Amyloid pathology but not APOE ε4 status is permissive for tau-related hippocampal dysfunction.

We investigated whether the impact of tau-pathology on memory performance and on hippocampal/medial temporal memory function in non-demented individuals depends on the presence of amyloid pathology, irrespective of diagnostic clinical stage. We conducted a cross-sectional analysis of the observational, multicentric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE). Two hundred and thirty-five participants completed task functional MRI and provided CSF (92 cognitively unimpaired, 100 experiencing subjective cognitive decline and 43 with mild cognitive impairment). Presence (A+) and absence (A-) of amyloid pathology was defined by CSF amyloid-ß42 (Aß42) levels. Free recall performance in the Free and Cued Selective Reminding Test, scene recognition memory accuracy and hippocampal/medial temporal functional MRI novelty responses to scene images were related to CSF total-tau and phospho-tau levels separately for A+ and A- individuals. We found that total-tau and phospho-tau levels were negatively associated with memory performance in both tasks and with novelty responses in the hippocampus and amygdala, in interaction with Aß42 levels. Subgroup analyses showed that these relationships were only present in A+ and remained stable when very high levels of tau (>700 pg/ml) and phospho-tau (>100 pg/ml) were excluded. These relationships were significant with diagnosis, age, education, sex, assessment site and Aß42 levels as covariates. They also remained significant after propensity score based matching of phospho-tau levels across A+ and A- groups. After classifying this matched sample for phospho-tau pathology (T-/T+), individuals with A+/T+ were significantly more memory-impaired than A-/T+ despite the fact that both groups had the same amount of phospho-tau pathology. ApoE status (presence of the E4 allele), a known genetic risk factor for Alzheimer's disease, did not mediate the relationship between tau pathology and hippocampal function and memory performance. Thus, our data show that the presence of amyloid pathology is associated with a linear relationship between tau pathology, hippocampal dysfunction and memory impairment, although the actual severity of amyloid pathology is uncorrelated. Our data therefore indicate that the presence of amyloid pathology provides a permissive state for tau-related hippocampal dysfunction and hippocampus-dependent recognition and recall impairment. This raises the possibility that in the predementia stage of Alzheimer's disease, removing the negative impact of amyloid pathology could improve memory and hippocampal function even if the amount of tau-pathology in CSF is not changed, whereas reducing increased CSF tau-pathology in amyloid-negative individuals may not proportionally improve memory function.

A comprehensive score reflecting memory-related fMRI activations and deactivations as potential biomarker for neurocognitive aging.

Older adults and particularly those at risk for developing dementia typically show a decline in episodic memory performance, which has been associated with altered memory network activity detectable via functional magnetic resonance imaging (fMRI). To quantify the degree of these alterations, a score has been developed as a putative imaging biomarker for successful aging in memory for older adults (Functional Activity Deviations during Encoding, FADE; Düzel et al., Hippocampus, 2011; 21: 803-814). Here, we introduce and validate a more comprehensive version of the FADE score, termed FADE-SAME (Similarity of Activations during Memory Encoding), which differs from the original FADE score by considering not only activations but also deactivations in fMRI contrasts of stimulus novelty and successful encoding, and by taking into account the variance of young adults' activations. We computed both scores for novelty and subsequent memory contrasts in a cohort of 217 healthy adults, including 106 young and 111 older participants, as well as a replication cohort of 117 young subjects. We further tested the stability and generalizability of both scores by controlling for different MR scanners and gender, as well as by using different data sets of young adults as reference samples. Both scores showed robust age-group-related differences for the subsequent memory contrast, and the FADE-SAME score additionally exhibited age-group-related differences for the novelty contrast. Furthermore, both scores correlate with behavioral measures of cognitive aging, namely memory performance. Taken together, our results suggest that single-value scores of memory-related fMRI responses may constitute promising biomarkers for quantifying neurocognitive aging.

Aggregation-resistant alpha-synuclein tetramers are reduced in the blood of Parkinson's patients.

Synucleinopathies such as Parkinson's disease (PD) are defined by the accumulation and aggregation of the α-synuclein protein in neurons, glia and other tissues. We have previously shown that destabilization of α-synuclein tetramers is associated with familial PD due to SNCA mutations and demonstrated brain-region specific alterations of α-synuclein multimers in sporadic PD patients following the classical Braak spreading theory. In this study, we assessed relative levels of disordered and higher-ordered multimeric forms of cytosolic α-synuclein in blood from familial PD with G51D mutations and sporadic PD patients. We used an adapted in vitro-cross-linking protocol for human EDTA-whole blood. The relative levels of higher-ordered α-synuclein tetramers were diminished in blood from familial PD and sporadic PD patients compared to controls. Interestingly, the relative amount of α-synuclein tetramers was already decreased in asymptomatic G51D carriers, supporting the hypothesis that α-synuclein multimer destabilization precedes the development of clinical PD. Our data, therefore suggest that measuring α-synuclein tetramers in blood may have potential as a facile biomarker assay for early detection and quantitative tracking of PD progression.

Case report: Anti-ARHGAP26 autoantibodies in atypical dementia with Lewy bodies.

Background: Dementia with Lewy bodies (DLB) is the second most common type of neurodegenerative dementia. Here, we report a case of dementia associated with anti-Rho-GTPase-activating protein 26 (ARHGAP26) autoantibodies, which have never been previously linked to DLB. Methods: We describe the case of a 78-year-old man who underwent cerebrospinal fluid (CSF) analysis, magnetic resonance imaging (MRI), 18F-fluorodesoxyglucose positron emission tomography (FDG-PET), and a detailed neuropsychological evaluation. Results: The patient presented with mild dementia syndrome associated with extrapyramidal symptoms. Neuropsychological testing revealed impaired cognitive flexibility, figural memory, and verbal memory. Fluctuating cognitive abilities with deficits in attention-executive dysfunction and visuoconstruction also developed over time. A brain MRI showed reduced biparietal and cerebellar brain volume with generalized accentuation of the outer CSF spaces. The patient's CSF revealed anti-ARHGAP26 autoantibodies, which were also detectable in serum. In the differential complementary imaging diagnosis at 2 years, an FDG-PET revealed decreased occupancy of the posterior cingulum and precuneus. Although the FDG-PET, MRI, and clinical findings were potentially consistent with Alzheimer's disease, negative amyloid biomarkers in the CSF made an AD diagnosis highly unlikely. Single photon emission computed tomography (SPECT) with [(123)I] N-omega-fluoropropyl-2beta-carbomethoxy-3beta-{4-iodophenyl}nortropane ([(123)I]FP-CIT) showed right-sided predominance, reduced dopamine transporter uptake in the putamen, consistent with a positive indicative biomarker finding typical of DLB. Considering the clinically probable DLB associated with the two core features of Parkinsonism and fluctuating cognition with deficits in attention, supported by an abundant tracer uptake in the right putamen and lower uptake in the left putamen on 123I-FP-CIT-SPECT as an indicative biomarker, we started an antidementia drug using a cholinesterase inhibitor. Conclusions: Our report shows that atypical DLB may be associated with anti-ARHGAP26 autoantibodies, although their role and significance in the pathogenesis of DLB are unknown. However, it has to be mentioned that it is also possible that antibody-specific synthesis of anti-ARHGAP26 autoantibodies is a hallmark of a rare autoimmune disease that may cause the clinical and laboratory features involving altered dopamine transporter uptake on 123I-FP-CIT-SPECT, dementia, and mild Parkinson's symptoms rather than idiopathic DLB with only two core DLB features and inconsistent cognitive and imaging findings. Further research is needed to investigate the role of these autoantibodies in different dementias, particularly in DLB and mixed DLB-AD types.

Brain reserve contributes to distinguishing preclinical Alzheimer's stages 1 and 2.

BACKGROUND: In preclinical Alzheimer's disease, it is unclear why some individuals with amyloid pathologic change are asymptomatic (stage 1), whereas others experience subjective cognitive decline (SCD, stage 2). Here, we examined the association of stage 1 vs. stage 2 with structural brain reserve in memory-related brain regions. METHODS: We tested whether the volumes of hippocampal subfields and parahippocampal regions were larger in individuals at stage 1 compared to asymptomatic amyloid-negative older adults (healthy controls, HCs). We also tested whether individuals with stage 2 would show the opposite pattern, namely smaller brain volumes than in amyloid-negative individuals with SCD. Participants with cerebrospinal fluid (CSF) biomarker data and bilateral volumetric MRI data from the observational, multi-centric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) study were included. The sample comprised 95 amyloid-negative and 26 amyloid-positive asymptomatic participants as well as 104 amyloid-negative and 47 amyloid-positive individuals with SCD. Volumes were based on high-resolution T2-weighted images and automatic segmentation with manual correction according to a recently established high-resolution segmentation protocol. RESULTS: In asymptomatic individuals, brain volumes of hippocampal subfields and of the parahippocampal cortex were numerically larger in stage 1 compared to HCs, whereas the opposite was the case in individuals with SCD. MANOVAs with volumes as dependent data and age, sex, years of education, and DELCODE site as covariates showed a significant interaction between diagnosis (asymptomatic versus SCD) and amyloid status (Aß42/40 negative versus positive) for hippocampal subfields. Post hoc paired comparisons taking into account the same covariates showed that dentate gyrus and CA1 volumes in SCD were significantly smaller in amyloid-positive than negative individuals. In contrast, CA1 volumes were significantly (p = 0.014) larger in stage 1 compared with HCs. CONCLUSIONS: These data indicate that HCs and stages 1 and 2 do not correspond to linear brain volume reduction. Instead, stage 1 is associated with larger than expected volumes of hippocampal subfields in the face of amyloid pathology. This indicates a brain reserve mechanism in stage 1 that enables individuals with amyloid pathologic change to be cognitively normal and asymptomatic without subjective cognitive decline.

Mild Amnestic Cognitive Impairment and Depressive Symptoms in Autoimmune Encephalitis Associated with Serum Anti-Neurexin-3α Autoantibodies.

(1) Background: autoimmune encephalitis associated with neurexin-3α antibodies is a seldom reported disease entity often accompanied by a severe clinical neuropsychiatric syndrome. (2) Method: we report on the case of a 58-year-old man diagnosed with neurexin-3α-associated autoimmune encephalitis revealing cognitive decline and depression before the proof of neurexin-3α antibodies. He underwent neuropsychological testing, peripheral blood and cerebrospinal fluid analysis, neuroimaging and electroencephalography. (3) Results: our patient's main clinical feature was amnestic cognitive decline in combination with depressive symptoms. CSF analysis showed elevated phosphorylated tau protein 181 and positive proof of serum neurexin-3α antibodies in a cell-based assay. An 18F-FDG-PET/CT of the brain initially showed bilateral cerebral hypometabolism prefrontal and parietal, which was absent in follow up. The brain MRI was unremarkable. EEG recordings showed frontotemporal slowing in the theta and delta range. (4) Conclusions: taken together, we assumed autoimmune encephalitis associated with serum neurexin-3α antibodies. To the best of our knowledge, we are the first to report on a predominantly mild clinical manifestation entailing amnestic mild cognitive impairment in addition to depression, thus broadening the clinical spectrum associated with neurexin-3α antibodies.

Motivational salience modulates hippocampal repetition suppression and functional connectivity in humans.

Repetition suppression (RS) is a rapid decrease of stimulus-related neuronal responses upon repeated presentation of a stimulus. Previous studies have demonstrated that negative emotional salience of stimuli enhances RS. It is, however, unclear how motivational salience of stimuli, such as reward-predicting value, influences RS for complex visual stimuli, and which brain regions might show differences in RS for reward-predicting and neutral stimuli. Here we investigated the influence of motivational salience on RS of complex scenes using event-related functional magnetic resonance imaging. Thirty young healthy volunteers performed a monetary incentive delay task with complex scenes (indoor vs. outdoor) serving as neutral or reward-predicting cue pictures. Each cue picture was presented three times. In line with previous findings, reward anticipation was associated with activations in the ventral striatum, midbrain, and orbitofrontal cortex (OFC). Stimulus repetition was associated with pronounced RS in ventral visual stream areas like the parahippocampal place area (PPA). An interaction of reward anticipation and RS was specifically observed in the anterior hippocampus, where a response decrease across repetitions was observed for the reward-predicting scenes only. Functional connectivity analysis further revealed specific activity-dependent connectivity increases of the hippocampus and the PPA and OFC. Our results suggest that hippocampal RS is sensitive to reward-predicting properties of stimuli and might therefore reflect a rapid, adaptive neural response mechanism for motivationally salient information.