Neuroimmune dysfunction is a cardinal feature of neurodegenerative diseases. But how immune dysregulation in the brain and peripheral organs contribute to neurodegeneration remains unclear. Here, we discuss the recent advances highlighting neuroimmune dysfunction as a key disease-driving factor in frontotemporal dementia (FTD). We provide an overview of the clinical observations supporting a high prevalence of autoimmune diseases in FTD patients with mutations in GRN or C9orf72. We then focus on a myriad of evidence from human genetic studies, mouse models, in vitro assays, and multi-omics platform, which indicate that haploinsufficiency in GRN and C9orf72 promotes neuroimmune dysfunction and contributes to neurodegeneration and premature death. These compelling data provide key insights to disease mechanisms, biomarker discovery, and therapeutic interventions for FTD (120 words).

Ion-ion interactions in charge detection mass spectrometers that use electrostatic traps to measure masses of individual ions have not been reported previously, although ion trajectory simulations have shown that these types of interactions affect ion energies and thereby degrade measurement performance. Here, examples of interactions between simultaneously trapped ions that have masses ranging from ca. 2 to 350 MDa and ca. 100 to 1000 charges are studied in detail using a dynamic measurement method that makes it possible to track the evolution of the mass, charge, and energy of individual ions over their trapping lifetimes. Signals from ions that have similar oscillation frequencies can have overlapping spectral leakage artifacts that result in slightly increased uncertainties in the mass determination, but these effects can be mitigated by the careful choice of parameters used in the short-time Fourier transform analysis. Energy transfers between physically interacting ions are also observed and quantified with individual ion energy measurement resolution as high as ∼950. The mass and charge of interacting ions do not change, and their corresponding measurement uncertainties are equivalent to ions that do not undergo physical interactions. Simultaneous trapping of multiple ions in CDMS can greatly decrease the acquisition time necessary to accumulate a statistically meaningful number of individual ion measurements. These results demonstrate that while ion-ion interactions can occur when multiple ions are trapped, they have negligible effects on mass accuracy when using the dynamic measurement method.

Effects of electrospray voltage on cluster size and abundance formed from aqueous CsI were investigated with emitter tip diameters between 260 ± 7 nm and 2.45 ± 0.30 μm. Cluster size increases with increasing voltage, increasing solution concentration and increasing emitter diameter consistent with formation of larger initial droplet sizes. For emitters with tip diameters above ∼1 μm, varying the voltage either up or down leads to reproducible voltage-dependent extents of cluster formation. In contrast, higher voltages with submicron diameter emitters can lead to only Cs⁺ and Cs(H₂O)⁺ and no clusters. This change in ion formation reproducibly occurs at spray potentials >1.3 kV for 260 nm emitters and appears to be induced by a corona discharge and material build-up at the emitter tip. Under conditions where abundant Cs⁺ is observed and no clusters are formed, ions such as K⁺ and Cu¹⁺ are also observed but ions with more negative solvation energies, such as Ba²⁺, are not. Similarly, ions from bradykinin and ubiquitin are observed predischarge but not post discharge. Ions with more positive solvation energies can desorb directly from the air-water interface that is created at the tip of these emitters, whereas ions with more negative solvation energies as well as peptide and protein ions do not. These results indicate that ion desorption directly from solution can occur, and similar experiments with even smaller emitters may lead to new insights into ion formation in electrospray ionization.

The sizes and shapes of nanoparticles play a critical role in their chemical and material properties. Common sizing methods based on light scattering or mobility lack individual particle specificity, and microscopy-based methods often require cumbersome sample preparation and image analysis. A promising alternative method for the rapid and accurate characterization of nanoparticle size is charge detection mass spectrometry (CDMS), an emerging technique that measures the masses of individual ions. A recently constructed CDMS instrument designed specifically for high acquisition speed, efficiency, and accuracy is described. This instrument does not rely on an ion energy filter or estimates of ion energy that have been previously required for mass determination, but instead uses direct, in situ measurements. A standardized sample of ∼100 nm diameter polystyrene nanoparticles and ∼50 nm polystyrene nanoparticles with amine-functionalized surfaces are characterized using CDMS and transmission electron microscopy (TEM). Individual nanoparticle masses measured by CDMS are transformed to diameters, and these size distributions are in close agreement with distributions measured by TEM. CDMS analysis also reveals dimerization of ∼100 nm nanoparticles in solution that cannot be determined by TEM due to the tendency of nanoparticles to agglomerate when dried onto a surface. Comparing the acquisition and analysis times of CDMS and TEM shows particle sizing rates up to ∼80× faster are possible using CDMS, even when samples ∼50× more dilute were used. The combination of both high-accuracy individual nanoparticle measurements and fast acquisition rates by CDMS represents an important advance in nanoparticle analysis capabilities.

Several crucial reasons exist to determine whether an adult has had a reading disorder (RD) and to predict a child's likelihood of developing RD. The Adult Reading History Questionnaire (ARHQ) is among the most commonly used self-reported questionnaires. High ARHQ scores indicate an increased likelihood that an adult had RD as a child and that their children may develop RD. This study focused on whether a subset of ARHQ items (ARHQ-Brief) could be equally effective in assessing adults' reading history as the full ARHQ. We used a machine learning approach, lasso (known as L1 regularization), and identified 6 of 23 items that resulted in the ARHQ-Brief. Data from 97 adults and 47 children were included. With the ARHQ-Brief, we report a threshold of 0.323 as suitable to identify past likelihood of RD in adults with a sensitivity of 72.4% and a specificity of 81.5%. Comparison of predictive performances between ARHQ-Brief and the full ARHQ showed that ARHQ-Brief explained an additional 10%-35.2% of the variance in adult and child reading. Furthermore, we validated ARHQ-Brief's superior ability to predict reading ability using an independent sample of 28 children. We close by discussing limitations and future directions.

Instrumental resolution of Fourier transform-charge detection mass spectrometry instruments with electrostatic ion trap detection of individual ions depends on the precision with which ion energy is determined. Energy can be selected using ion optic filters or from harmonic amplitude ratios (HARs) that provide Fellgett's advantage and eliminate the necessity of ion transmission loss to improve resolution. Unlike the ion energy-filtering method, the resolution of the HAR method increases with charge (improved S/N) and thus with mass. An analysis of the HAR method with current instrumentation indicates that higher resolution can be obtained with the HAR method than the best resolution demonstrated for instruments with energy-selective optics for ions in the low MDa range and above. However, this gain is typically unrealized because the resolution obtainable with molecular systems in this mass range is limited by sample heterogeneity. This phenomenon is illustrated with both tobacco mosaic virus (0.6-2.7 MDa) and AAV9 (3.7-4.7 MDa) samples where mass spectral resolution is limited by the sample, including salt adducts, and not by instrument resolution. Nevertheless, the ratio of full to empty AAV9 capsids and the included genome mass can be accurately obtained in a few minutes from 1× PBS buffer solution and an elution buffer containing 300+ mM nonvolatile content despite extensive adduction and lower resolution. Empty and full capsids adduct similarly indicating that salts encrust the complexes during late stages of droplet evaporation and that mass shifts can be calibrated in order to obtain accurate analyte masses even from highly salty solutions.

Short-time Fourier transforms with short segment lengths are typically used to analyze single ion charge detection mass spectrometry (CDMS) data either to overcome effects of frequency shifts that may occur during the trapping period or to more precisely determine the time at which an ion changes mass or charge, or enters an unstable orbit. The short segment lengths can lead to scalloping loss unless a large number of zero-fills are used, making computational time a significant factor in real-time analysis of data. Apodization specific fitting leads to a 9-fold reduction in computation time compared to zero-filling to a similar extent of accuracy. This makes possible real-time data analysis using a standard desktop computer. Rectangular apodization leads to higher resolution than the more commonly used Gaussian or Hann apodization and makes it possible to separate ions with similar frequencies, a significant advantage for experiments in which the masses of many individual ions are measured simultaneously. Equally important is a >20% increase in S/N obtained with rectangular apodization compared to Gaussian or Hann, which directly translates to a corresponding improvement in accuracy of both charge measurements and ion energy measurements that rely on the amplitudes of the fundamental and harmonic frequencies. Combined with computing the fast Fourier transform in a lower-level language, this fitting procedure eliminates computational barriers and should enable real-time processing of CDMS data on a laptop computer.

Clinical phenotyping of primary progressive aphasia has largely focused on speech and language presentations, leaving other cognitive domains under-examined. This study investigated the diagnostic utility of visuospatial profiles and examined their neural basis among the three main primary progressive aphasia variants. We studied the neuropsychological performances of 118 primary progressive aphasia participants and 30 cognitively normal controls, across 11 measures of visuospatial cognition, and investigated their neural correlates via voxel-based morphometry analysis using visuospatial composite scores derived from principal component analysis. The principal component analysis identified three main factors: visuospatial-executive, visuospatial-memory and visuomotor components. Logopenic variant primary progressive aphasia performed significantly worst across all components; nonfluent/agrammatic variant primary progressive aphasia showed deficits in the visuospatial-executive and visuomotor components compared with controls; and the semantic variant primary progressive aphasia scored significantly lower than nonfluent/agrammatic variant primary progressive aphasia and control in the visuospatial-memory component. Grey matter volumes over the right parieto-occipital cortices correlated with visuospatial-executive performance; volumetric changes in the right anterior parahippocampal gyrus and amygdala were associated with visuospatial-memory function, and visuomotor composite scores correlated significantly with the grey matter volume at the right precentral gyrus. Discriminant function analysis identified three visuospatial measures: Visual Object and Space Perception and Benson figure copy and recall test, which classified 79.7% (94/118) of primary progressive aphasia into their specific variant. This study shows that each primary progressive aphasia variant also carries a distinctive visuospatial cognitive profile that corresponds with grey matter volumetric changes and in turn can be largely represented by their performance on the visuomotor, visuospatial-memory and executive functions.

Typical Alzheimer disease (AD) features an amnestic syndrome that reflects the progression of pathology through specific neural networks. However, a subset of patients exhibits atypical onset with prominent language, behavioral, or visuospatial deficits that are not explained by current neuropathological staging schemes. Astrogliopathy featuring tau inclusions with thorn-shaped and granular fuzzy morphologies is common in the aging brain and collectively known as aging-related tau astrogliopathy (ARTAG). Prior studies have identified tau-positive thorn-shaped astrocytes in the white matter that associate with a primary progressive aphasia phenotype in an AD cohort. However, a possible contribution of ARTAG copathology to AD clinical heterogeneity has yet to be systematically examined. To investigate whether ARTAG pathology contributes to atypical presentations, we mapped the presence and density of ARTAG subtypes throughout cortical and subcortical regions in a well-characterized cohort of AD cases enriched for atypical presentations. In our cohort, ARTAG pathology is frequent and correlates with older age and higher Braak stage. ARTAG subtypes exhibit distinct distribution patterns with subpial and subependymal deposition occurring in the amygdala, while white and grey matter astrocytic deposition are distributed throughout cortical regions. However, ARTAG pathology is equally prevalent in cases with typical and atypical clinical presentations.

Introduction

The effect of bilingualism on age at onset has yet to be examined within different clinical variants of Alzheimer's disease.

Methods

We reviewed the research charts of 287 well-characterized participants with either amnestic Alzheimer's dementia or logopenic variant primary progressive aphasia (lvPPA) and identified bilingual speakers based on regular use of two or more languages and/or ability to communicate with native speakers in two or more languages. We evaluated whether bilingual speakers demonstrated a delay in age of symptom onset relative to monolingual speakers while controlling for other variables known to influence cognitive reserve.

Results

A 5-year delay in age at symptom onset was observed for bilingual relative to monolingual speakers with lvPPA. This delay in onset was not observed in the amnestic Alzheimer's dementia cohort.

Discussion

Bilingualism may serve as a unique cognitive reserve variable in lvPPA, but not in amnestic Alzheimer's dementia.