Background Delirium may be one of the presenting symptoms of COVID-19, complicating diagnosis and care of elderly patients with dementia. We aim to identify the prevalence and prognostic significance of delirium as the sole onset manifestation of COVID-19. Methods This is a retrospective single-centre study based on review of medical charts, conducted during the outbreak peak (March 27-April 18, 2020) in a Lombard dementia facility, including 59 elderly subjects with dementia and laboratory-confirmed COVID-19. Findings Of the 59 residents, 57 (96⋅6%) tested positive (mean age: 82⋅8; women: 66⋅7%). Comorbidities were present in all participants, with 18/57 (31⋅6%) having three or more concomitant diseases. Delirium -Onset COVID-19 (DOC) was observed in 21/57 (36⋅8%) subjects who were chiefly older (mean age: 85⋅4 y/o) and with multiple comorbidities. Eleven/21 DOC patients (52⋅4%) had hypoactive delirium , while hyperactive delirium occurred in ten/21 (47⋅6%). Lymphopenia was present in almost all subjects (median: 1⋅3 × 10 9 /L). Overall mortality rate was 24⋅6% (14/57) and dementia severity per se had no impact on short-term mortality due to COVID-19. DOC was strongly associated with higher mortality ( p <0⋅001). Also, DOC and male gender were independently associated with increased risk of mortality (OR: 17⋅0, 95% CI: 2⋅8–102⋅7, p = 0⋅002 and 13⋅6, 95% CI: 2⋅3–79⋅2, p = 0⋅001 respectively). Interpretation Delirium occurrence in the elderly with dementia may represent a prodromal phase of COVID-19, and thus deserves special attention, especially in the presence of lymphopenia. Hypoxia and a severe inflammatory state may develop subsequently. DOC cases have higher short-term mortality rate. Funding None.

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The actual role of SARS-CoV-2 in brain damage remains controversial due to lack of matched controls. We aim to highlight to what extent is neuropathology determined by SARS-CoV-2 or by pre-existing conditions. Findings of 9Coronavirus disease 2019 (COVID-19) cases and 6 matched non-COVID controls (mean age 79 y/o) were compared. Brains were analyzed through immunohistochemistry to detect SARS-CoV-2, lymphocytes, astrocytes, endothelium, and microglia. A semi-quantitative scoring was applied to grade microglial activation. Thal-Braak stages and the presence of small vessel disease were determined in all cases. COVID-19 cases had a relatively short clinical course (0-32 days; mean: 10 days), and did not undergo mechanical ventilation. Five patients with neurocognitive disorder had delirium. All COVID-19 cases showed non-SARS-CoV-2-specific changes including hypoxic-agonal alterations, and a variable degree of neurodegeneration and/or pre-existent SVD. The neuroinflammatory picture was dominated by ameboid CD68 positive microglia, while only scant lymphocytic presence and very few traces of SARS-CoV-2 were detected. Microglial activation in the brainstem was significantly greater in COVID-19 cases (p = 0.046). Instead, microglial hyperactivation in the frontal cortex and hippocampus was clearly associated to AD pathology (p = 0.001), regardless of the SARS-CoV-2 infection. In COVID-19 cases complicated by delirium (all with neurocognitive disorders), there was a significant enhancement of microglia in the hippocampus (p = 0.048). Although higher in cases with both Alzheimer's pathology and COVID-19, cortical neuroinflammation is not related to COVID-19 per se but mostly to pre-existing neurodegeneration. COVID-19 brains seem to manifest a boosting of innate immunity with microglial reinforcement, and adaptive immunity suppression with low number How to cite this article:

Our current knowledge of the structure, function, and diseases of the brain comes from direct examination of its substance. In the last centuries, only a few elite had managed to retrieve, gather, and preserve the elusive brain for their own research. The resulting brain collections, stored in formalin-filled jars or dried up in cabinets, served anatomical, neuropathological, anthropometric, ideological, and diagnostic purposes. In the 1960s, the first modern brain banks actively collecting and strategically preserving both diseased and healthy brains to be consequently distributed to the scientific community were instituted. In an era where state-of-the-art biochemical “Omic” studies and advanced metabolic and molecular neuroimaging exist, it is now, more than ever, that postmortem brain investigations must be performed. Only through the comparison and integration of postmortem neuropathological and biochemical findings and antemortem data from clinical, neuropsychological neuroimaging, and other biomarker examinations can we truly understand neurological disease mechanisms. Brain banks supplying brain specimens, antemortem information, and postmortem diagnosis are a major benefactor of brain research.

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Primary four-repeat tauopathies are characterized by depositions of the four-repeat isoform of the microtubule binding protein, tau. The two most common sporadic four-repeat tauopathies are progressive supranuclear palsy and corticobasal degeneration. Because tau PET tracers exhibit poor binding affinity to four-repeat pathology, determining how well in vivo MRI findings relate to underlying pathology is critical to evaluating their utility as surrogate markers to aid in diagnosis and as outcome measures for clinical trials. We studied the relationship of cross-sectional imaging findings, such as MRI volume loss and diffusion tensor imaging white matter tract abnormalities, to tau histopathology in four-repeat tauopathies. Forty-seven patients with antemortem 3 T MRI volumetric and diffusion tensor imaging scans plus post-mortem pathological diagnosis of a four-repeat tauopathy (28 progressive supranuclear palsy; 19 corticobasal degeneration) were included in the study. Tau lesion types (pretangles/neurofibrillary tangles, neuropil threads, coiled bodies, astrocytic lesions) were semiquantitatively graded in disease-specific cortical, subcortical and brainstem regions. Antemortem regional volumes, fractional anisotropy and mean diffusivity were modelled using linear regression with post-mortem tau lesion scores considered separately, based on cellular type (neuronal versus glial), or summed (total tau). Results showed that greater total tau burden was associated with volume loss in the subthalamic nucleus (P = 0.001), midbrain (P &lt; 0.001), substantia nigra (P = 0.03) and red nucleus (P = 0.004), with glial lesions substantially driving the associations. Decreased fractional anisotropy and increased mean diffusivity in the superior cerebellar peduncle correlated with glial tau in the cerebellar dentate (P = 0.04 and P = 0.02, respectively) and red nucleus (P &lt; 0.001 for both). Total tau and glial pathology also correlated with increased mean diffusivity in the midbrain (P = 0.02 and P &lt; 0.001, respectively). Finally, increased subcortical white matter mean diffusivity was associated with total tau in superior frontal and precentral cortices (each, P = 0.02). Overall, results showed clear relationships between antemortem MRI changes and pathology in four-repeat tauopathies. Our findings show that brain volume could be a useful surrogate marker of tau pathology in subcortical and brainstem regions, whereas white matter integrity could be a useful marker of tau pathology in cortical regions. Our findings also suggested an important role of glial tau lesions in the pathogenesis of neurodegeneration in four-repeat tauopathies. Thus, development of tau PET tracers selectively binding to glial tau lesions could potentially uncover mechanisms of disease progression.

In a constantly aging population, the prevalence of neurodegenerative disorders is expected to rise. Understanding disease mechanisms is the key to find preventive and curative measures. The most effective way to achieve this is through direct examination of diseased and healthy brain tissue. The authors present a protocol to obtain, process, characterize and store good quality brain tissue donated by individuals registered in an antemortem brain donation program. The donation program includes a face-to-face empathic approach to people, a collection of complementary clinical, biological, social and lifestyle information and serial multi-dimensional assessments over time to track individual trajectories of normal aging and cognitive decline. Since many neurological diseases are asymmetrical, our brain bank offers a unique protocol for slicing fresh specimens. Brain sections of both hemispheres are alternately frozen (at-80 °C) or fixed in formalin; a fixed slice on one hemisphere corresponds to a frozen one on the other hemisphere. With this approach, a complete histological characterization of all frozen material can be obtained, and omics studies can be performed on histologically well-defined tissues from both hemispheres thus offering a more complete assessment of neurodegenerative disease mechanisms. Correct and definite diagnosis of these diseases can only be achieved by combining the clinical syndrome with the neuropathological evaluation, which often adds important etiological clues necessary to interpret the pathogenesis. This method can be time consuming, expensive and limited as it only covers a limited geographical area. Regardless of its limitations, the high degree of characterization it provides can be rewarding. Our ultimate goal is to establish the first Italian Brain Bank, all the while emphasizing the importance of neuropathologically verified epidemiological studies. 3. Meanwhile in the USA, Wallace Tourtelotte introduced antemortem brain donation programs to facilitate solicitation of

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