Association of CSF Biomarkers With Hippocampal-Dependent Memory in Preclinical Alzheimer Disease.

OBJECTIVE: To determine whether memory tasks with demonstrated sensitivity to hippocampal function can detect variance related to preclinical Alzheimer disease (AD) biomarkers, we examined associations between performance in 3 memory tasks and CSF ß-amyloid (Aß)42/Aß40 and phosopho-tau181 (p-tau181) in cognitively unimpaired older adults (CU). METHODS: CU enrolled in the Stanford Aging and Memory Study (n = 153; age 68.78 ± 5.81 years; 94 female) completed a lumbar puncture and memory assessments. CSF Aß42, Aß40, and p-tau181 were measured with the automated Lumipulse G system in a single-batch analysis. Episodic memory was assayed using a standardized delayed recall composite, paired associate (word-picture) cued recall, and a mnemonic discrimination task that involves discrimination between studied "target" objects, novel "foil" objects, and perceptually similar "lure" objects. Analyses examined cross-sectional relationships among memory performance, age, and CSF measures, controlling for sex and education. RESULTS: Age and lower Aß42/Aß40 were independently associated with elevated p-tau181. Age, Aß42/Aß40, and p-tau181 were each associated with (1) poorer associative memory and (2) diminished improvement in mnemonic discrimination performance across levels of decreased task difficulty (i.e., target-lure similarity). P-tau mediated the effect of Aß42/Aß40 on memory. Relationships between CSF proteins and delayed recall were similar but nonsignificant. CSF Aß42 was not significantly associated with p-tau181 or memory. CONCLUSIONS: Tests designed to tax hippocampal function are sensitive to subtle individual differences in memory among CU and correlate with early AD-associated biomarker changes in CSF. These tests may offer utility for identifying CU with preclinical AD pathology.

Memory failure predicted by attention lapsing and media multitasking.

With the explosion of digital media and technologies, scholars, educators and the public have become increasingly vocal about the role that an 'attention economy' has in our lives1. The rise of the current digital culture coincides with longstanding scientific questions about why humans sometimes remember and sometimes forget, and why some individuals remember better than others2-6. Here we examine whether spontaneous attention lapses-in the moment7-12, across individuals13-15 and as a function of everyday media multitasking16-19-negatively correlate with remembering. Electroencephalography and pupillometry measures of attention20,21 were recorded as eighty young adults (mean age, 21.7 years) performed a goal-directed episodic encoding and retrieval task22. Trait-level sustained attention was further quantified using task-based23 and questionnaire measures24,25. Using trial-to-trial retrieval data, we show that tonic lapses in attention in the moment before remembering, assayed by posterior alpha power and pupil diameter, were correlated with reductions in neural signals of goal coding and memory, along with behavioural forgetting. Independent measures of trait-level attention lapsing mediated the relationship between neural assays of lapsing and memory performance, and between media multitasking and memory. Attention lapses partially account for why we remember or forget in the moment, and why some individuals remember better than others. Heavier media multitasking is associated with a propensity to have attention lapses and forget.

Hippocampal and cortical mechanisms at retrieval explain variability in episodic remembering in older adults.

Age-related episodic memory decline is characterized by striking heterogeneity across individuals. Hippocampal pattern completion is a fundamental process supporting episodic memory. Yet, the degree to which this mechanism is impaired with age, and contributes to variability in episodic memory, remains unclear. We combine univariate and multivariate analyses of fMRI data from a large cohort of cognitively normal older adults (N=100) to measure hippocampal activity and cortical reinstatement during retrieval of trial-unique associations. Trial-wise analyses revealed that (a) hippocampal activity scaled with reinstatement strength, (b) cortical reinstatement partially mediated the relationship between hippocampal activity and associative retrieval, (c) older age weakened cortical reinstatement and its relationship to memory behaviour. Moreover, individual differences in the strength of hippocampal activity and cortical reinstatement explained unique variance in performance across multiple assays of episodic memory. These results indicate that fMRI indices of hippocampal pattern completion explain within- and across-individual memory variability in older adults.

Network degeneration and dysfunction in presymptomatic C9ORF72 expansion carriers.

Hexanucleotide repeat expansions in C9ORF72 are the most common known genetic cause of familial and sporadic frontotemporal dementia and amyotrophic lateral sclerosis. Previous work has shown that patients with behavioral variant frontotemporal dementia due to C9ORF72 show salience and sensorimotor network disruptions comparable to those seen in sporadic behavioral variant frontotemporal dementia, but it remains unknown how early in the lifespan these and other changes in brain structure and function arise. To gain insights into this question, we compared 15 presymptomatic carriers (age 43.7 ± 10.2 years, nine females) to matched healthy controls. We used voxel-based morphometry to assess gray matter, diffusion tensor imaging to interrogate white matter tracts, and task-free functional MRI to probe the salience, sensorimotor, default mode, and medial pulvinar thalamus-seeded networks. We further used a retrospective chart review to ascertain psychiatric histories in carriers and their non-carrier family members. Carriers showed normal cognition and behavior despite gray matter volume and brain connectivity deficits that were apparent as early as the fourth decade of life. Gray matter volume deficits were topographically similar though less severe than those in patients with behavioral variant frontotemporal dementia due to C9ORF72, with major foci in cingulate, insula, thalamus, and striatum. Reduced white matter integrity was found in the corpus callosum, cingulum bundles, corticospinal tracts, uncinate fasciculi and inferior longitudinal fasciculi. Intrinsic connectivity deficits were detected in all four networks but most prominent in salience and medial pulvinar thalamus-seeded networks. Carrier and control groups showed comparable relationships between imaging metrics and age, suggesting that deficits emerge during early adulthood. Carriers and non-carrier family members had comparable lifetime histories of psychiatric symptoms. Taken together, the findings suggest that presymptomatic C9ORF72 expansion carriers exhibit functionally compensated brain volume and connectivity deficits that are similar, though less severe, to those reported during the symptomatic phase. The early adulthood emergence of these deficits suggests that they represent aberrant network patterning during development, an early neurodegeneration prodrome, or both.

Early-onset Alzheimer's disease versus frontotemporal dementia: resolution with genetic diagnoses?

We report a diagnostically challenging case of a 64-year-old man with a history of remote head trauma who developed mild behavioral changes and dyscalculia. He was diagnosed with clinical Alzheimer's disease (AD), with additional features consistent with behavioral variant frontotemporal dementia. Structural magnetic resonance imaging revealed atrophy in bilateral frontal and parietal cortices and hippocampi on visual inspection and left frontal pole and bilateral anterior temporal encephalomalacia, suspected to be due to head trauma. Consistent with the diagnosis of Alzheimer's pathology, positron emission tomography (PET) with Pittsburgh compound B suggested the presence of beta-amyloid. Fluorodeoxyglucose PET demonstrated hypometabolism in bilateral frontal and temporoparietal cortices. Voxel-based morphometry showed atrophy predominant in ventral frontal regions (bilateral orbitofrontal cortex, pregenual anterior cingulate/medial superior frontal gyrus), bilateral mid cingulate, bilateral lateral temporal cortex, and posterior insula. Bilateral caudate, thalamus, hippocampi, and cerebellum were prominently atrophied. Unexpectedly, a pathologic hexanucleotide repeat expansion in C9ORF72 was identified in this patient. This report underscores the clinical variability in C9ORF72 expansion carriers and the need to consider mixed pathologies, particularly when imaging studies are inconsistent with a single syndrome or pathology.

Altered network connectivity in frontotemporal dementia with C9orf72 hexanucleotide repeat expansion.

Hexanucleotide repeat expansion in C9orf72 represents the most common genetic cause of familial and sporadic behavioural variant frontotemporal dementia. Previous studies show that some C9orf72 carriers with behavioural variant frontotemporal dementia exhibit distinctive atrophy patterns whereas others show mild or undetectable atrophy despite severe behavioural impairment. To explore this observation, we examined intrinsic connectivity network integrity in patients with or without the C9orf72 expansion. We studied 28 patients with behavioural variant frontotemporal dementia, including 14 C9orf72 mutation carriers (age 58.3 ± 7.7 years, four females) and 14 non-carriers (age 60.8 ± 6.9 years, four females), and 14 age- and sex-matched healthy controls. Both patient groups included five patients with comorbid motor neuron disease. Neuropsychological data, structural brain magnetic resonance imaging, and task-free functional magnetic resonance imaging were obtained. Voxel-based morphometry delineated atrophy patterns, and seed-based intrinsic connectivity analyses enabled group comparisons of the salience, sensorimotor, and default mode networks. Single-patient analyses were used to explore network imaging as a potential biomarker. Despite contrasting atrophy patterns in C9orf72 carriers versus non-carriers, patient groups showed topographically similar connectivity reductions in the salience and sensorimotor networks. Patients without C9orf72 expansions exhibited increases in default mode network connectivity compared to controls and mutation carriers. Across all patients, behavioural symptom severity correlated with diminished salience network connectivity and heightened default mode network connectivity. In C9orf72 carriers, salience network connectivity reduction correlated with atrophy in the left medial pulvinar thalamic nucleus, and this region further showed diminished connectivity with key salience network hubs. Single-patient analyses revealed salience network disruption and default mode network connectivity enhancement in C9orf72 carriers with early-stage or slowly progressive symptoms. The findings suggest that patients with behavioural variant frontotemporal dementia with or without the C9orf72 expansion show convergent large-scale network breakdowns despite distinctive atrophy patterns. Medial pulvinar degeneration may contribute to the behavioural variant frontotemporal dementia syndrome in C9orf72 carriers by disrupting salience network connectivity. Task-free functional magnetic resonance imaging shows promise in detecting early-stage disease in C9orf72 carriers and may provide a unifying biomarker across diverse anatomical variants.