the US-representative Health and Retirement Study (N = 8469; 76 ± 7 years old; 5% dementia) to extend external validity. Regressions tested cross-sectional associations between loneliness and (1) Alzheimer's disease (AD) and cerebrovascular pathology; (2) five cognitive domains; and (3) relationships between pathology and cognition, adjusting for depression. RESULTS: In weighted models, greater loneliness was associated with microinfarcts, lower episodic and working memory in the absence of AD pathology, lower working memory in the absence of infarcts, a stronger association of infarcts with lower episodic memory, and a stronger association of microinfarcts with lower working and semantic memory. DISCUSSION: Loneliness may relate to AD through multiple pathways involving cerebrovascular pathology and cognitive reserve. HIGHLIGHTS: Loneliness was associated with worse cognition in five domains. Loneliness was associated with the presence of microinfarcts. Loneliness moderated cognition-neuropathology associations. Transportability methods can provide insight into selection bias.

Florbetaben amyloid PET acquisition time: Influence on Centiloids and interpretation.

INTRODUCTION: Amyloid positron emission tomography (PET) acquisition timing impacts quantification. METHODS: In florbetaben (FBB) PET scans of 245 adults with and without cognitive impairment, we investigated the impact of post-injection acquisition time on Centiloids (CLs) across five reference regions. CL equations for FBB were derived using standard methods, using FBB data collected between 90 and 110 min with paired Pittsburgh compound B data. Linear mixed models and t-tests evaluated the impact of acquisition time on CL increases. RESULTS: CL values increased significantly over the scan using the whole cerebellum, cerebellar gray matter, and brainstem as reference regions, particularly in amyloid-positive individuals. In contrast, CLs based on white matter-containing reference regions decreased across the scan. DISCUSSION: The quantification of CLs in FBB PET imaging is influenced by both the overall scan acquisition time and the choice of reference region. Standardized acquisition protocols or the application of acquisition time-specific CL equations should be implemented in clinical protocols. HIGHLIGHTS: Acquisition timing affects florbetaben positron emission tomography (PET) scan quantification, especially in amyloid-positive participants. The impact of acquisition timing on quantification varies across common reference regions. Consistent acquisitions and/or appropriate post-injection adjustments are needed to ensure comparability of PET data.

Dopaminergic medication normalizes aberrant cognitive control circuit signalling in Parkinson's disease.

Dopaminergic medication is widely used to alleviate motor symptoms of Parkinson's disease, but these medications also impact cognition with significant variability across patients. It is hypothesized that dopaminergic medication impacts cognition and working memory in Parkinson's disease by modulating frontoparietal-basal ganglia cognitive control circuits, but little is known about the underlying causal signalling mechanisms and their relation to individual differences in response to dopaminergic medication. Here we use a novel state-space computational model with ultra-fast (490 ms resolution) functional MRI to investigate dynamic causal signalling in frontoparietal-basal ganglia circuits associated with working memory in 44 Parkinson's disease patients ON and OFF dopaminergic medication, as well as matched 36 healthy controls. Our analysis revealed aberrant causal signalling in frontoparietal-basal ganglia circuits in Parkinson's disease patients OFF medication. Importantly, aberrant signalling was normalized by dopaminergic medication and a novel quantitative distance measure predicted individual differences in cognitive change associated with medication in Parkinson's disease patients. These findings were specific to causal signalling measures, as no such effects were detected with conventional non-causal connectivity measures. Our analysis also identified a specific frontoparietal causal signalling pathway from right middle frontal gyrus to right posterior parietal cortex that is impaired in Parkinson's disease. Unlike in healthy controls, the strength of causal interactions in this pathway did not increase with working memory load and the strength of load-dependent causal weights was not related to individual differences in working memory task performance in Parkinson's disease patients OFF medication. However, dopaminergic medication in Parkinson's disease patients reinstated the relation with working memory performance. Our findings provide new insights into aberrant causal brain circuit dynamics during working memory and identify mechanisms by which dopaminergic medication normalizes cognitive control circuits.

Influence of common reference regions on regional tau patterns in cross-sectional and longitudinal [18F]-AV-1451 PET data.

Tau PET has allowed for critical insights into in vivo patterns of tau accumulation and change in individuals early in the Alzheimer's disease (AD) continuum. A key methodological step in tau PET analyses is the selection of a reference region, but there is not yet consensus on the optimal region especially for longitudinal tau PET analyses. This study examines how reference region selection influences results related to disease stage at baseline and over time. Longitudinal flortaucipir ([18F]-AV1451) PET scans were examined using several common reference regions (e.g., eroded subcortical white matter, inferior cerebellar gray matter) in 62 clinically unimpaired amyloid negative (CU A-) individuals, 73 CU amyloid positive (CU A+) individuals, and 64 amyloid positive individuals with mild cognitive impairment (MCI A+) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cross-sectionally, both reference regions resulted in robust group differences between CU A-, CU A+, and MCI A+ groups, along with significant associations with CSF phosphorylated tau (pTau-181). However, these results were more focally specific and akin to Braak Staging when using eroded white matter, whereas effects with inferior cerebellum were globally distributed across most cortical regions. Longitudinally, utilization of eroded white matter revealed significant accumulation greater than zero across more regions whereas change over time was diminished using inferior cerebellum. Interestingly, the inferior temporal target region seemed most robust to reference region selection with expected cross-sectional and longitudinal signal across both reference regions. With few exceptions, baseline tau did not significantly predict longitudinal change in tau in the same region regardless of reference region. In summary, reference region selection deserves further evaluation as this methodological step may lead to disparate findings. Inferior cerebellar gray matter may be more sensitive to cross-sectional flortaucipir differences, whereas eroded subcortical white matter may be more sensitive for longitudinal analyses examining regional patterns of change.

Amygdala subnuclei volume in bipolar spectrum disorders: Insights from diffusion-based subsegmentation and a high-risk design.

Amygdala abnormalities are widely documented in bipolar spectrum disorders (BSD). Amygdala volume typically is measured after BSD onset; thus, it is not known whether amygdala abnormalities predict BSD risk or relate to the disorder. Additionally, past literature often treated the amygdala as a homogeneous structure, and did not consider its distinct subnuclei and their differential connectivity to other brain regions. To address these issues, we used a behavioral high-risk design and diffusion-based subsegmentation to examine amygdala subnuclei among medication-free individuals with, and at risk for, BSD. The behavioral high-risk design (N = 114) included low-risk (N = 37), high-risk (N = 47), and BSD groups (N = 30). Diffusion-based subsegmentation of the amygdala was conducted to determine whether amygdala volume differences related to particular subnuclei. Individuals with a BSD diagnosis showed greater whole, bilateral amygdala volume compared to Low-Risk individuals. Examination of subnuclei revealed that the BSD group had larger volumes compared to the High-Risk group in both the left medial and central subnuclei, and showed larger volume in the right lateral subnucleus compared to the Low-Risk group. Within the BSD group, specific amygdala subnuclei volumes related to time since first episode onset and number of lifetime episodes. Taken together, whole amygdala volume analyses replicated past findings of enlargement in BSD, but did not detect abnormalities in the high-risk group. Examination of subnuclei volumes detected differences in volume between the high-risk and BSD groups that were missed in the whole amygdala volume. Results have implications for understanding amygdala abnormalities among individuals with, and at risk for, a BSD.

Dynamic Shifts in Large-Scale Brain Network Balance As a Function of Arousal.

The ability to temporarily prioritize rapid and vigilant reactions over slower higher-order cognitive functions is essential for adaptive responding to threat. This reprioritization is believed to reflect shifts in resource allocation between large-scale brain networks that support these cognitive functions, including the salience and executive control networks. However, how changes in communication within and between such networks dynamically unfold as a function of threat-related arousal remains unknown. To address this issue, we collected functional MRI data and continuously assessed the heart rate from 120 healthy human adults as they viewed emotionally arousing and ecologically valid cinematographic material. We then developed an analysis method that tracks dynamic changes in large-scale network cohesion by quantifying the level of within-network and between-network interaction. We found a monotonically increasing relationship between heart rate, a physiological index of arousal, and within-network cohesion in the salience network, indicating that coordination of activity within the salience network dynamically tracks arousal. Strikingly, salience-executive control between-network cohesion peaked at moderate arousal. These findings indicate that at moderate arousal, which has been associated with optimal noradrenergic signaling, the salience network is optimally able to engage the executive control network to coordinate cognitive activity, but is unable to do so at tonically elevated noradrenergic levels associated with acute stress. Our findings extend neurophysiological models of the effects of stress-related neuromodulatory signaling at the cellular level to large-scale neural systems, and thereby explain shifts in cognitive functioning during acute stress, which may play an important role in the development and maintenance of stress-related mental disorders. SIGNIFICANCE STATEMENT: How does brain functioning change in arousing or stressful situations? Extant literature suggests that through global projections, arousal-related neuromodulatory changes can rapidly alter coordination of neural activity across brain-wide neural systems or large-scale networks. Since it is unknown how such processes unfold, we developed a method to dynamically track levels of within-network and between-network interaction. We applied this technique to human neuroimaging data acquired while participants watched realistic and emotionally arousing cinematographic material. Results demonstrate that cohesion within the salience network monotonically increases with arousal, while cohesion of this network with the executive control network peaks at moderate arousal. Our findings explain how cognitive performance shifts as a function of arousal, and provide new insights into vulnerability for stress-related psychopathology.

Brain hyper-connectivity and operation-specific deficits during arithmetic problem solving in children with developmental dyscalculia.

Developmental dyscalculia (DD) is marked by specific deficits in processing numerical and mathematical information despite normal intelligence (IQ) and reading ability. We examined how brain circuits used by young children with DD to solve simple addition and subtraction problems differ from those used by typically developing (TD) children who were matched on age, IQ, reading ability, and working memory. Children with DD were slower and less accurate during problem solving than TD children, and were especially impaired on their ability to solve subtraction problems. Children with DD showed significantly greater activity in multiple parietal, occipito-temporal and prefrontal cortex regions while solving addition and subtraction problems. Despite poorer performance during subtraction, children with DD showed greater activity in multiple intra-parietal sulcus (IPS) and superior parietal lobule subdivisions in the dorsal posterior parietal cortex as well as fusiform gyrus in the ventral occipito-temporal cortex. Critically, effective connectivity analyses revealed hyper-connectivity, rather than reduced connectivity, between the IPS and multiple brain systems including the lateral fronto-parietal and default mode networks in children with DD during both addition and subtraction. These findings suggest the IPS and its functional circuits are a major locus of dysfunction during both addition and subtraction problem solving in DD, and that inappropriate task modulation and hyper-connectivity, rather than under-engagement and under-connectivity, are the neural mechanisms underlying problem solving difficulties in children with DD. We discuss our findings in the broader context of multiple levels of analysis and performance issues inherent in neuroimaging studies of typical and atypical development.

Immature integration and segregation of emotion-related brain circuitry in young children.

The human brain undergoes protracted development, with dramatic changes in expression and regulation of emotion from childhood to adulthood. The amygdala is a brain structure that plays a pivotal role in emotion-related functions. Investigating developmental characteristics of the amygdala and associated functional circuits in children is important for understanding how emotion processing matures in the developing brain. The basolateral amygdala (BLA) and centromedial amygdala (CMA) are two major amygdalar nuclei that contribute to distinct functions via their unique pattern of interactions with cortical and subcortical regions. Almost nothing is currently known about the maturation of functional circuits associated with these amygdala nuclei in the developing brain. Using intrinsic connectivity analysis of functional magnetic resonance imaging data, we investigated developmental changes in functional connectivity of the BLA and CMA in twenty-four 7- to 9-y-old typically developing children compared with twenty-four 19- to 22-y-old healthy adults. Children showed significantly weaker intrinsic functional connectivity of the amygdala with subcortical, paralimbic, and limbic structures, polymodal association, and ventromedial prefrontal cortex. Importantly, target networks associated with the BLA and CMA exhibited greater overlap and weaker dissociation in children. In line with this finding, children showed greater intraamygdala connectivity between the BLA and CMA. Critically, these developmental differences were reproducibly identified in a second independent cohort of adults and children. Taken together, our findings point toward weak integration and segregation of amygdala circuits in young children. These immature patterns of amygdala connectivity have important implications for understanding typical and atypical development of emotion-related brain circuitry.

Atypical child-parent neural synchrony is linked to negative family emotional climate and children's psychopathological symptoms.

[Correction Notice: An Erratum for this article was reported in Vol 79(2) of American Psychologist (see record 2024-62662-005). In the article "Atypical Child-Parent Neural Synchrony Is Linked to Negative Family Emotional Climate and Children's Psychopathological Symptoms," by Haowen Su, Christina B. Young, Zhuo Rachel Han, Jianjie Xu, Bingsen Xiong, Zisen Zhou, Jingyi Wang, Lei Hao, Zhi Yang, Gang Chen, and Shaozheng Qin (American Psychologist, 2024, Vol. 79, No. 2, pp. 210-224, https://doi.org/10.1037/amp0001173), Figure 2 and its caption were corrected to fix a mismatch between the r coefficients and scatterplots. The caption was changed from "(c) Child-parent hippocampal activity concordance was significantly higher for boundary than nonboundary event time series (Z = 2.30, p = .01). (d) Child-parent vmPFC activity concordance was marginally significantly higher for boundary than nonboundary time series (Z = -1.39, p = .08)" to "(c) Child-parent vmPFC activity concordance was marginally significantly lower for boundary than nonboundary time series (Z = -1.39, p = .08). (d) Child- parent hippocampal activity concordance was significantly higher for boundary than nonboundary event time series (Z = 2.30, p = .01)." In addition, in the second sentence of the second paragraph of the "Reduced Child-Parent vmPFC Connectivity With the Hippocampus Links to Negative Family Emotional Climate and Children's Internalizing Symptoms" section, "anxious/depressed" and "internalizing" were switched. All versions of this article have been corrected.] Family emotional climate is fundamental to children's well-being and mental health. Family environments filled with negative emotions may lead to increased psychopathological symptoms in the child through dysfunctional child-parent interactions. Single-brain paradigms have uncovered changes in brain systems and networks related to negative family environments, but how the neurobiological reciprocity between child and parent brains is associated with children's psychopathological symptoms remains unknown. Here, we first investigated the relation between family emotional climate and children's psychopathological symptoms in 395 child-parent dyads. Using a naturalistic movie-watching functional magnetic resonance imaging technique in a subsample of 50 child-parent dyads, we further investigated the neurobiological underpinnings of how family emotional climates are associated with children's psychopathological symptoms through child-parent neural synchrony. Children from negative family emotional climate experienced significantly more severe psychopathological symptoms. In comparison to child-stranger dyads, child-parent dyads exhibited higher intersubject correlations in the dorsal and ventral portions of the medial prefrontal cortex (mPFC), and greater concordance of activity with widespread regions critical for socioemotional skills. Critically, negative family emotional climate was associated with decreased intersubject functional correlation between the ventral-mPFC and the hippocampus during movie watching in child-parent dyads, which further accounted for higher children's internalizing symptoms. Together, our findings provide insights into the neurobiological mechanisms that negative family environments can cause and maintain psychopathological symptoms in children through atypical child-parent neural synchrony. This has important implications for a better understanding of how child-parent connections may mediate the relation between environmental risks and developmental outcomes. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Multiple biomarkers improve diagnostic accuracy across Lewy body and Alzheimer's disease spectra.

OBJECTIVE: More than half of neurodegenerative disease patients have multiple pathologies at autopsy; however, most receive one diagnosis during life. We used the α-synuclein seed amplification assay (αSyn-SAA) and CSF biomarkers for amyloidosis and Alzheimer's disease (AD) neuropathological change (ADNC) to determine the frequency of co-pathologies in participants clinically diagnosed with Lewy body (LB) disease or AD. METHODS: Using receiver operating characteristic analyses on retrospective CSF samples from 150 participants determined αSyn-SAA accuracy, sensitivity, and specificity for identifying clinically defined LB disease and predicting future change in clinical diagnosis. CSF biomarkers helped determine the frequency of concomitant Lewy body pathology, ADNC, and/or amyloidosis in participants with LB disease and AD, across clinical spectra. RESULTS: Following a decade-long follow-up, the clinically or autopsy-defined diagnosis changed for nine participants. αSyn-SAA demonstrated improved accuracy (91.3%), sensitivity (89.3%), and specificity (93.3%) for identifying LB disease compared to all non-LB disease, highlighting the limitations of clinical diagnosis alone. When examining biomarkers of co-pathology, amyloidosis was present in 18%, 48%, and 71% (χ2(2) = 13.56, p = 0.001) and AD biomarkers were present in 0%, 8.7%, and 42.9% (χ2(2) = 18.44, p < 0.001) of LB disease participants with different stages of cognitive impairment respectively. Co-occurring biomarkers for αSyn-SAA and amyloidosis were present in 12% and 14% of AD compared to 43% and 57% LB disease participants with different stages of cognitive impairment (χ2(3) = 13.87, p = 0.003). INTERPRETATION: Our study shows that using a combination of αSyn-SAA and AD biomarkers can identify people with αSyn, ADNC, and co-pathology better and earlier than traditional clinical diagnostic criteria alone.

Associations Between Glucose Metabolism Measures and Amyloid-ß and Tau Load on PET 14 Years Later: Findings From the Framingham Heart Study.

OBJECTIVE: Type 2 diabetes and glucose metabolism have previously been linked to Alzheimer disease (AD). Yet, findings on the relation of glucose metabolism with amyloid-ß and tau pathology later in life remain unclear. RESEARCH DESIGN AND METHODS: We included 288 participants (mean age 43.1 years, SD 10.7, range 20-70 years) without dementia, from the Framingham Heart Study, who had available measures of glucose metabolism (i.e., one-time fasting plasma glucose and insulin) and positron emission tomography (PET) measures of amyloid-ß and/or tau 14 years later. We performed linear regression analyses to test associations of plasma glucose (continuously and categorically; elevated defined as >100 mg/dL), plasma insulin, homeostatic model assessment for insulin resistance (HOMA-IR) with amyloid-ß or tau load on PET. When significant, we explored whether age, sex, and APOE ε4 allele carriership (AD genetic risk) modified these associations. RESULTS: Our findings indicated that elevated plasma glucose was associated with greater tau load 14 years later (B [95% CI] = 0.03 [0.01-0.05], P = 0.024 after false discovery rate [FDR] correction) but not amyloid-ß. APOE ε4 carriership modified this association (B [95% CI] = -0.08 [-0.12 to -0.03], P = 0.001), indicating that the association was only present in APOE ε4 noncarriers (n = 225). Plasma insulin and HOMA-IR were not associated with amyloid-ß or tau load 14 years later after FDR correction. CONCLUSIONS: Our findings suggest that glucose metabolism is associated with increased future tau but not amyloid-ß load. This provides relevant knowledge for prevention strategies and prognostics to improve health care.

The Parkinson's Disease Composite of Executive Functioning: A Measure for Detecting Cognitive Decline in Clinical Trials.

BACKGROUND AND OBJECTIVES: Executive functioning is one of the first domains to be impaired in Parkinson disease (PD), and the majority of patients with PD eventually develop dementia. Thus, developing a cognitive endpoint measure specifically assessing executive functioning is critical for PD clinical trials. The objective of this study was to develop a cognitive composite measure that is sensitive to decline in executive functioning for use in PD clinical trials. METHODS: We used cross-sectional and longitudinal follow-up data from PD participants enrolled in the PD Cognitive Genetics Consortium, a multicenter setting focused on PD. All PD participants with Trail Making Test, Digit Symbol, Letter-Number Sequencing, Semantic Fluency, and Phonemic Fluency neuropsychological data collected from March 2010 to February 2020 were included. Baseline executive functioning data were used to create the Parkinson's Disease Composite of Executive Functioning (PaCEF) through confirmatory factor analysis. We examined the changes in the PaCEF over time, how well baseline PaCEF predicts time to cognitive progression, and the required sample size estimates for PD clinical trials. PaCEF results were compared with the Montreal Cognitive Assessment (MoCA), individual tests forming the PaCEF, and tests of visuospatial, language, and memory functioning. RESULTS: A total of 841 participants (251 no cognitive impairment [NCI], 480 mild cognitive impairment [MCI], and 110 dementia) with baseline data were included, of which the mean (SD) age was 67.1 (8.9) years and 270 were women (32%). Five hundred forty five PD participants had longitudinal neuropsychological data spanning 9 years (mean [SD] 4.5 [2.2] years) and were included in analyses examining cognitive decline. A 1-factor model of executive functioning with excellent fit (comparative fit index = 0.993, Tucker-Lewis index = 0.989, and root mean square error of approximation = 0.044) was used to calculate the PaCEF. The average annual change in PaCEF ranged from 0.246 points per year for PD-NCI participants who remained cognitively unimpaired to -0.821 points per year for PD-MCI participants who progressed to dementia. For PD-MCI, baseline PaCEF, but not baseline MoCA, significantly predicted time to dementia. Sample size estimates were 69%-73% smaller for PD-NCI trials and 16%-19% smaller for PD-MCI trials when using the PaCEF rather than MoCA as the endpoint. DISCUSSION: The PaCEF is a sensitive measure of executive functioning decline in PD and will be especially beneficial for PD clinical trials.

Reliability of remote National Alzheimer's Coordinating Center Uniform Data Set data.

INTRODUCTION: The National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) neuropsychological battery is being used to track cognition in participants across the country, but it is unknown if scores obtained through remote administration can be combined with data obtained in person. METHODS: The remote UDS battery includes the blind version of the Montreal Cognitive Assessment (MoCA), Number Span, Semantic and Phonemic Fluency, and Craft Story. For these tests, we assessed intraclass correlation coefficients (ICCs) between in-person and remote scores in 3838 participants with both in-person and remote UDS assessments, and we compared annual score changes between modalities in a subset that had two remote assessments. RESULTS: All tests exhibited moderate to good reliability between modalities (ICCs = 0.590-0.787). Annual score changes were also comparable between modalities except for Craft Story Immediate Recall, Semantic Fluency, and Phonemic Fluency. DISCUSSION: Our findings generally support combining remote and in-person scores for the majority of UDS tests.

Computerized cognitive practice effects in relation to amyloid and tau in preclinical Alzheimer's disease: Results from a multi-site cohort.

Scalable cognitive paradigms that provide metrics such as the Computerized Cognitive Composite (C3) may be sensitive enough to relate to Alzheimer's disease biomarkers in the preclinical clinically unimpaired (CU) stage. We examined CU older adults (n = 3287) who completed alternate versions of the C3 approximately 51 days apart. A subset of CU with abnormal amyloid also completed tau positron emission tomography (PET) imaging. C3 initial performance and practice effects were examined in relation to amyloid status and continuous regional tau burden. Initial C3 performance was associated with amyloid status across all participants, and with tau burden in the medial temporal lobe and early cortical regions in CU with abnormal amyloid. Short-term practice effects were associated with reduced tau in these regions in CU with abnormal amyloid, but were not associated with amyloid status. Thus, computerized cognitive testing repeated over a short follow-up period provides additional insights into early Alzheimer's disease processes.

APOE effects on regional tau in preclinical Alzheimer's disease.

BACKGROUND: APOE variants are strongly associated with abnormal amyloid aggregation and additional direct effects of APOE on tau aggregation are reported in animal and human cell models. The degree to which these effects are present in humans when individuals are clinically unimpaired (CU) but have abnormal amyloid (Aß+) remains unclear. METHODS: We analyzed data from CU individuals in the Anti-Amyloid Treatment in Asymptomatic AD (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies. Amyloid PET data were available for 4486 participants (3163 Aß-, 1323 Aß+) and tau PET data were available for a subset of 447 participants (55 Aß-, 392 Aß+). Linear models examined APOE (number of e2 and e4 alleles) associations with global amyloid and regional tau burden in medial temporal lobe (entorhinal, amygdala) and early neocortical regions (inferior temporal, inferior parietal, precuneus). Consistency of APOE4 effects on regional tau were examined in 220 Aß + CU and mild cognitive impairment (MCI) participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). RESULTS: APOE2 and APOE4 were associated with lower and higher amyloid positivity rates, respectively. Among Aß+ CU, e2 and e4 were associated with reduced (-12 centiloids per allele) and greater (+15 centiloids per allele) continuous amyloid burden, respectively. APOE2 was associated with reduced regional tau in all regions (-0.05 to -0.09 SUVR per allele), whereas APOE4 was associated with greater regional tau (+0.02 to +0.07 SUVR per allele). APOE differences were confirmed by contrasting e3/e3 with e2/e3 and e3/e4. Mediation analyses among Aß+ s showed that direct effects of e2 on regional tau were present in medial temporal lobe and early neocortical regions, beyond an indirect pathway mediated by continuous amyloid burden. For e4, direct effects on regional tau were only significant in medial temporal lobe. The magnitude of protective e2 effects on regional tau was consistent across brain regions, whereas detrimental e4 effects were greatest in medial temporal lobe. APOE4 patterns were confirmed in Aß+ ADNI participants. CONCLUSIONS: APOE influences early regional tau PET burden, above and beyond effects related to cross-sectional amyloid PET burden. Therapeutic strategies targeting underlying mechanisms related to APOE may modify tau accumulation among Aß+ individuals.