Patrick Hof

• Icahn School of Medicine at Mount Sinai

In this study, we further characterized a non-transgenic model of tauopathy by examining tau protein changes using ELISA and Western blot upon inoculation of human tau oligomers (TO) and human tau synthetic pre-formed fibrils (TF) into the medial entorhinal cortex of Wistar rats. Our analyses showed that inoculation with TO did not significantly al...

Background Compared to other primates, humans display unique behaviors including language and complex tool use. These abilities are made possible in part by the cerebellum. This region of the hindbrain, comprising the flocculus, vermis, and lateral hemispheres, has expanded throughout primate evolution, particularly in great apes. Given the cerebel...

In modern war theaters, exposures to blast overpressures are one of the most common causes of brain injury. These pervasive events result in acute and chronic cerebrovascular degenerative processes. Using a rat model of blast-induced mild traumatic brain injury, we identified intramural periarterial hematomas as early primary acute lesions induced...

Primate species differ drastically from most other mammals in how they visually perceive their environments, which is particularly important for foraging, predator avoidance, and detection of social cues. Background/Objectives: Although it is well established that primates display diversity in color vision and various ecological specializations, it...

Paleoneurology reconstructs the evolutionary history of nervous systems through direct observations from the fossil record and comparative data from extant species. While this approach can provide direct evidence of phylogenetic links among species, it is constrained by the availability and quality of data that can be gleaned from the fossil record...

Paleoneurology reconstructs the evolutionary history of nervous systems through direct observations from the fossil record and comparative data from extant species. While this approach can provide direct evidence of phylogenetic links among species, it is constrained by the availability and quality of data that can be gleaned from the fossil record...

Background Nonhuman primates are arguably the best models for Alzheimer’s disease (AD), due to close similarities with humans in physiology and behavior, brain structure and function, and aging patterns. The common marmoset (Callithrix jacchus) is particularly valuable because it has the shortest lifespan of all anthropoids (10‐12 years), exhibits...

Background In Alzheimer’s disease (AD), specific brain regions become vulnerable to pathology while others remain resilient. New methods of imaging such as highly multiplexed immunofluorescence (MxIF) provide an abundance of spatial information, while analytical techniques like machine learning (ML) can address questions of cellular contributors to...

Accurate labeling of specific layers in the human cerebral cortex is crucial for advancing our understanding of neurodevelopmental and neurodegenerative disorders. Building on recent advancements in ultra-high-resolution ex vivo MRI, we present a novel semi-supervised segmentation model capable of identifying supragranular and infragranular layers...

Although the mammalian cerebral cortex is most often described as a hexalaminar structure, there are cortical areas (primary motor cortex) and species (elephants, cetaceans, and hippopotami), where a cytoarchitecturally indistinct, or absent, layer 4 is noted. Thalamocortical projections from the core, or first order, thalamic system terminate prim...

The Evolutionary Roots of Human Brain Diseases takes an innovative approach and assembles recent findings ranging from evolutionary biology and anthropology to clinical neurosciences, all showing the price on health of human brain evolution. Written by experts in their field, the chapters explore the tenet that extensive human brain development dur...

In this novel large-scale multiplexed immunofluorescence study we comprehensively characterized and compared layer-specific proteomic features within regions of interest of the widely divergent dorsolateral prefrontal cortex (A46) and primary visual cortex (A17) of adult rhesus monkeys. Twenty-eight markers were imaged in rounds of sequential stain...

3D reconstruction of human brain volumes at high resolution is now possible thanks to advancements in tissue clearing methods and fluorescence microscopy techniques. Analyzing the massive data produced with these approaches requires automatic methods able to perform fast and accurate cell counting and localization. Recent advances in deep learning...

Understanding cellular architectures and their connectivity is essential for interrogating system function and dysfunction. However, we lack technologies for mapping the multiscale details of individual cells and their connectivity in the human organ–scale system. We developed a platform that simultaneously extracts spatial, molecular, morphologica...

The evolutionary history of canids and felids is marked by a deep time separation that has uniquely shaped their behavior and phenotype towards refined predatory abilities. The caudate nucleus is a subcortical brain structure associated with both motor control as well as cognitive, emotional and executive functions. We used a combination of three d...

Cloud computing enables small businesses to use computing resources more flexibly and efficiently, thereby gaining a competitive advantage and better adapting to market changes.-Cloud computing provides small businesses with many advantages, allowing them to operate more flexibly and efficiently. Here are some of the key benefits of cloud computing...

Schizophrenia is a complex mental condition, with key symptoms marked for diagnosis including delusions, hallucinations, disorganized thinking, reduced emotional expression, and social dysfunction. In the context of major developmental hypotheses of schizophrenia, notably those concerning maternal immune activation and neuroinflammation, we studied...

Introduction Auditory information is relayed from the cochlea via the eighth cranial nerve to the dorsal and ventral cochlear nuclei (DCN, VCN). The organization, neurochemistry and circuitry of the cochlear nuclei (CN) have been studied in many species. It is well-established that glycine is an inhibitory transmitter in the CN of rodents and cats,...

Primate evolution has led to a remarkable diversity of behavioral specializations and pronounced brain size variation among species (Barton, 2012; DeCasien & Higham, 2019; Powell, Isler, & Barton, 2017). Gene expression provides a promising opportunity for studying the molecular basis of brain evolution, but it has been explored in very few primate...

Blast-induced neurotrauma has received much attention over the past decade. Vascular injury occurs early following blast exposure. Indeed, in animal models that approximate human mild traumatic brain injury or subclinical blast exposure, vascular pathology can occur in the presence of a normal neuropil, suggesting that the vasculature is particular...

Background Nonhuman primate models of human aging are necessary to understand functional decline and identify vulnerabilities to aging pathologies. Longitudinal studies are critical and common marmosets ( Callithrix jacchus ) are ideal as they have a short lifespan (∼12 yr) and naturally develop neuropathology relevant to Alzheimer’s disease (AD)....

The basolateral amygdala (BLA) projects to the frontal cortex (FC) in both rodents and primates, but the comparative organization of single-neuron BLA-FC projections is unknown. Using a barcoded connectomic approach, we found that BLA neurons are more likely to project to multiple distinct parts of FC in mice than in macaques. Further, while single...

Accurate labeling of specific layers in the human cerebral cortex is crucial for advancing our understanding of neurodevelopmental and neurodegenerative disorders. Leveraging recent advancements in ultra-high resolution ex vivo MRI, we present a novel semi-supervised segmentation model capable of identifying supragranular and infragranular layers i...

Comparative “omics” studies have revealed unique aspects of human neurobiology, yet an evolutionary perspective of the brain N-glycome is lacking. We performed multiregional characterization of rat, macaque, chimpanzee, and human brain N-glycomes using chromatography and mass spectrometry and then integrated these data with complementary glycotrans...

Functional output of the hippocampus, a brain region subserving memory function, depends on highly orchestrated cellular and molecular processes that regulate synaptic plasticity throughout life. The structural requirements of such plasticity and molecular events involved in this regulation are poorly understood. Specific molecules, including tissu...

Many military veterans who experienced blast-related traumatic brain injuries in the conflicts in Iraq and Afghanistan currently suffer from chronic cognitive and mental health problems that include depression and post-traumatic stress disorder (PTSD). Male rats exposed to repetitive low-level blast develop cognitive and PTSD-related behavioral tra...

Investigating evolutionary changes in frontal cortex microstructure is crucial to understanding how modifications of neuron and axon distributions contribute to phylogenetic variation in cognition. In the present study, we characterized microstructural components of dorsolateral prefrontal cortex, orbitofrontal cortex, and primary motor cortex from...

Background The main advantage of ultra‐high field (UHF) magnetic resonance neuroimaging is theincreased signal‐to‐noise ratio (SNR) compared with lower field strength imaging. However, the wavelength effect associated with UHF MRI results in radiofrequency (RF) inhomogeneity, compromising whole brain coverage for many commercial coils. Approaches t...

Brain cells are arranged in laminar, nuclear, or columnar structures, spanning a range of scales. Here, we construct a reliable cell census in the frontal lobe of human cerebral cortex at micrometer resolution in a magnetic resonance imaging (MRI)–referenced system using innovative imaging and analysis methodologies. MRI establishes a macroscopic r...

Variation in cytoarchitecture is the basis for the histological definition of cortical areas. We used single cell transcriptomics and performed cellular characterization of the human cortex to better understand cortical areal specialization. Single-nucleus RNA-sequencing of 8 areas spanning cortical structural variation showed a highly consistent c...

The nucleus accumbens (NAc) is central to motivation and action, exhibiting one of the highest densities of neuropeptide Y (NPY) in the brain. Within the NAc, NPY plays a role in reward and is involved in emotional behavior and in increasing alcohol and drug addiction and fat intake. Here, we examined NPY innervation and neurons of the NAc in human...

Characterizing cellular diversity at different levels of biological organization and across data modalities is a prerequisite to understanding the function of cell types in the brain. Classification of neurons is also essential to manipulate cell types in controlled ways and to understand their variation and vulnerability in brain disorders. The BR...

Background The primary histological characteristic of Alzheimer's disease is the presence of neurofibrillary tangles, which are large aggregates of tau protein. Aging is the primary risk factor for the development of Alzheimer's disease, however, the underlying causes of tau protein aggregation and toxicity are unclear. Aims Here we investigated t...

In the course of military operations in modern war theaters, blast exposures are associated with the development of a variety of mental health disorders associated with a post-traumatic stress disorder-related features, including anxiety, impulsivity, insomnia, suicidality, depression, and cognitive decline. Several lines of evidence indicate that...

The role of metals in the pathogenesis of Alzheimer’s disease (AD) is still debated. Although previous research has linked changes in essential metal homeostasis and exposure to environmental heavy metals to the pathogenesis of AD, more research is needed to determine the relationship between metals and AD. In this review, we included human studies...

Many military veterans who experienced blast-related traumatic brain injuries (TBIs) in the conflicts in Iraq and Afghanistan suffer from chronic cognitive and mental health problems, including post-traumatic stress disorder (PTSD). Male rats subjected to repetitive low-level blast exposure develop chronic cognitive and PTSD-related traits that dev...

The tauopathy of Alzheimer’s disease (AD) is first observed in the brainstem and entorhinal cortex, spreading trans-synaptically along specific pathways to other brain regions with recognizable patterns. Tau propagation occurs retrogradely and anterogradely (trans-synaptically) along a given pathway and through exosomes and microglial cells. Some a...

The superior olivary complex (SOC) is a collection of nuclei in the hindbrain of mammals with numerous roles in hearing, including localization of sound sources in the environment, encoding temporal and spectral elements of sound, and descending modulation of the cochlea. While there have been several investigations of the SOC in primates, there ar...

Background Major depressive disorder (MDD) is a prevalent health problem with complex pathophysiology that is not clearly understood. Prior work has implicated the hippocampus in MDD, but how hippocampal subfields influence or are affected by MDD requires further characterization with high-resolution data. This will help ascertain the accuracy and...

Background: The apolipoprotein E (APOE, gene; apoE, protein) ε4 allele is the most common identified genetic risk factor for typical late-onset sporadic Alzheimer’s disease (AD). Each APOE ε4 allele roughly triples the relative risk for AD compared to that of the reference allele, APOE ε3. Methods: We have employed hyperspectral fluorescence imagi...

The basolateral amygdala (BLA) projects widely across the macaque frontal cortex, and amygdalo-frontal projections are critical for optimal emotional responding and decision-making. Yet, little is known about the single-neuron architecture of these projections: namely, whether single BLA neurons project to multiple parts of the frontal cortex. Here...

Aging and neurodegenerative disorders, such as Alzheimer's disease (AD), trigger an immune response known as glial activation in the brain. Recent evidence indicates species differences in inflammatory responses to AD pathology, highlighting the need for additional comparative studies to further understand human‐specific neuropathologies. In the pr...

Prematurely born infants are deprived of maternal hormones and cared for in the stressful environment of Neonatal Intensive Care Units (NICUs). They suffer from long-lasting deficits in learning and memory. Here, we show that prematurity and associated neonatal stress disrupt dentate gyrus (DG) development and induce long-term cognitive deficits an...

Comparative “omics” studies have revealed unique aspects of human neurobiology, yet an evolutionary perspective of the brain N-glycome is lacking. Here, we performed multi-regional characterization of rat, macaque, chimpanzee, and human brain N-glycomes using chromatography and mass spectrometry, then integrated these data with complementary glycot...

Various metals have been associated with the pathogenesis of Alzheimer’s disease (AD), principally heavy metals that are environmental pollutants (such as As, Cd, Hg, and Pb) and essential metals whose homeostasis is disturbed in AD (such as Cu, Fe, and Zn). Although there is evidence of the involvement of these metals in AD, further research is ne...

The importance of assessing neurochemical processes in the cetacean brain as a tool for monitoring their cognitive health and to indirectly model human neurodegenerative conditions is increasingly evident, although available data are largely semiquantitative. High-resolution MRI for post-mortem brains and stereology allow for quantitative assessmen...

Aims Considering the substantial variability in treatment response across patients with spinal muscular atrophy (SMA), reliable markers for monitoring response to therapy and predicting treatment responders need to be identified. The study aimed to determine if measured concentrations of disease biomarkers (total tau protein, neurofilament light ch...

A decrease in serotonergic transmission throughout the brain is among the earliest pathological changes in Alzheimer’s disease (AD). Serotonergic receptors are also affected in AD. Polymorphisms in genes of serotonin (5HT) receptors have been mostly associated with behavioral and psychological symptoms of dementia (BPSD). In this study, we examined...

The ventral tegmental area (VTA) is one of the major sources of dopamine in the brain and has been associated with reward prediction, error-based reward learning, volitional drive and anhedonia. However, precise anatomical investigations of the VTA have been prevented by the use of standard-resolution MRI, reliance on subjective manual tracings, an...

The investigation of neurobiological and neuropathological changes that affect synaptic integrity and function with aging is key to understanding why the aging brain is vulnerable to Alzheimer's disease. We investigated the cellular characteristics in the cerebral cortex of behaviorally characterized marmosets, based on their trajectories of cognit...

Variation in cortical cytoarchitecture is the basis for histology-based definition of cortical areas, such as Brodmann areas. Single cell transcriptomics enables higher-resolution characterization of cell types in human cortex, which we used to revisit the idea of the canonical cortical microcircuit and to understand functional areal specialization...

Characterizing cellular diversity at different levels of biological organization across data modalities is a prerequisite to understanding the function of cell types in the brain. Classification of neurons is also required to manipulate cell types in controlled ways, and to understand their variation and vulnerability in brain disorders. The BRAIN...

Chronic mental health problems are common among military veterans who suffered blast-related traumatic brain injuries. The reasons for this association remain unexplained. Male rats exposed to repetitive low-level blast overpressure (BOP) exposures exhibit chronic cognitive and post-traumatic stress disorder (PTSD)-related traits that develop in a...

Age-related cognitive impairment is multifactorial, with numerous underlying and frequently co-morbid pathological correlates. Amyloid beta (Aβ) plays a major role in Alzheimer’s type age-related cognitive impairment, in addition to other etiopathologies such as Aβ-independent hyperphosphorylated tau, cerebrovascular disease, and myelin damage, whi...

Chronic traumatic encephalopathy (CTE) is a tauopathy associated with repetitive mild head impacts characterized by perivascular hyperphosphorylated tau (p-tau) in neurofibrillary tangles (NFTs) and neurites in the depths of the neocortical sulci. In moderate to advanced CTE, NFTs accumulate in the hippocampus, potentially overlapping neuroanatomic...

The granular dorsolateral prefrontal cortex (dlPFC) is an evolutionary specialization of primates that is centrally involved in cognition. Here, we assessed over 600,000 single-nucleus transcriptomes from adult human, chimpanzee, macaque, and marmoset dlPFC. While most transcriptomically-defined cell subtypes are conserved, we detected several only...

Astrocytes are the main homeostatic cell of the brain involved in many processes related to cognition, immune response, and energy expenditure. It has been suggested that the distribution of astrocytes is associated with brain size, and that they are specialized in humans. To evaluate these, we quantified astrocyte density, soma volume, and total g...

Epigenetic age has emerged as an important biomarker of biological aging. It has revealed that some tissues age faster than others, which is vital to understanding the complex phenomenon of aging and developing effective interventions. Previous studies have demonstrated that humans exhibit heterogeneity in pace of epigenetic aging among brain struc...

Traumatic brain injury (TBI) is a leading cause of neurologic impairment and death that remains poorly understood. Rodent models have yet to produce clinical therapies, and the exploration of larger and more diverse models remains relatively scarce. We investigated the potential for brain injury after headbutting in two combative bovid species by a...

The combination of optical tissue transparency with immunofluorescence allows the molecular characterization of biological tissues in 3D. However, adult human organs are particularly challenging to become transparent because of the autofluorescence contributions of aged tissues. To meet this challenge, we optimized SHORT (SWITCH—H2O2—antigen Retrie...

Little is known about the development of the human entorhinal cortex (EC), a major hub in a widespread network for learning and memory, spatial navigation, high‐order processing of object information, multimodal integration, attention and awareness, emotion, motivation, and perception of time. We analyzed a series of 20 fetal and two adult human br...

Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) plaques. The pathogenesis of PART is n...

Many military veterans who experienced blast-related traumatic brain injuries (TBIs) in the conflicts in Iraq and Afghanistan suffer from chronic cognitive and mental health problems, including post-traumatic stress disorder (PTSD). Transcranial laser therapy (TLT) uses low-power lasers emitting light in the far- to near-infrared ranges. Beneficial...

Background: Cerebral microvasculature abnormalities are implicated in Alzheimer's disease (AD) neuropathology. Ischemic lesions causing neuronal damage are often found in AD brains. The brain responds to ischemia by stimulating tissue neovascularization via sprouting angiogenesis, impairment of this function renders the brain vulnerable to the ins...

In recent years, new human magnetic resonance imaging systems operating at static magnetic fields strengths of 7 Tesla or higher have become available, providing better signal sensitivity compared with lower field strengths. However, imaging human-sized objects at such high field strength and associated precession frequencies is limited due to the...

Muskoxen (Ovibos moschatus) have thick skulls and large horns as a consequence of their extreme headbutting behavior. Despite the common belief that this headgear protects their brains from extreme impacts, preliminary studies indicate otherwise, as shown by the presence of traumatic brain injury (TBI)-like pathology highlighted by tau-positive his...

The combination of tissue clearing techniques with advanced optical microscopy facilitates the achievement of three-dimensional (3D) reconstruction of macroscopic specimens at high resolution. Whole mouse organs or even bodies have been analyzed, while the reconstruction of the human nervous system remains a challenge. Although several tissue proto...

Cells are not uniformly distributed in the human cerebral cortex. Rather, they are arranged in a regional and laminar fashion that span a range of scales. Here we demonstrate an innovative imaging and analysis pipeline to construct a reliable cell census across the human cerebral cortex. Magnetic resonance imaging (MRI) is used to establish a macro...

Cerebral vascular injury as a consequence of blast-induced traumatic brain injury is primarily the result of blast wave-induced mechanical disruptions within the neurovascular unit. In rodent models of blast-induced traumatic brain injury, chronic vascular degenerative processes are associated with the development of an age-dependent post-traumatic...

The primary motor cortex (M1) is essential for voluntary fine-motor control and is functionally conserved across mammals¹. Here, using high-throughput transcriptomic and epigenomic profiling of more than 450,000 single nuclei in humans, marmoset monkeys and mice, we demonstrate a broadly conserved cellular makeup of this region, with similarities t...

Traumatic brain injury (TBI) is a risk factor for the later development of neurodegenerative diseases that may have various underlying pathologies. Chronic traumatic encephalopathy (CTE) in particular is associated with repetitive mild TBI (mTBI) and is characterized pathologically by aggregation of hyperphosphorylated tau into neurofibrillary tang...

Varicose projection astrocytes (VP-As) are found in the cerebral cortex and have been described to be specific to humans and chimpanzees. To further examine the phylogenetic distribution of this cell type, we analyzed cortical tissue from several primates ranging from primitive primates to primates evolutionary closer to human such as apes. We spec...

Background The dopaminergic system is functionally compromised in Alzheimer’s dis-ease (AD). The activity of monoamine oxidase B (MAOB), the enzyme involved in the degradation of dopamine, is increased during AD. Also, increased expression of MAOB occurs in the post-mortem hippocampus and neocortex of patients with AD. The MAOB rs1799836 polymorphi...

Abnormally phosphorylated tau, an early neuropathologic marker of Alzheimer’s disease (AD), first occurs in the brain’s entorhinal cortex layer II (ECII) and then spreads to the CA1 field of the hippocampus. Animal models of tau propagation aiming to recapitulate this phenomenon mostly show tau transfer from ECII stellate neurons to the dentate gyr...

Neurodevelopmental disorders (NDDs) are conditions that present with brain dysfunction due to alterations in the processes of brain development. They present with neuropsychiatric, cognitive, and motor symptoms. Autism spectrum disorder (ASD) and Fragile X syndrome (FXS) are two of the most common NDDs. Human brain tissue is a scarce resource that...

Increasing interest in studies of prenatal human brain development, particularly using new single-cell genomics and anatomical technologies to create cell atlases, creates a strong need for accurate and detailed anatomical reference atlases. In this study, we present two cellular-resolution digital anatomical atlases for prenatal human brain at pos...

Elephants are large-brained, social mammals with a long lifespan. Studies of elephants can provide insight into the aging process, which may be relevant to understanding diseases that affect elderly humans because of their shared characteristics that have arisen through independent evolution. Elephants become sexually mature at 12 to 14 years of ag...

Public awareness of traumatic brain injury (TBI) in the military increased recently because of the conflicts in Iraq and Afghanistan where blast injury was the most common mechanism of injury. Besides overt injuries, concerns also exist over the potential adverse consequences of subclinical blast exposures, which are common for many service members...

Increasing interest in studies of prenatal human brain development, particularly using new single-cell genomics and anatomical technologies to create cell atlases, creates a strong need for accurate and detailed anatomical reference atlases. In this study, we present two cellular-resolution digital anatomical atlases for prenatal human brain at pos...