In vivo tau pathology is associated with synaptic loss and altered synaptic function

BACKGROUND: The mechanism of synaptic loss in Alzheimer’s disease is poorly understood and may be associated with tau pathology. In this combined positron emission tomography (PET) and magnetoencephalography (MEG) study, we aimed to investigate spatial associations between regional tau pathology ([{18}^F]flortaucipir PET), synaptic density (synaptic vesicle 2A [11C]UCB-J PET) and synaptic function (MEG) in Alzheimer’s disease. METHODS: Seven amyloid-positive Alzheimer’s disease subjects from the Amsterdam Dementia Cohort underwent dynamic 130-minV [{18}^F]flortaucipir PET, dynamic 60-min [{11}^C]UCB-J PET with arterial sampling and 2 × 5-min resting-state MEG measurement. [{18^}F]flortaucipir- and [{11}^C]UCB-J-specific binding (binding potential, BPND) and MEG spectral measures (relative delta, theta and alpha power; broadband power; and peak frequency) were assessed in cortical brain regions of interest. Associations between regional [{18}^F]flortaucipir BPND, [{11}^C]UCB-J BP_{ND} and MEG spectral measures were assessed using Spearman correlations and generalized estimating equation models. RESULTS: Across subjects, higher regional [{18}^F]flortaucipir uptake was associated with lower [{11}^C]UCB-J uptake. Within subjects, the association between [{11}^C]UCB-J and [{18}^F]flortaucipir depended on within-subject neocortical tau load; negative associations were observed when neocortical tau load was high, gradually changing into opposite patterns with decreasing neocortical tau burden. Both higher [{18}^F]flortaucipir and lower [{11}^C]UCB-J uptake were associated with altered synaptic function, indicative of slowing of oscillatory activity, most pronounced in the occipital lobe. CONCLUSIONS: These results indicate that in Alzheimer’s disease, tau pathology is closely associated with reduced synaptic density and synaptic dysfunction

Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a “shift” of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis

Testing causality in the association between amyloid‐β and tau in genetically identical twins

Abstract Background The amyloid‐cascade hypothesis of Alzheimer’s disease posits that there is a causal relationship between amyloid‐β (Aβ) and tau pathology. However, the mechanism through which Aβ would cause tau remains unclear. We cannot exclude the possibility of an additional underlying factor influencing Aβ at one time‐point and tau at a later time‐point. One such potential underlying factor can be genetic variation among individuals. This study aimed to examine the relationship between Aβ and tau, taking potential genetic confounding into account using a genetically identical twin design. Methods We included 70 identical twins (35 pairs) from the EMIF‐AD PreclinAD study with normal baseline cognition. We extracted baseline global [ 18 F]flutemetamol (Aβ)‐PET binding potential (BP ND ) and 4‐year follow‐up [ 18 F]flortaucipir (tau)‐PET BP ND in a temporal meta‐region‐of‐interest. If Aβ is causally related to tau, the twin with more Aβ should also have more tau compared to the co‐twin. We tested this using regional and voxel‐wise within‐pair difference models, in which the within‐pair difference in Aβ is regressed on the within‐pair difference in tau. The resulting effect represents an association that is free of confounding due to factors that are shared between twins of the same pair, which includes genetic factors (twins are genetically identical), but also shared demographic (e.g. sex, age) and shared environmental (e.g. raised in the same family) factors. Results Participant characteristics are shown in Table 1 . Total group analysis showed that global Aβ‐PET BP ND was associated with temporal tau‐PET BP ND (β=0.49, p <0.001) ( Fig‐1A ). The twin‐difference model replicated this. We observed a highly comparable effect size for the association between within‐pair differences in global Aβ‐PET and within‐pair differences in temporal tau‐PET (β=0.56, p <0.001) ( Fig‐1B ). Compared to the total group voxel‐wise analysis, we observed an overlapping (and more widespread) pattern when regressing within‐pair differences in global Aβ‐PET on within‐pair differences in voxel‐wise tau‐PET, except for effects on tau in the medial temporal lobe ( Fig‐2 ). Conclusion Our within‐pair difference results show that the association between Aβ and tau is minimally affected by confounding by genetic variation. Our voxel‐wise results support a causal association between global Aβ and tau outside of the medial temporal lobe