Cerebrospinal fluid levels of synaptic and neuronal integrity correlate with gray matter volume and amyloid load in the precuneus of cognitively intact older adults.

The main pathophysiological alterations of Alzheimer's disease (AD) include loss of neuronal and synaptic integrity, amyloidogenic processing, and neuroinflammation. Similar alterations can, however, also be observed in cognitively intact older subjects and may prelude the clinical manifestation of AD. The objectives of this prospective cross-sectional study in a cohort of 38 cognitively intact older adults were twofold: (i) to investigate the latent relationship among cerebrospinal fluid (CSF) biomarkers reflecting the main pathophysiological processes of AD, and (ii) to assess the correlation between these biomarkers and gray matter volume as well as amyloid load. All subjects underwent extensive neuropsychological examinations, CSF sampling, [18 F]-flutemetamol amyloid positron emission tomography, and T1 -weighted magnetic resonance imaging. A factor analysis revealed one factor that explained most of the variance in the CSF biomarker dataset clustering t-tau, α-synuclein, p-tau181 , neurogranin, BACE1, visinin-like protein 1, chitinase-3-like protein 1 (YKL-40), Aß1-40 and Aß1-38 . Higher scores on this factor correlated with lower gray matter volume and with higher amyloid load in the precuneus. At the level of individual CSF biomarkers, levels of visinin-like protein 1, neurogranin, BACE1, Aß1-40 , Aß1-38, and YKL-40 all correlated inversely with gray matter volume of the precuneus. These findings demonstrate that in cognitively intact older subjects, CSF levels of synaptic and neuronal integrity biomarkers, amyloidogenic processing and measures of innate immunity (YKL-40) display a latent structure of common variance, which is associated with loss of structural integrity of brain regions implicated in the earliest stages of AD. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript, and for *Preregistration* because the study was pre-registered at https://osf.io/7qm9t/. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

Core auditory processing deficits in primary progressive aphasia.

The extent to which non-linguistic auditory processing deficits may contribute to the phenomenology of primary progressive aphasia is not established. Using non-linguistic stimuli devoid of meaning we assessed three key domains of auditory processing (pitch, timing and timbre) in a consecutive series of 18 patients with primary progressive aphasia (eight with semantic variant, six with non-fluent/agrammatic variant, and four with logopenic variant), as well as 28 age-matched healthy controls. We further examined whether performance on the psychoacoustic tasks in the three domains related to the patients' speech and language and neuropsychological profile. At the group level, patients were significantly impaired in the three domains. Patients had the most marked deficits within the rhythm domain for the processing of short sequences of up to seven tones. Patients with the non-fluent variant showed the most pronounced deficits at the group and the individual level. A subset of patients with the semantic variant were also impaired, though less severely. The patients with the logopenic variant did not show any significant impairments. Significant deficits in the non-fluent and the semantic variant remained after partialling out effects of executive dysfunction. Performance on a subset of the psychoacoustic tests correlated with conventional verbal repetition tests. In sum, a core central auditory impairment exists in primary progressive aphasia for non-linguistic stimuli. While the non-fluent variant is clinically characterized by a motor speech deficit (output problem), perceptual processing of tone sequences is clearly deficient. This may indicate the co-occurrence in the non-fluent variant of a deficit in working memory for auditory objects. Parsimoniously we propose that auditory timing pathways are altered, which are used in common for processing acoustic sequence structure in both speech output and acoustic input.

3D Shape Perception in Posterior Cortical Atrophy: A Visual Neuroscience Perspective.

Posterior cortical atrophy (PCA) is a rare focal neurodegenerative syndrome characterized by progressive visuoperceptual and visuospatial deficits, most often due to atypical Alzheimer's disease (AD). We applied insights from basic visual neuroscience to analyze 3D shape perception in humans affected by PCA. Thirteen PCA patients and 30 matched healthy controls participated, together with two patient control groups with diffuse Lewy body dementia (DLBD) and an amnestic-dominant phenotype of AD, respectively. The hierarchical study design consisted of 3D shape processing for 4 cues (shading, motion, texture, and binocular disparity) with corresponding 2D and elementary feature extraction control conditions. PCA and DLBD exhibited severe 3D shape-processing deficits and AD to a lesser degree. In PCA, deficient 3D shape-from-shading was associated with volume loss in the right posterior inferior temporal cortex. This region coincided with a region of functional activation during 3D shape-from-shading in healthy controls. In PCA patients who performed the same fMRI paradigm, response amplitude during 3D shape-from-shading was reduced in this region. Gray matter volume in this region also correlated with 3D shape-from-shading in AD. 3D shape-from-disparity in PCA was associated with volume loss slightly more anteriorly in posterior inferior temporal cortex as well as in ventral premotor cortex. The findings in right posterior inferior temporal cortex and right premotor cortex are consistent with neurophysiologically based models of the functional anatomy of 3D shape processing. However, in DLBD, 3D shape deficits rely on mechanisms distinct from inferior temporal structural integrity. SIGNIFICANCE STATEMENT: Posterior cortical atrophy (PCA) is a neurodegenerative syndrome characterized by progressive visuoperceptual dysfunction and most often an atypical presentation of Alzheimer's disease (AD) affecting the ventral and dorsal visual streams rather than the medial temporal system. We applied insights from fundamental visual neuroscience to analyze 3D shape perception in PCA. 3D shape-processing deficits were affected beyond what could be accounted for by lower-order processing deficits. For shading and disparity, this was related to volume loss in regions previously implicated in 3D shape processing in the intact human and nonhuman primate brain. Typical amnestic-dominant AD patients also exhibited 3D shape deficits. Advanced visual neuroscience provides insight into the pathogenesis of PCA that also bears relevance for vision in typical AD.

Amyloid imaging in cognitively normal older adults: comparison between (18)F-flutemetamol and (11)C-Pittsburgh compound B.

PURPOSE: Preclinical, or asymptomatic, Alzheimer's disease (AD) refers to the presence of positive AD biomarkers in the absence of cognitive deficits. This research concept is being applied to define target populations for clinical drug development. In a prospective community-recruited cohort of cognitively intact older adults, we compared two amyloid imaging markers within subjects: (18)F-flutemetamol and (11)C-Pittsburgh compound B (PIB). METHODS: In 32 community-recruited cognitively intact older adults aged between 65 and 80 years, we determined the concordance between binary classification based on (18)F-flutemetamol versus (11)C-PIB according to semiquantitative assessment (standardized uptake value ratio in composite cortical volume, SUVRcomp) and, alternatively, according to visual reads. We also determined the correlation between (18)F-flutemetamol and (11)C-PIB SUVR and evaluated how this was affected by the reference region chosen (cerebellar grey matter versus pons) and the use of partial volume correction (PVC) in this population. RESULTS: Binary classification based on semiquantitative assessment was concordant between (18)F-flutemetamol and (11)C-PIB in 94 % of cases. Concordance of blinded binary visual reads between tracers was 84 %. The Spearman correlation between (18)F-flutemetamol and (11)C-PIB SUVRcomp with cerebellar grey matter as reference region was 0.84, with a slope of 0.98. Correlations in neocortical regions were significantly lower with the pons as reference region. PVC improved the correlation in striatum and medial temporal cortex. CONCLUSION: For the definition of preclinical AD based on (18)F-flutemetamol, concordance with (11)C-PIB was highest using semiquantitative assessment with cerebellar grey matter as reference region.

Representation of Semantic Similarity in the Left Intraparietal Sulcus: Functional Magnetic Resonance Imaging Evidence.

According to a recent study, semantic similarity between concrete entities correlates with the similarity of activity patterns in left middle IPS during category naming. We examined the replicability of this effect under passive viewing conditions, the potential role of visuoperceptual similarity, where the effect is situated compared to regions that have been previously implicated in visuospatial attention, and how it compares to effects of object identity and location. Forty-six subjects participated. Subjects passively viewed pictures from two categories, musical instruments and vehicles. Semantic similarity between entities was estimated based on a concept-feature matrix obtained in more than 1,000 subjects. Visuoperceptual similarity was modeled based on the HMAX model, the AlexNet deep convolutional learning model, and thirdly, based on subjective visuoperceptual similarity ratings. Among the IPS regions examined, only left middle IPS showed a semantic similarity effect. The effect was significant in hIP1, hIP2, and hIP3. Visuoperceptual similarity did not correlate with similarity of activity patterns in left middle IPS. The semantic similarity effect in left middle IPS was significantly stronger than in the right middle IPS and also stronger than in the left or right posterior IPS. The semantic similarity effect was similar to that seen in the angular gyrus. Object identity effects were much more widespread across nearly all parietal areas examined. Location effects were relatively specific for posterior IPS and area 7 bilaterally. To conclude, the current findings replicate the semantic similarity effect in left middle IPS under passive viewing conditions, and demonstrate its anatomical specificity within a cytoarchitectonic reference frame. We propose that the semantic similarity effect in left middle IPS reflects the transient uploading of semantic representations in working memory.