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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.

Background: Olfactory deficiency can be present in preclinical Alzheimer's (AD) and Parkinson's disease (PD), predicting their subsequent manifestation, including mild cognitive impairment (MCI). Analyzing key regions within the olfactory circuit could reveal important insights into the neuropathological progression. Dysfunction in the olfactory circuit has been shown in the olfactory nerve in limited postmortem studies, including involvement of a key region, the piriform cortex. FDG‐positron emission tomography (PET) and fMRI have shown differential and reduced piriform cortex metabolism/activation in AD. Thus, the piriform cortex is a promising candidate in the early identification of neurodegenerative pathology underlying olfaction. We used tau MR‐PET to analyze the piriform cortex, in comparison to the adjacent medial temporal lobe. Method: We analyzed 115 subjects: 23 were excluded (incomplete data), leaving 31 amyloid‐negative and 25 amyloid‐positive healthy controls, 8 MCI, 15 AD, and 13 PD. All subjects underwent MR‐PET using tau tracer PI‐2620 with a simultaneous coregistered sagittal T1‐weighted 3D IR‐FSPGR and a simultaneous/recently acquired coronal T2‐weighted FSE. Automatic Segmentation of Hippocampal Subfields was performed, including the entorhinal‐perirhinal cortices (Fig. 1D‐F). Referencing published piriform segmentation guidelines, we manually segmented blind to subject diagnosis the frontal/temporal portions of the piriform cortex (Fig. 1C), including multiple independent quality control checks. As tau distributions appeared non‐normal among the five ordinal patient categories (Amyloid–HC, Amyloid+HC, MCI, AD, Normal PD), we used a nonparametric Jonckheere‐Terpstra test in Stata to test for ordinal increase in tau uptake across four regions bilaterally (whole hippocampus = CA1‐4 + DG + subiculum, entorhinal‐perirhinal, amygdala, and piriform). Result: We found an ordinal increase in piriform tau uptake with increasing disease severity (amyloid‐negative controls, amyloid‐positive controls, MCI and AD) (Figure 2A‐D). Amyloid‐positive controls showed significantly greater uptake than amyloid‐negative controls. Piriform uptake was not elevated in cognitively unimpaired PD compared to Amyloid‐HC. Piriform volume was statistically equivalent across groups, except PD had lower volumes (Figure 2E‐H). Negative correlations were present between memory performance and piriform uptake (Figure 3). Conclusion: Cross‐sectionally, there is an early increase in tau uptake in the piriform cortex in AD but not in PD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Olfactory dysfunction can be an early sign of Alzheimer's disease (AD). We used tau positron emission tomography‐magnetic resonance (PET‐MR) to analyze a key region of the olfactory circuit, the piriform cortex, in comparison to the adjacent medial temporal lobe. METHODS: Using co‐registered magnetic resonance imaging (MRI) and 18F‐PI‐2620 tau PET‐MR scans in 94 older adults, we computed tau uptake in the piriform‐periamygdaloid cortex, amygdala, entorhinal‐perirhinal cortices, and hippocampus. RESULTS: We found an ordinal cross‐sectional increase in piriform cortex tau uptake with increasing disease severity (amyloid‐negative controls, amyloid‐positive controls, mild cognitive impairment [MCI] and AD), comparable to entorhinal‐perirhinal cortex. Amyloid‐positive controls showed significantly greater tau uptake than amyloid‐negative controls. Negative correlations were present between memory performance and piriform uptake. Piriform uptake was not elevated in cognitively unimpaired Parkinson's disease. DISCUSSION: Cross‐sectionally, there is an early increase in tau uptake in the piriform cortex in AD but not in Parkinson's disease. Highlights: Positron emission tomography–magnetic resonance (PET‐MR) analysis of the piriform cortex sheds light on its role as a potential early region affected by neurodegenerative disorders underlying olfactory dysfunction.Uptake of tau tracer was elevated in the piriform cortex in Alzheimer's disease (AD) and mild cognitive impairment (MCI) but not in Parkinson's disease (PD).Memory performance was worse with greater piriform uptake. [ABSTRACT FROM AUTHOR]

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-β 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-β 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-β 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-β. 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-β 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-β load. This provides relevant knowledge for prevention strategies and prognostics to improve health care. [ABSTRACT FROM AUTHOR]

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/Aβ42, and CSF Aβ42/Aβ40 or amyloid‐β 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 [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is the most common form of dementia. Neuropathologically, AD stands out as a mixed proteinopathy. Beta‐amyloid and tau biomarkers can now add in‐vivo support to the AD diagnosis. Rarely, a patient with AD confirmed at autopsy may have a negative amyloid PET. Here we describe a pedigree in whom the index case was amyloid PET‐negative. We performed genetic sequencing of two affected siblings to identify a set of candidate single nucleotide variants (SNVs) and structural variants (SVs) associated with disease and rare in healthy older controls from several large genetic databases. Method: We performed long‐read sequencing (LRS) to comprehensively evaluate both SNVs and SVs. The index case, an APOE3/E4 male, developed memory trouble at 68 that progressed to probable AD at 72. Notably (Fig. 1) his amyloid‐PET scan, which was confirmed to be of high technical quality, was negative. His tau PET scan was positive and his plasma Abeta42/40 was in the expected range for Stanford AD patients. His family history is extensive and suggestive of an autosomal dominant pattern of late‐onset AD (Fig. 2). The patient's sister was diagnosed with AD at 62. We filtered their shared heterozygous SNVs keeping those with a minor allele frequency < 0.01 in gnomAD and that were not present in any ADSP healthy controls (HC) over 70y.o. (N = 19771;62.1%females;81±6.4y.o). Shared SVs were kept as candidates if they were not seen in any Stanford LRS HC (N = 95;59%females;72±1.5y.o.) Result: Neuropathological analysis revealed that both siblings met the A3B3C3 criteria for AD and had cerebral amyloid angiopathy. Among rare mutations on genes expressed in the brain (Table 1), a novel missense in ADNP (Activity‐Dependent‐Neuroprotector‐Homeobox), and a 267bp deletion on TET1 (Tet‐Methylcytosine‐Dioxygenase) were identified. The 3426bp insertion on ATP8A2 (ATPase‐Phospholipid‐Transporting‐8A2) was the longest, rare insertion found. Additionally, a large duplication (∼20Kbp) and inversion (∼160Kbp) were observed. Conclusion: This study highlights an unusual AD pedigree and emphasizes the potential utility of LRS in identifying causal SNVs and SVs. In future work we plan to perform additional amyloid stains to understand why the index case PET was amyloid‐negative. We are also assessing additional family members to improve our ability to identify a causal mutation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 moviewatching 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. [ABSTRACT FROM AUTHOR]

Background: APOE*4 status and sex (and their interaction) are among the strongest risk factors for late‐onset Alzheimer's disease (AD). We thus sought to perform large‐scale, stratified genome‐wide association study (GWAS) of AD to chart the role of common genetic variation in AD sexual dimorphism and heterogeneity of APOE*4‐related AD risk. Method: The study overview and GWAS models are shown in Figure.1A. SNP‐array AD GWAS datasets primarily composing the ADGC, together with whole‐genome sequencing (WGS) from ADSP (NG00067.v7), provided case‐control diagnoses for phase‐1. The UK Biobank provided subjects with ICD codes and family history of AD status for phase‐2. Subjects were of European ancestry. Linear mixed model regressions were performed (LMM‐BOLT v.2.3.4) on AD outcome measures, adjusting for sex, APOE*4/APOE*2 dosage, genetic principal components, and array/batch/center. GWAS hits (P<5e‐*8) were evaluated for interactions effects (meta‐regression for phase1+2 meta‐analyses) and assessed in functional follow‐up analyses. The effect of stratification on genetic risk scores (GRS) predictive performance on AD risk was also evaluated. Result: Stratified AD GWAS identified 28 loci/variants, including 5 known lead variants in known AD loci, 6 novel independent variants in known AD loci, and 17 novel loci (Figure.1B). 13 out of 17 novel loci showed varying degrees of functional support, with 4 also showing evidence for QTL colocalization (Figure.2). Many implicated genes showed prior support or effects relevant to AD: MARCHF10 was recently implicated as a risk gene for all‐cause dementia; EMP2 is a regulator of cell membrane composition, cell‐matrix adhesion, and blood vessel endothelial cell migration; SLIT2 binds APP, and EYA4 and TBC1D9 have respectively been implicated in brain tau deposition and MAPT haplotype‐stratified GWAS. Nonetheless, most novel hits were low/uncommon frequency variants and QTL colocalization evidence was limited. Further, there appeared to be no predictive benefit for stratified GRS analyses (Figure.3). Conclusion: We identified novel loci/variants differentially associated with AD risk across APOE*4 and/or sex. Yet, we inferred relatively limited evidence for stratified effects (propensity for low frequency hits and no benefit for stratified GRS). Overall, our findings contribute to our understanding of the genetic etiology of AD, which in turn contributes to advance personalized genetic medicine. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]