Lea Tenenholz Grinberg

• MD, PhD
• Professor (Associate) at University of California, San Francisco

Sleep disturbances are prevalent in Alzheimer’s disease (AD) and Progressive Supranuclear Palsy (PSP), often exacerbating disease progression. Understanding the neuropathological basis of these disturbances is essential for identifying potential therapeutic targets. This study investigates the intermediate nucleus (IntN) of the human hypothalamus—a...

Germline genetic architecture of Alzheimer's disease (AD) indicates microglial mechanisms of disease susceptibility and outcomes. However, the mechanisms that enable microglia to mediate protective responses to AD pathology remain elusive. Adgrg1 is specifically expressed in yolk-sac-derived microglia. This study reveals the role of yolk-sac-derive...

Background The association of moderate and severe dementia with low body mass index (BMI) is well described, but weight decline seems to also occur in individuals with preclinical neuropathologies. Considering that up to one-fifth of individuals with normal cognition meet the criteria for a dementia-related neuropathological diagnosis, autopsy stud...

Histopathological studies in Alzheimer's disease (AD) suggest severe and region-specific neurodegeneration of the basal forebrain cholinergic system (BFCS). Here, we studied the between-center reliability and diagnostic accuracy of MRI-based BFCS volumetry in a large multicenter data set, including participants with prodromal (n = 41) or clinically...

INTRODUCTION Alzheimer's disease (AD) neuropathological changes present with amnestic and nonamnestic (atypical) syndromes. The contribution of comorbid neuropathology as a substratum of atypical expression of AD remains under investigated. METHODS We examined whether atypical AD exhibited increased comorbid neuropathology compared to typical AD a...

The majority of people with dementia live in low or middle-income countries (LMICs) where resources that play a crucial role in brain health, such as quality education, are still not widely available. In Brazil, illiteracy remains a prevalent issue, especially in communities with lower socioeconomic status (SES). The PROAME study set out to explore...

Background: Sleep-wake dysfunction is an early and common event in Alzheimers disease (AD). The lateral hypothalamic area (LHA) regulates the sleep and wake cycle through wake-promoting orexinergic and sleep-promoting melanin-concentrating hormone (MCH) neurons. These neurons share close anatomical proximity with functional reciprocity. This study...

Individuals with Alzheimers Disease (AD) experience circadian rhythm disorder. The circadian rhythm is synchronized by a master clock, the suprachiasmatic nucleus (SCN), which is a tiny hypothalamic nucleus. Little is known about the molecular and pathological changes that occur in the SCN during AD progression. We examined postmortem brains of 12...

The short association fibers or U-fibers travel in the superficial white matter (SWM) beneath the cortical layer. While the U-fibers play a crucial role in various brain disorders, there is a lack of effective tools to reconstruct their highly curved trajectory from diffusion MRI (dMRI). In this work, we propose a novel surface-based framework for...

Posterior cortical atrophy (PCA) is a clinically defined syndrome characterized by impairment in higher‐order visual processing. The underlying pathology in PCA is most commonly Alzheimer’s disease (AD), but large‐scale biomarker and neuropathological studies are lacking. In this ongoing project we aim to describe demographic, clinical, biomarker a...

Dementia affects more Black individuals, likely due to a combination of environmental and biological factors1,2,3. APOE ε4 allele risk of dementia is different between individuals with European (EUR) and African (AFR) ancestries4,5,6. It is unclear what drives these differences in Alzheimer’s disease (AD) neuropathology among patients with cognitiv...

Background Most people with dementia already live in low‐ to middle‐income countries (LMIC). However, most evidence regarding dementia prevention comes from high‐income countries that have different socioeconomic status (SES) and risk factors prevalence than LMIC. In this session, we will present results on risk and protective factors for dementia...

Neuroimaging of brainstem structures has gained importance in ADRD as these regions degenerate early in AD. In recent years there has been an explosion of novel neuroimaging sequences to image the brainstem. However, most of these methods lack validation against the ground truth, i.e tissue visualization, making these methods less attractive for cl...

Early‐onset Alzheimer’s Disease presentations (EOAD, under 65) frequently present with atypical phenotypes and a more aggressive disease course with a higher burden of neuropsychiatric symptoms than late‐onset AD (LOAD). Current treatments for sleep and behavioral disturbances are still non‐specific, causing side effects (e.g., sedation, falls). Id...

Loss‐of‐function mutations in progranulin (GRN) are an autosomal dominant cause of frontotemporal dementia (FTD). Progranulin is critical for maintenance of lysosomal function. Patients with FTD due to GRN mutations (FTD‐GRN) exhibit signs of lysosomal dysfunction, which may contribute to FTD‐GRN pathogenesis. To assess the potential involvement of...

Defective clearance of tau by neuronal autophagy has been implicated in the accumulation of toxic forms of tau in Alzheimer’s disease (AD). A novel, endogenous activator of chaperone‐mediated autophagy (CMA‐modulator) was identified in cell culture experiments (Cuervo laboratory, unpublished data). It is unclear what role this endogenous CMA‐modula...

The role of hippocampal connectivity for good memory performance is well known in persons with high educational level. However, it is understudied the role of hippocampal connectivity in illiterate populations. Thirty‐nine illiterate adults from Brazil underwent a literacy assessment, structural and resting state functional MRI and an episodic memo...

The pathognomonic lesion of chronic traumatic encephalopathy (CTE) is the perivascular deposition of neuronal phosphorylated tau (p‐tau). Patchy p‐tau deposits initially accumulate in frontotemporal cortices. Medial temporal lobes (MTL) become involved in late stage. Validated in vivo biomarkers for CTE p‐tau do not exist. 18F‐MK‐6240 is a second‐g...

Sleep‐wake disturbance precedes the prodromal stage of Alzheimer’s disease (AD) and is characterized by excessive daytime sleepiness and sundowning. In contrast, hyper‐insomnia is seen in progressive supranuclear palsy (PSP), a pure 4‐repeat tauopathy. The wake‐promoting histaminergic (HA) neurons of the tuberomamillary nucleus (TMN) together with...

The proteolytic ubiquitin‐proteasome system (UPS) is a main control mechanism of tau degradation in eukaryotic cells. Although the UPS is an integral regulator for tau turnover in healthy neurons, preliminary data suggests that the pathological tau in Alzheimer’s Disease (AD) is polyubiquitinated. This is an intriguing conundrum where the polyubiqu...

: The excitatory neurons of the entorhinal cortex are extremely vulnerable to Alzheimer’s disease (AD). Recently, we demonstrated that among those neurons, expressing high levels of RORB, are more vulnerable than other neighboring excitatory neuronal subpopulations. Our single nucleus RNA sequencing of 10 EC at progressive stages of AD neurofibrill...

Dementia is more prevalent in Blacks than in Whites, likely due to a combination of environmental and biological factors. Paradoxically, clinical studies suggest an attenuation of APOE ε4 risk of dementia in African ancestry (AFR), but a dearth of neuropathological data preclude the interpretation of the biological factors underlying these findings...

Background : Apolipoprotein E gene (APOE) ε4 allele is associated with a higher risk of carotid atherosclerosis, but less is known about the association of APOE with intracranial atherosclerotic disease (IAD). We aimed to investigate the association of APOE alleles with IAD in a cross-sectional autopsy study. Methods : We measured the stenosis in...

Background: Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagno...

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and Alzheimer’s disease neuropathologic change (ADNC) are each associated with substantial cognitive impairment in aging populations. However, the prevalence of LATE-NC across the full range of ADNC remains uncertain. To address this knowledge gap, neuropathologic...

Focal anterior temporal lobe (ATL) degeneration often preferentially affects the left or right hemisphere. While patients with left-predominant ATL (lATL) atrophy show severe anomia and verbal semantic deficits and meet criteria for semantic variant primary progressive aphasia (svPPA) and semantic dementia, patients with early right ATL (rATL) atro...

IMPORTANCE The neurological substrates of visual creativity are unknown. We demonstrate the role of dorsomedial visual cortex in emergence of visual artistic creativity (VAC) in the setting of dementia. Our findings illuminate neural substrates of human creativity and suggest that hyperactivation of specific brain areas may manifest as enhanced cog...

Latin American and Caribbean countries face complex challenges to improve brain health and reduce the impact of dementia. Regional hubs devoted to research, capacity building, implementation science, and education are critically needed. The Latin American Brain Health Institute represent an important step to address many of these needs.

Background Fragile X syndrome, the major cause of inherited intellectual disability among men, is due to deficiency of the synaptic functional regulator FMR1 protein (FMRP), encoded by the FMRP translational regulator 1 ( FMR1 ) gene. FMR1 alternative splicing produces distinct transcripts that may consequently impact FMRP functional roles. In tran...

Objective: To establish a microcephaly cut-off size in adults using head circumference as an indirect measure of brain size, as well as to explore factors associated with microcephaly via data mining. Methods: In autopsy studies, head circumference was measured with an inelastic tape placed around the skull. Total brain volume was also directly...

Background: Traumatic encephalopathy syndrome (TES) has overlapping clinical symptoms with Alzheimer's disease (AD). AD pathology commonly co-occurs with chronic traumatic encephalopathy (CTE) pathology. There are currently no validated CTE biomarkers. AD-specific biomarkers like plasma P-tau181 and P-tau217 may help to identify TES patients who h...

Aim: Tau truncation (tr-tau) by active caspase-6 (aCasp-6) generates tau fragments that may be toxic. Yet, the relationship between aCasp-6, different forms of tr-tau, and hyperphosphorylated tau (p-tau) accumulation in human brains with Alzheimer's disease (AD) and other tauopathies remains unclear. Methods: We generated two neoepitope monoclon...

Associations between age-related neuropathological lesions and adult-onset lifetime major depressive disorder (a-MDD), late-life MDD (LLD), or depressive symptoms close to death (DS) were examined in a large community sample of non-demented older adults. 741 individuals (age at death=72.2±11.7 years) from the Biobank for Aging Studies were analyzed...

Importance: The accurate diagnosis of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) is hampered by imperfect clinical-pathological correlations. Objective: To assess and compare the diagnostic value of the magnetic resonance parkinsonism index (MRPI) and other magnetic resonance imaging-based measures of cerebral atrop...

Traumatic encephalopathy syndrome (TES) criteria were developed to aid diagnosis of chronic traumatic encephalopathy (CTE) pathology during life. Interpreting clinical and biomarker findings in patients with TES during life requires autopsy-based determination of the neuropathological profile. We report a clinico-pathological series of 9 patients w...

Activation of microglia is a prominent pathological feature in tauopathies, including Alzheimer’s disease. How microglia activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, activated by tau, drives microglial-mediated tau propagation and...

Importance: Sleep disturbance is common among patients with neurodegenerative diseases. Examining the subcortical neuronal correlates of sleep disturbances is important to understanding the early-stage sleep neurodegenerative phenomena. Objectives: To examine the correlation between the number of important subcortical wake-promoting neurons and...

Lewy body disease, an α-synucleinopathy, is the neuropathological counterpart of idiopathic Parkinson’s disease and one of the most frequent neurodegenerative diseases in humans [1]. Parkinson’s disease features compelling motor symptoms. Parkinson summarized these symptoms under the mixed Greek-Latin term paralysis agitans (shaking palsy) [2], and...

Background: The histaminergic neurons of the tuberomammillary nucleus (TMN) of the hypothalamus are key wake-promoting neurons (WPN). Previously we demonstrated that TMN neurons degenerate by 80% in Alzheimer’s disease (AD), whereas it remains relatively preserved in progressive supranuclear palsy (PSP), a pure 4-repeat tauopathy. This pattern of v...

Background The association between lifetime alcohol abuse and a higher risk to develop dementia is well known. However, it is unknown whether older adults who begin abusing alcohol late in life have an underlying neurodegenerative disease. Objective Identify the frequency of lifelong alcohol abuse (L-AA), late-onset alcohol abuse (LO-AA), and alco...

Dementia is more prevalent in Blacks than in Whites, likely due to a combination of environmental and biological factors. Paradoxically, clinical studies suggest an attenuation of APOE ϵ4 risk of dementia in African ancestry (AFR), but lack of neuropathological data preclude the interpretation of the biological factors underlying these findings, in...

Objective: This study aimed to compare causes of death in the most prevalent neuropathologically diagnosed dementias. Methods: We analyzed causes of death in a community-based cohort of participants aged 50 or older, submitted to full-body autopsy and a comprehensive neuropathologic examination of the brain. Individuals with Alzheimer disease (A...

Background Obsessive-compulsive disorder (OCD) is characterized by intrusive thoughts and repetitive actions, that presents the involvement of the cortico-striatal areas. The contribution of environmental risk factors to OCD development suggests that epigenetic mechanisms may contribute to its pathophysiology. DNA methylation changes and gene expre...

Background The Locus coeruleus(LC) is one of the first sites of tau aggregation and suffers from dramatic volume loss early on. Due to the shrinking of the LC preceding the onset of clinical symptoms of AD by decades, a precise understanding of the neurobiological correlates of MRI signal may turn LC neuroimaging into an early non‐invasive staging...

Background: Sleep plays a key role in the origination and progression of neurodegenerative diseases. We have recently shown that the key areas that regulate sleep and wakefulness in the subcortical nuclei are particularly vulnerable to tau-inclusion and neuronal loss even in the early stages in AD. Nevertheless, it remains uncertain whether the pa...

Background Imaging methods that are non‐destructive preserve tissue integrity and lead to improved topography analysis for the study of neurodegenerative diseases like Alzheimer’s Disease (AD). Immunofluorescence (IF) staining methods facilitate such investigations by addressing a gradient of intensity variations relevant for in situ cell detection...

Background: Tau truncation by active caspase-6 facilitates tau pathogenesis by producing toxic fragments prone to self-aggregation. We previously demonstrated that neuronal active caspase-6 co-occurs with phosphorylated tau (p-tau) during the earliest stages of Alzheimer's disease (AD) and that the percentage of neurons positive for both active ca...

Background: Tau post-translational modifications (PTMs) are associated with progressive tau accumulation and neuronal loss in tauopathies, including forms of frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). Proteolytic cleavage of tau by active caspases, including caspase-6, represents an underexplored tau PTM implicated in t...

Background: Early-onset AD (EOAD, onset of symptoms before age 65), is viewed as a relatively pure form of AD with a more homogeneous neuropathological substrate. Method: We sought to compare the frequency of copathologies in an autopsy series of 96 patients with EOAD (median age of onset (AOO) = 55 years, 44 females) and 48 with late-onset AD (...

Background: The classic most common clinical variant of Alzheimer´s Disease(AD) is the progressive amnestic-dysexecutive predominant syndrome. Atypical or focal cortical AD clinical presentations are characterized by unusual symptoms that include corticobasal syndrome(CBS), logopenic variant primary progressive aphasia(lvPPA), posterior cortical a...

Background: Sleep disturbances are common precognitive symptoms of Alzheimer's disease (AD). Wake-promoting orexinergic neurons (Oxe) in the lateral hypothalamic area (LHA) are key regulators of sleep-wake states. We recently reported a major loss of Oxe in the terminal stages of AD. This was unexpected, because clinical research shows elevated or...

Background: Sleep-wake disturbances are a prominent feature in Alzheimer's Disease (AD), negatively impacting patients and caregivers' quality of life. Growing evidence suggests that sleep-wake dysregulation happens early in AD due to the AD-tau degeneration of the arousal system (i.e., locus coeruleus). However, whether the pattern of sleep-wake...

O capítulo, com autoria de neuropatologistas, descreve o conhecimento atualizado da patologia das principais doenças do sistema nervoso e contém 123 figuras das lesões macro e microscópicas, além de algumas figuras de neuroimagem, e 35 quadros que ajudam na compreensão e aprendizado dos temas.

Homozygous mutations of granulin precursor (GRN) lead to neuronal ceroid lipofuscinosis, a severe neurodevelopmental disease, in humans and neuroinflammation in mice. Haploinsufficiency of GRN almost invariably causes frontotemporal dementia (FTD). The GRN locus produces progranulin (PGRN), a lysosomal precursor protein that is cleaved to granulin...

Background Plasma tau phosphorylated at threonine 217 (p-tau217) and plasma tau phosphorylated at threonine 181 (p-tau181) are associated with Alzheimer's disease tau pathology. We compared the diagnostic value of both biomarkers in cognitively unimpaired participants and patients with a clinical diagnosis of mild cognitive impairment, Alzheimer's...

The most common neurodegenerative syndrome associated with Pick’s disease pathology (PiD) is behavioral variant frontotemporal dementia (bvFTD), which features profound social behavioral changes. Rarely, PiD can manifest as an Alzheimer’s disease (AD)-type dementia with early memory impairment. We describe a patient with AD-type dementia and pure P...

Disturbances of the sleep/wake cycle in Alzheimer's disease (AD) are common, frequently precede cognitive decline, and tend to worsen with disease progression. Sleep is critical to the maintenance of homeostatic and circadian function, and chronic sleep disturbances have significant cognitive and physical health consequences that likely exacerbate...

Anterior temporal lobe (ATL) degeneration is caused by a pathological process that has a focal onset in the left or right hemisphere. Patients with left-lateralized ATL atrophy typically meet criteria for semantic variant primary progressive aphasia (PPA), a clinical syndrome characterized by loss of verbal semantic knowledge. There is less consens...

Background There is an increasing awareness that sleep disturbances are a risk factor for dementia. Prior case-control studies suggested that brain grey matter (GM) changes involving cortical (i.e, prefrontal areas) and subcortical structures (i.e, putamen, thalamus) could be associated with insomnia status. However, it remains unclear whether ther...

Patients with early-onset Alzheimer's disease (EOAD) are commonly excluded from large-scale observational and therapeutic studies due to their young age, atypical presentation, or absence of pathogenic mutations. The goals of the Longitudinal EOAD Study (LEADS) are to (1) define the clinical, imaging, and fluid biomarker characteristics of EOAD; (2...

Patient-derived cells hold great promise for precision medicine approaches in human health. Fibroblast cells have been a major source of human cells for reprogramming and differentiating into specific cell types for disease modeling. Such cells can be isolated at various stages during life (presymptomatic, symptomatic, and postmortem) and thus can...

Background: Body mass index (BMI) in midlife is associated with dementia. However, the association between BMI and late-life obesity is controversial. Few studies have investigated the association between BMI and cognitive performance near the time of death using data from autopsy examination. We aimed to investigate the association between BMI and...

Alzheimer’s disease (AD) is neuropathologically characterized by the intracellular accumulation of hyperphosphorylated tau and the extracellular deposition of amyloid-β plaques, which affect certain brain regions in a progressive manner. The locus coeruleus (LC), a small nucleus in the pons of the brainstem, is widely recognized as one of the earli...

The farnesyltransferase inhibitor, Lonafarnib, reduces tau inclusions and associated atrophy in familial tauopathy models through activation of autophagy, mediated by the inhibition of farnesylation of the Ras GTPase, Rhes. While hinting at a role of Rhes in tau aggregation, it is unclear how translatable these results are for sporadic forms of tau...

One hallmark of human aging is increased brain inflammation represented by glial activation. With age, there is also diminished function of the adaptive immune system, and modest decreases in circulating B- and T-lymphocytes. Lymphocytes traffic through the human brain and reside there in small numbers, but it is unknown how this changes with age....

The increase in senescent cells in tissues, including the brain, is a general feature of normal aging and age-related pathologies. Senescent cells exhibit a specific phenotype, which includes an altered nuclear morphology and transcriptomic changes. Astrocytes undergo senescence in vitro and in age-associated neurodegenerative diseases, but little...

Introduction: Neurophysiological manifestations selectively associated with amyloid beta and tau depositions in Alzheimer's disease (AD) are useful network biomarkers to identify peptide specific pathological processes. The objective of this study was to validate the associations between reduced neuronal synchrony within alpha oscillations and neu...

Importance The presence of atrophy on magnetic resonance imaging can support the diagnosis of the behavioral variant of frontotemporal dementia (bvFTD), but reproducible measurements are lacking. Objective To assess the diagnostic and prognostic utility of 6 visual atrophy scales (VAS) and the Magnetic Resonance Parkinsonism Index (MRPI). Design,...

Copathologies play an important role in the expression of the AD clinical phenotype and may influence treatment efficacy. Early-onset AD (EOAD), defined as manifesting before age 65, is viewed as a relatively pure form of AD with a more homogeneous neuropathological substrate. We sought to compare the frequency of common neuropathological diagnoses...

Background: Tau post-translational modifications (PTMs) are associated with progressive tau accumulation and neuronal loss in tauopathies, including forms of frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD). Tau proteolysis by caspases, including caspase-6, represents an understudied PTM that may increase neurotoxicity and tau...

Although, the clinical variants of Alzheimer's disease (AD) show distinct patterns of cognitive and behavioral decline, disease progression, and neuropathological features, it is unclear if this clinical heterogeneity extends to sleep‐wake patterns. Sleep and wake disturbances are frequent in typical AD, often preceding memory loss and negatively i...

Objective: We aimed to evaluate, by immunohistochemistry, astrocytes, tyrosine hydroxylase (TH) and structural proteins expression (neurofilaments and microtubules — MAP2) changes in postmortem brain samples of individuals with Lewy body pathology. Methods: Braak PD stage≥III samples, classified by neuropathology analysis, from The Biobank for Agi...

Background: Population aging will lead to a dramatic increase in dementia prevalence, which will disproportionally affect racial minorities. The presence of racial differences in dementia prevalence has been widely reported in United States, but there are no relevant studies on this topic in low-middle income countries (LMIC). Methods: In a cros...

Across Latin American and Caribbean countries (LACs), the fight against dementia faces pressing challenges, such as heterogeneity, diversity, political instability, and socioeconomic disparities. These can be addressed more effectively in a collaborative setting that fosters open exchange of knowledge. In this work, the Latin American and Caribbean...

Activation of microglia, the innate immune cells in brain, is a prominent pathological feature in tauopathies, including Alzheimers disease. How microglia activation contributes to tau toxicity remains largely unknown. Here we show that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, activated by tau, drives microg...

Introduction: Biological sex is an increasingly recognized factor driving clinical and structural heterogeneity in Alzheimer's disease, but its role in the behavioral variant of frontotemporal dementia (bvFTD) is unknown. Methods: We included 216 patients with bvFTD and 235 controls with magnetic resonance imaging (MRI) from a large multicenter...

The choroid plexus (CP) is an important structure for the brain. Besides its major role in the production of cerebrospinal fluid (CSF), it conveys signals originating from the brain, and from the circulatory system, shaping brain function in health and in pathology. Previous studies in rodents have revealed altered transcriptome both during aging a...

Background Polymorphisms in TMEM106B, a gene on chromosome 7p21.3 involved in lysosomal trafficking, correlates to worse neuropathological and clinical outcomes in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) with TDP‐43 inclusions. In a small cohort of C9orf72 expansion carriers, we previously found an atypical,...

Currently, the neuropathological diagnosis of Lewy body disease (LBD) may be stated according to several staging systems, which include the Braak Lewy body stages (Braak), the consensus criteria by McKeith and colleagues (McKeith), the modified McKeith system by Leverenz and colleagues (Leverenz), and the Unified Staging System by Beach and colleag...

Aim Tau truncation (tr-tau) by active caspase-6 (aCasp-6) generates toxic tau fragments prone to self-aggregation. Yet, the relationship between aCasp-6, different forms of tr-tau, and hyperphosphorylated tau (p-tau) accumulation in human brains with Alzheimer's disease (AD) and other tauopathies remains unclear. Methods We generated two neoepitope...

Study Objectives: The lateral hypothalamic area (LHA) is one of the key regions orchestrating sleep and wake control. It is the site of wake-promoting orexinergic and sleep-promoting melanin-concentrating hormone (MCH) neurons, which share a close anatomical and functional relation. The aim of the study was to investigate the degeneration of MCH ne...

Although psychosis is a defining feature of Lewy body disease, psychotic symptoms occur in a subset of patients with every major neurodegenerative disease. Few studies, however, have compared disease-related rates of psychosis prevalence in a large autopsy-based cohort, and it remains unclear how diseases differ with respect to the nature or conten...

Alzheimer’s disease (AD) is characterized by the selective vulnerability of specific neuronal populations, the molecular signatures of which are largely unknown. To identify and characterize selectively vulnerable neuronal populations, we used single-nucleus RNA sequencing to profile the caudal entorhinal cortex and the superior frontal gyrus—brain...

Tau post-translational modifications (PTMs) are associated with progressive tau accumulation and neuronal loss in tauopathies, including forms of frontotemporal lobar degeneration (FTLD) and Alzheimer’s disease (AD). Proteolytic cleavage of tau by active caspases, including caspase-6, represents an underexplored tau PTM implicated in tau pathology....

Brain arteriolosclerosis (B-ASC), characterized by pathologic arteriolar wall thickening, is a common finding at autopsy in aged persons and is associated with cognitive impairment. Hypertension and diabetes are widely recognized as risk factors for B-ASC. Recent research indicates other and more complex risk factors and pathogenetic mechanisms. He...

Background: The role of hippocampal connectivity for good memory performance is well known in persons with high educational level. However, it is understudied the role of hippocampal connectivity in illiterate populations. Objectives: To determine whether the hippocampal connectivity correlate with episodic memory in illiterate adults. Methods: Thi...

The pathological hallmark of Parkinson’s disease (PD) is the loss of neuromelanin-containing dopaminergic neurons within the substantia nigra pars compacta (SNpc). Additionally, numerous studies indicate an altered synaptic function during disease progression. To gain new insights into the molecular processes underlying the alteration of synaptic f...

Background Using a multimodal imaging approach with neurophysiological assessments incorporated alongside molecular markers in patients with AD, we have previously demonstrated frequency‐specific neural synchronization deficits distinctly associated with tau and Aβ tracer uptake. Reduced alpha (8‐12 Hz) synchrony (alpha hyposynchrony) closely mappe...

Background Few studies have evaluated the relationship between in vivo [ ¹⁸ F]Flortaucipir (FTP) PET and post‐mortem pathology. Method We sought to compare antemortem FTP‐PET to neuropathology in a consecutive series of patients with a broad spectrum of neurodegenerative diseases. 80‐100 min FTP‐PET standardized uptake value ratio (SUVR) images we...

Background Sleep disorders represent one of the leading causes of life impairment and a major therapeutic challenge in patients with Alzheimer’s disease (AD) and tauopathies. However, the disease specific neurobiological basis of these sleep disturbances remains mostly elusive. Melanin‐concentrating hormone (MCH) neurons are a conserved neuronal po...

Background Chronic traumatic encephalopathy (CTE) is a tauopathy associated with repeated brain injuries. The presence of co‐pathologies is not uncommon in individuals with CTE. Here, we described clinical and neuropathological findings of amateur soccer with a history of progressive parkinsonism and dementia. Method 63‐years old male with no fami...

Background There is an increasing awareness that sleep disturbances are a risk factor for dementia (Sindi, 2018). Prior case‐control studies have suggested that certain alterations in brain structure could be associated with insomnia status (Sexton, 2014; Grau‐Rivera, 2019). Specifically, they mainly described smaller cortical volumes in orbitofron...

Background The cerebellum has not been extensively studied in the setting of Alzheimer’s disease (AD). As the disease progresses, the cerebellum is one of the last brain regions to accumulate β‐amyloid (βA) deposits usually as diffuse plaques. However, distinct morphologies are described in the cerebellum in early‐onset Alzheimer’s disease (EOAD)....

Background Cognitive reserve refers to the resilience education and life‐time mental activity confer against neurodegenerative disease. Mostly understood within Alzheimer’s disease (AD), we investigated the impact education and occupation history have within frontotemporal dementia (FTD). Methods Employing the United States Bureau of Labor Statist...

Background The ascending reticular activating system (ARAS) is a collection of interconnected brain nuclei that regulates wakefulness, alertness and modulate behaviors. The critical components of ARAS degenerates early during Alzheimer’s disease progression in association with abnormal tau build‐up. Despite accumulating evidence, the role of AD‐rel...