Disruption of sleep and circadian rhythms is one of the earliest symptoms of Alzheimer's disease (AD). Circadian entrainment and modulation of alertness are non-visual responses to light driven by intrinsically photosensitive retinal ganglion cells (ipRGCs). To explore structural and functional changes of ipRGCs and ipRGC circuits in AD, we analyzed the retinas and brains of 13 elderly patients ranging from normal cognition to AD and performed ex vivo extracellular electrophysiological recordings on freshly harvested retinas. While no impairment of rods and cones was observed, there was a severe loss of ipRGCs in AD donors. Importantly, the remaining ipRGCs exhibited morphological alterations, hyperexcitability, and were not able to sustain high levels of activation. These changes may be ipRGC subtype-specific and vary across donors with pathological severity. Altered ipRGC circuits and function could contribute to the disruption of sleep and circadian rhythms reported in AD patients. Measuring ipRGC-dependent responses to light could be a promising way to predict or monitor pathological changes in the brain.

Mesoscopic brain imaging, enabled by advances in tissue clearing, light-sheet microscopy, and large-scale image processing, allows detailed analysis of cellular and molecular architecture across whole neural circuits. However, applying these methods to postmortem human brain tissue is hindered by strong autofluorescence, high tissue density, and fixation-induced damage. We introduce CleLight, a light-enhanced clearing method that increases tissue transparency while quenching autofluorescence. Combined with complementary chemical treatments, CleLight supports multiplexed immunolabeling and high-resolution imaging of centimeter-thick, formalin-fixed, paraffin-embedded human brain sections. It is compatible with a wide range of antibodies and fluorescent dyes, enabling the visualization of physiological and pathological features across diverse CNS regions in healthy and diseased samples. CleLight offers a simple, robust, and scalable workflow for clearing, deep labeling, and volumetric imaging of human brain tissue. Its compatibility with conventional histology and archival material makes it well suited for organ-wide pathological studies in large patient cohorts and historical brain collections. ### Competing Interest Statement The authors have declared no competing interest. Swiss National Science Foundation, https://ror.org/00yjd3n13, 219457 Wyss Center for Bio and Neuroengineering

Disruption of sleep and circadian rhythms is one of the earliest symptoms of Alzheimer's disease (AD). Circadian entrainment and the modulation of alertness are non-visual responses to light driven by intrinsically photosensitive retinal ganglion cells (ipRGCs). However, little is known about ipRGCs in the context of AD. To explore structural and functional changes of ipRGCs and ipRGC circuits, we analyzed the retinas and brains of 13 elderly patients (9 males, 4 females, aged 69-103) ranging from normal to neuropathologically defined AD. We performed extracellular electrophysiological recordings on freshly harvested retinas using multi-electrode arrays. While rod and cone responses were moderately affected, we found a decreased density of ipRGCs in donors with advanced AD pathology, which was confirmed by immunostaining. The remaining ipRGCs displayed morphological alterations as well as abnormal responses to light, including hyperexcitability. These changes appeared to be subtype-specific and correlated with the advancement of the disease. Altered ipRGCs circuits and function could contribute to the disruption of sleep and circadian rhythms reported in AD patients. The measurement of ipRGC-dependent responses to light could constitute a promising tool to predict or monitor pathological changes in the brain. ### Competing Interest Statement DM is an advisory board member for Optomed, Finland. All other authors declare that they have no competing interest.

Microglial activation plays central roles in neuroinflammatory and neurodegenerative diseases. Positron emission tomography (PET) targeting 18 kDa Translocator Protein (TSPO) is widely used for localising inflammation in vivo, but its quantitative interpretation remains uncertain. We show that TSPO expression increases in activated microglia in mouse brain disease models but does not change in a non-human primate disease model or in common neurodegenerative and neuroinflammatory human diseases. We describe genetic divergence in the TSPO gene promoter, consistent with the hypothesis that the increase in TSPO expression in activated myeloid cells depends on the transcription factor AP1 and is unique to a subset of rodent species within the Muroidea superfamily. Finally, we identify LCP2 and TFEC as potential markers of microglial activation in humans. These data emphasise that TSPO expression in human myeloid cells is related to different phenomena than in mice, and that TSPO-PET signals in humans reflect the density of inflammatory cells rather than activation state.

Increase in the brain expression of the 18 kDa translocator protein (TSPO) is considered as a marker of neuroinflammation in the context of brain diseases, such as Alzheimer’s disease (AD). However, in non-demented subjects with Alzheimer’s neuropathology, TSPO accumulation in hippocampus subdivisions has not been fully characterized.To determine if TSPO is associated with the presence of amyloid β plaques and/or phosphorylated Tau accumulation, we analyzed hippocampal sections using immunohistochemistry of 14 non-demented subjects with positive staining for Aβ and/or phosphorylated Tau. TSPO expression was heterogenous with higher accumulation in the CA2/3 and subiculum subfields of the hippocampus. Its distribution closely resembled that of the microglial IBA1 marker and of the Aβ42 amyloid form. In addition, positive correlations were observed between TSPO and IBA1 densities in CA4, CA2/3 and the subiculum but not with either the astrocyte GFAP marker or the AD-type Aβ and Tau markers. This study sustains the hypothesis that TSPO is mainly associated with microglia and in Aβ42-rich subdivisions in the hippocampus of non-demented elderly individuals.

AIMS: Cerebral amyloid angiopathy (CAA) represents the deposition of amyloid beta protein (Abeta) in the meningeal and intracerebral vessels. It is often observed as an accompanying lesion of Alzheimer's disease (AD) or in the brain of elderly individuals even in the absence of dementia. CAA is largely age-dependent. In subjects with severe CAA a higher frequency of vascular lesions has been reported. The goal of our study was to define the frequency and distribution of CAA in a one-year autopsy population (91 cases) from the Department of Internal Medicine, Rehabilitation, and Geriatrics, Geneva. MATERIALS AND METHODS: Five brain regions were examined, including the hippocampus, and the inferior temporal, frontal, parietal, and occipital cortex, using an antibody against Abeta, and simultaneously assessing the severity of AD-type pathology with Braak stages for neurofibrillary tangles identified with an anti-tau antibody. In parallel, the relationships of CAA with vascular brain lesions were established. RESULTS: CAA was present in 53.8% of the studied population, even in cases without AD (50.6%). The strongest [...] KOVARI, Eniko Veronika, et al. The relationship between cerebral amyloid angiopathy and cortical microinfarcts in brain ageing and Alzheimer's disease. Neuropathology and Applied Neurobiology, 2013, vol. 39, no. 5, p. 498-509 DOI : 10.1111/nan.12003

Dopaminergic neurons (DA) of the substantia nigra pars compacta (SNpc) selectively and progressively degenerate in Parkinson's disease (PD). Until now, molecular analyses of DA in PD have been limited to genomic or transcriptomic approaches, whereas, to the best of our knowledge, no proteomic or combined multiomic study examining the protein profile of these neurons is currently available. In this exploratory study, we used laser capture microdissection to extract regions from DA in 10 human SNpc obtained at autopsy in PD patients and control subjects. Extracted RNA and proteins were identified by RNA sequencing and nanoliquid chromatography-mass spectrometry, respectively, and the differential expression between PD and control group was assessed. Qualitative analyses confirmed that the microdissection protocol preserves the integrity of our samples and offers access to specific molecular pathways. This multiomic analysis highlighted differential expression of 52 genes and 33 proteins, including molecules of interest already known to be dysregulated in PD, such as LRP2, PNMT, CXCR4, MAOA and CBLN1 genes, or the Aldehyde dehydrogenase 1 protein. On the other hand, despite the same samples were used for both analyses, correlation between RNA and protein expression was low, as exemplified by the CST3 gene encoding for the cystatin C protein. This is the first exploratory study analyzing both gene and protein expression of laser-dissected neuronal parts from SNpc in PD. Data are available via ProteomeXchange with identifier PXD024748 and via GEO with identifier GSE 169755.

Neuropathological studies of older populations reveal the presence of cerebrovascular pathology in the vast majority of autopsied cases. These are mostly comprised of microscopic lesions such as focal and diffuse gliosis, demyelination, microinfarcts, and microbleeds. Clinicopathological studies provide strong evidence that microinfarcts are the most powerful vascular correlate of cognitive function. These lesions are highly prevalent at advanced ages and tend to occur in watershed areas of the brain. Most are smaller than 500 microns and not visible with currently available in vivo neuroimaging techniques. As a result, their presence is frequently undetected and their potential role in the development of dementia in older people has generally been ignored. The present review underlines their importance as a promising new target for the prevention and treatment of cognitive decline and suggests that optimal blood pressure reduction goals may need to be reviewed if the current hypothesis relating microinfarcts to underlying cerebral hypoperfusion can be confirmed.

Cortical microinfarcts (CMI) are increasingly recognized in the neurological community as a biomarker related to cognitive impairment and dementia. If their radiological depiction has been largely described in experimental settings using ultra-high-field magnetic resonance imaging (MRI), less is known about their visibility on routinely used 3-T MRI. In this radiologic-pathologic correlation study, using 3-T post-mortem MRI, we searched for hippocampal CMI, in a double-blinded fashion, and found that only 4/36, or 11%, were clearly demonstrated on both radiological and histopathological exams.

Corticobasal degeneration typically progresses gradually over 5–7 years from onset till death. Fulminant corticobasal degeneration cases with a rapidly progressive course were rarely reported (RP-CBD). This study aimed to investigate their neuropathological characteristics. Of the 124 autopsy-confirmed corticobasal degeneration cases collected from 14 centres, we identified 6 RP-CBD cases (4.8%) who died of advanced disease within 3 years of onset. These RP-CBD cases had different clinical phenotypes including rapid global cognitive decline ( N = 2), corticobasal syndrome ( N = 2) and Richardson’s syndrome ( N = 2). We also studied four corticobasal degeneration cases with an average disease duration of 3 years or less, who died of another unrelated illness (Intermediate-CBD). Finally, we selected 12 age-matched corticobasal degeneration cases out of a cohort of 110, who had a typical gradually progressive course and reached advanced clinical stage (End-stage-CBD). Quantitative analysis showed high overall tau burden ( p = 0.2) and severe nigral cell loss ( p = 0.47) in both the RP-CBD and End-stage-CBD groups consistent with advanced pathological changes, while the Intermediate-CBD group (mean disease duration = 3 years) had milder changes than End-stage-CBD ( p < 0.05). These findings indicated that RP-CBD cases had already developed advanced pathological changes as those observed in End-stage-CBD cases (mean disease duration = 6.7 years), but within a significantly shorter duration (2.5 years; p < 0.001). Subgroup analysis was performed to investigate the cellular patterns of tau aggregates in the anterior frontal cortex and caudate by comparing neuronal-to-astrocytic plaque ratios between six RP-CBD cases, four Intermediate-CBD and 12 age-matched End-stage-CBD. Neuronal-to-astrocytic plaque ratios of Intermediate-CBD and End-stage-CBD, but not RP-CBD, positively correlated with disease duration in both the anterior frontal cortex and caudate ( p = 0.02). In contrast to the predominance of astrocytic plaques we previously reported in preclinical asymptomatic corticobasal degeneration cases, neuronal tau aggregates predominated in RP-CBD exceeding those in Intermediate-CBD (anterior frontal cortex: p < 0.001, caudate: p = 0.001) and End-stage-CBD (anterior frontal cortex: p = 0.03, caudate: p = 0.01) as demonstrated by its higher neuronal-to-astrocytic plaque ratios in both anterior frontal cortex and caudate. We did not identify any difference in age at onset, any pathogenic tau mutation or concomitant pathologies that could have contributed to the rapid progression of these RP-CBD cases. Mild TDP-43 pathology was observed in three RP-CBD cases. All RP-CBD cases were men. The MAPT H2 haplotype, known to be protective, was identified in one RP-CBD case (17%) and 8 of the matched End-stage-CBD cases (67%). We conclude that RP-CBD is a distinct aggressive variant of corticobasal degeneration with characteristic neuropathological substrates resulting in a fulminant disease process as evident both clinically and pathologically. Biological factors such as genetic modifiers likely play a pivotal role in the RP-CBD variant and should be the subject of future research.

Many studies have explored the role of TSPO (18 kDa translocator protein) as a marker of neuroinflammation using single-photon emission computed tomography (SPECT) or positron emission tomography (PET). In vivo imaging does not allow to determine the cells in which TSPO is altered. We propose a methodology based on fluorescence-activated cell sorting to sort different cell types of radioligand-treated tissues. We compared left/right hippocampus of rats in response to a unilateral injection of lipopolysaccharide (LPS), ciliary neurotrophic factor (CNTF) or saline. We finally applied this methodology in human samples (Alzheimer's disease patients and controls). Our data show that the pattern of TSPO overexpression differs across animal models of acute neuroinflammation. LPS induces a microglial expansion and an increase in microglial TSPO binding. CNTF is associated with an increase in TSPO binding in microglia and astrocytes in association with an increase in the number of microglial binding sites per cell. In humans, we show that the increase in CLINDE binding in Alzheimer's disease concerns microglia and astrocytes in the presence of a microglial expansion. Thus, the cellular basis of TSPO overexpression is condition dependent, and alterations in TSPO binding found in PET/SPECT imaging studies cannot be attributed to particular cell types indiscriminately.

Medial temporal lobe (MTL) atrophy is an important marker for the clinical diagnosis of Alzheimer's disease at its prodromal stages. Several brain lesions have been associated with MTL atrophy including hippocampal sclerosis, neurodegenerative neuronal loss, and vascular pathology. To better explore the relationship between MTL volume on MRI and age-related degenerative and microvascular hippocampal pathology, we compared MTL volume on postmortem whole brain MRI and stereological estimates of the total number of neurons, cortical microinfarcts (CMIs), and neurofibrillary tangles (NFTs) in a consecutive autopsy series of 21 older individuals (11 females and 10 males, mean age 83.3 ± 5.8; range: 74-93 years, 7 demented and 14 nondemented). Our results revealed a very high percentage of cases with hippocampal CMIs (52%), particularly in the CA1 field. MTL volume was closely related to neuronal loss in both the CA1 area of the hippocampus (p = 0.0109) and the entorhinal cortex (p = 0.0272). MTL volume was not related to total CMI volume or to the total number of NFTs in our sample. In conclusion, hippocampal CMIs are very common in old age. MTL volume is determined essentially by the number of neurons in the hippocampus and does not appear to be related to the presence of NFTs or CMIs in this region.

Identification of white matter fiber tracts of the brain is crucial for delineating the tumor border during neurosurgery. A custom-built Mueller polarimeter was used in reflection configuration for the wide-field imaging of thick sections of fixed human brain and fresh calf brain. The maps of the azimuth of the fast optical axis of linear birefringent medium reconstructed from the experimental Mueller matrix images of the specimen by applying a non-linear data compression algorithm showed a strong correlation with the silver-stained sample histology image, which is the gold standard for ex-vivo brain fiber tract visualization. The polarimetric maps of fresh calf brain tissue demonstrated the same trends in the depolarization, the scalar retardance and the azimuth of the fast optical axis as seen in fixed human brain tissue. Thus, label-free imaging Mueller polarimetry shows promise as an efficient intra-operative modality for the visualization of healthy brain white matter fiber tracts, which could improve the accuracy of tumor border detection and, ultimately, patient outcomes.

Cerebral microbleeds (CMB) play an important role as an imaging biomarker notably in vascular and neurodegenerative diseases. Current clinical brain MRI underestimates the number of CMB with respect to histopathology. It is expected that small CMBs are more likely to be false-negatives, yet this has not been demonstrated and the average size of false-negative and true-positive CMBs have not been established. The radiologic-histopathologic correlation study was approved by the local review board and included 42 consecutive cases (mean age at death, 80.7 ± 10.0 years; 23 females and 19 men) between 12 January 2012 and 10 December 2012 having undergone brain autopsy. Postmortem SWI (susceptibility-weighted imaging) images were acquired on a clinical 3T system using parameters similar to clinical routine. The detection of CMB on postmortem MRI was compared with corresponding histopathological slices. Postmortem MRI detected 23 true-positive CMB. Histopathology additionally detected 68 CMBs (false-negative MRI CMBs). The average size true-positive MRI CMBs had on histopathology was 3.6 ± 7.1 mm3. The average size false-negative MRI CMBs was significantly smaller (p < 0.05), measuring 0.3 ± 1.2 mm3 on histopathology. Size matters. As expected, the average size of true-positive MRI CMB was around 10 times larger as compared with false-negative MRI CMB. Evidently, in addition to size, other factors will influence the detectability of CMB, including iron content, ratio of Fe2+/Fe3+, spatial configuration, and location, yet this remains to be elucidated in future studies.

Amyloid fibres attract considerable interest due to their biological role in neurodegenerative diseases and their potential as functional biomaterials. Here, we describe an intrinsic signal of amyloid fibres in the near-infrared range. When combined with their recently reported blue luminescence, it paves the way towards new blueprints for the label-free detection of amyloid deposits in in vitro and in vivo contexts. The blue luminescence allows for staining-free characterization of amyloid deposits in human samples. The near-infrared signal offers promising prospects for innovative diagnostic strategies for neurodegenerative diseases—to improve medical care and for the development of new therapies. As a proof of concept, we demonstrate direct detection of amyloid deposits within brains of living, aged mice with Alzheimer’s disease using non-invasive and contrast-agent-free imaging. Ultraviolet–visible–near-infrared optical properties of amyloids open new research avenues for amyloidosis as well as for next-generation biophotonic devices. Two optical signatures of amyloid fibres—luminescence in the blue and a near-infrared signal, which can be observed in in vitro and in vivo tissues—are reported. The findings allow for staining-free characterization of amyloid deposits in human samples and could open the door to innovative diagnostic strategies for neurodegenerative diseases.

Tau neuronal and glial pathologies drive the clinical presentation of Alzheimer's disease and related human tauopathies. There is a growing body of evidence indicating that pathological tau species can travel from cell to cell and spread the pathology through the brain. Throughout the last decade, physiological and pathological tau have become attractive targets for AD therapies. Several therapeutic approaches have been proposed, including the inhibition of protein kinases or protein-3-O-(N-acetyl-beta-D-glucosaminyl)-L-serine/threonine Nacetylglucosaminyl hydrolase, the inhibition of tau aggregation, active and passive immunotherapies, and tau silencing by antisense oligonucleotides. New tau therapeutics, across the board, have demonstrated the ability to prevent or reduce tau lesions and improve either cognitive or motor impairment in a variety of animal models developing neurofibrillary pathology. The most advanced strategy for the treatment of human tauopathies remains immunotherapy, which has already reached the clinical stage of drug development. Tau vaccines or humanised antibodies target a variety of tau species either in the intracellular or extracellular spaces. Some of them recognise the amino-terminus or carboxy-terminus, while others display binding abilities to the proline-rich area or microtubule binding domains. The main therapeutic foci in existing clinical trials are on Alzheimer's disease, progressive supranuclear palsy and non-fluent primary progressive aphasia. Tau therapy offers a new hope for the treatment of many fatal brain disorders. First efficacy data from clinical trials will be available by the end of this decade.

Air bubble artifacts on SWI post-mortem MRI studies may interfere with the detection of cerebral microbleeds. We investigated whether the utilization of a higher receiver bandwidth of 500 Hz/pixel could reduce cortical air bubble artifacts without compromising the detection of cerebral microbleeds in high-field MRI. All microbleeds remained clearly visible whereas a reduction of 17% of the long axis of the “halo” magnitude artifacts was achieved. On corresponding phase images, air bubble artifacts appeared identical.

Bacillus cereus is a widely-distributed, gram-positive or variable, rod-shaped bacterium frequently considered a contaminant in clinical specimens. It is recognized as a potential pathogen inducing self-limiting emetic or diarrheal food poisoning or localized infection in immunocompetent patients. True B. cereus bacteremia is uncommon and mainly observed in fragile patients, notably in immunocompromised individuals. We report clinical, radiological, and pathological findings of a 64-year-old patient with a history of acute myeloid leukemia who initially presented a fever while neutropenic after the induction of a second cycle of chemotherapy. He developed B. cereus bacteremia with invasive infection and a fatal outcome. The clinical and radiological data of this case are compared to a previously-published series of 21 patients from our institution with B. cereus bacteremia. This study highlights the clinical challenge to diagnose B. cereus and the importance of the delay between the detection of B. cereus and the initiation of an effective targeted antibiotic therapy. This case presented an aggressive evolution with multiple necrotic and hemorrhagic foci in the brain. Upon histological examination, B. cereus virulence was notably reflected by the dissection of blood vessel walls by the bacilli and luminal occlusion, a pattern that has not been yet reported. .

The involvement of the 18kDa translocator protein (TSPO), a marker of neuroinflammation, in Alzheimer's disease (AD) remains controversial. In the present report, we used [125I]-CLINDE, a SPECT TSPO radiotracer never before used in AD, and we investigated the relationship between TSPO and amyloid plaque density (using [125I]-DRM106) in a triple transgenic mouse model of AD (3xTgAD, APPSWE, PS1M146V and TauP301L). Our results show that TSPO increases appear before those of amyloid deposits. Moreover, the different parts of the hippocampus are differentially affected. Indeed, for both TSPO and amyloid, the subiculum is affected earlier and the ventral hippocampus later than the dorsal hippocampus. In the subiculum and the dorsal hippocampus of 3xTgAD mice, a positive correlation between TSPO and of amyloid deposit levels is observed. This data supports the hypothesis that TSPO could be used as a predictive marker of amyloid pathology. In addition, our immunohistochemical data shows a segregation of TSPO in the hippocampus and immunofluorescence imaging revealed a mainly microglial origin of the TSPO expression. Thus, imaging TSPO with CLINDE may be a good alternative to PET radiotracers.

Aging-related tau astrogliopathy (ARTAG) is a recently introduced terminology. To facilitate the consistent identification of ARTAG and to distinguish it from astroglial tau pathologies observed in the primary frontotemporal lobar degeneration tauopathies we evaluated how consistently neuropathologists recognize (1) different astroglial tau immunoreactivities, including those of ARTAG and those associated with primary tauopathies (Study 1); (2) ARTAG types (Study 2A); and (3) ARTAG severity (Study 2B). Microphotographs and scanned sections immunostained for phosphorylated tau (AT8) were made available for download and preview. Percentage of agreement and kappa values with 95% confidence interval (CI) were calculated for each evaluation. The overall agreement for Study 1 was >60% with a kappa value of 0.55 (95% CI 0.433-0.645). Moderate agreement (>90%, kappa 0.48, 95% CI 0.457-0.900) was reached in Study 2A for the identification of ARTAG pathology for each ARTAG subtype (kappa 0.37-0.72), whereas fair agreement (kappa 0.40, 95% CI 0.341-0.445) was reached for the evaluation of ARTAG severity. The overall assessment of ARTAG showed moderate agreement (kappa 0.60, 95% CI 0.534-0.653) among raters. Our study supports the application of the current harmonized evaluation strategy for ARTAG with a slight modification of the evaluation of its severity.