Ferritin nanocage-enabled detection of pathological tau in living human retinal cells.

Tauopathies, including Alzheimer's disease and Frontotemporal Dementia, are debilitating neurodegenerative disorders marked by cognitive decline. Despite extensive research, achieving effective treatments and significant symptom management remains challenging. Accurate diagnosis is crucial for developing effective therapeutic strategies, with hyperphosphorylated protein units and tau oligomers serving as reliable biomarkers for these conditions. This study introduces a novel approach using nanotechnology to enhance the diagnostic process for tauopathies. We developed humanized ferritin nanocages, a novel nanoscale delivery system, designed to encapsulate and transport a tau-specific fluorophore, BT1, into human retinal cells for detecting neurofibrillary tangles in retinal tissue, a key marker of tauopathies. The delivery of BT1 into living cells was successfully achieved through these nanocages, demonstrating efficient encapsulation and delivery into retinal cells derived from human induced pluripotent stem cells. Our experiments confirmed the colocalization of BT1 with pathological forms of tau in living retinal cells, highlighting the method's potential in identifying tauopathies. Using ferritin nanocages for BT1 delivery represents a significant contribution to nanobiotechnology, particularly in neurodegenerative disease diagnostics. This method offers a promising tool for the early detection of tau tangles in retinal tissue, with significant implications for improving the diagnosis and management of tauopathies. This study exemplifies the integration of nanotechnology with biomedical science, expanding the frontiers of nanomedicine and diagnostic techniques.

Exploring the significance of caspase-cleaved tau in tauopathies and as a complementary pathology to phospho-tau in Alzheimer's disease: implications for biomarker development and therapeutic targeting.

Tauopathies are neurodegenerative diseases that typically require postmortem examination for a definitive diagnosis. Detecting neurotoxic tau fragments in cerebrospinal fluid (CSF) and serum provides an opportunity for in vivo diagnosis and disease monitoring. Current assays primarily focus on total tau or phospho-tau, overlooking other post-translational modifications (PTMs). Caspase-cleaved tau is a significant component of AD neuropathological lesions, and experimental studies confirm the high neurotoxicity of these tau species. Recent evidence indicates that certain caspase-cleaved tau species, such as D13 and D402, are abundant in AD brain neurons and only show a modest degree of co-occurrence with phospho-tau, meaning caspase-truncated tau pathology is partially distinct and complementary to phospho-tau pathology. Furthermore, these caspase-cleaved tau species are nearly absent in 4-repeat tauopathies. In this review, we will discuss the significance of caspase-cleaved tau in the development of tauopathies, specifically emphasizing its role in AD. In addition, we will explore the potential of caspase-cleaved tau as a biomarker and the advantages for drug development targeting caspase-6. Developing specific and sensitive assays for caspase-cleaved tau in biofluids holds promise for improving the diagnosis and monitoring of tauopathies, providing valuable insights into disease progression and treatment efficacy.

Novel aspects of the phosphorylation and structure of pathological tau: implications for tauopathy biomarkers.

The deposition of highly phosphorylated and aggregated tau is a characteristic of tauopathies, including Alzheimer's disease. It has long been known that different isoforms of tau are aggregated in different cell types and brain regions in each tauopathy. Recent advances in analytical techniques revealed the details of the biochemical and structural biological differences of tau specific to each tauopathy. In this review, we explain recent advances in the analysis of post-translational modifications of tau, particularly phosphorylation, brought about by the development of mass-spectrometry and Phos-tag technology. We then discuss the structure of tau filaments in each tauopathy revealed by the advent of cryo-EM. Finally, we describe the progress in biofluid and imaging biomarkers for tauopathy. This review summarizes current efforts to elucidate the characteristics of pathological tau and the landscape of the use of tau as a biomarker to diagnose and determine the pathological stage of tauopathy.

Role of Tau protein in long COVID and potential therapeutic targets.

Introduction: Long COVID is an emerging public health burden and has been defined as a syndrome with common symptoms of fatigue, shortness of breath, cognitive dysfunction, and others impacting day-to-day life, fluctuating or relapsing over, occurring for at least two months in patients with a history of probable or confirmed SARS CoV-2 infection; usually three months from the onset of illness and cannot be explained by an alternate diagnosis. The actual prevalence of long-term COVID-19 is unknown, but it is believed that more than 17 million patients in Europe may have suffered from it during pandemic. Pathophysiology: Currently, there is limited understanding of the pathophysiology of this syndrome, and multiple hypotheses have been proposed. Our literature review has shown studies reporting tau deposits in tissue samples of the brain from autopsies of COVID-19 patients compared to the control group, and the in-vitro human brain organoid model has shown aberrant phosphorylation of tau protein in response to SARS-CoV-2 infection. Tauopathies, a group of neurodegenerative disorders with the salient features of tau deposits, can manifest different symptoms based on the anatomical region of brain involvement and have been shown to affect the peripheral nervous system as well and explained even in rat model studies. Long COVID has more than 203 symptoms, with predominant symptoms of fatigue, dyspnea, and cognitive dysfunction, which tauopathy-induced CNS and peripheral nervous system dysfunction can explain. There have been no studies up till now to reveal the pathophysiology of long COVID. Based on our literature review, aberrant tau phosphorylation is a promising hypothesis that can be explored in future studies. Therapeutic approaches for tauopathies have multidimensional aspects, including targeting post-translational modifications, tau aggregation, and tau clearance through the autophagy process with the help of lysosomes, which can be potential targets for developing therapeutic interventions for the long COVID. In addition, future studies can attempt to find the tau proteins in CSF and use those as biomarkers for the long COVID.

TAUCON and TAUCOM: A novel biosensor based on fluorescence resonance energy transfer for detecting tau hyperphosphorylation-associated cellular pathologies.

Tauopathies are neurodegenerative diseases characterized by abnormal conformational changes in tau protein. Early hyperphosphorylation-induced conformational changes are considered a hallmark of tauopathy, but real-time tracking methods are lacking. Here, we present two novel fluorescence resonance energy transfer (FRET)-based tau biosensors that detect such changes with high spatiotemporal resolution at the single-cell level. The TAUCON biosensor measures instantaneous conformational changes in hyperphosphorylated tau within 20 min, while the TAUCOM biosensor detects changes in the paper-clip structure of microtubule-associated tau. Our biosensors provide faster and more precise detection than conventional methods and can serve as valuable tools for investigating the initial causes, mechanisms, progression, and treatment of tauopathies.

Specific post-translational modifications of soluble tau protein distinguishes Alzheimer's disease and primary tauopathies.

Tau protein aggregates in several neurodegenerative disorders, referred to as tauopathies. The tau isoforms observed in post mortem human brain aggregates is used to classify tauopathies. However, distinguishing tauopathies ante mortem remains challenging, potentially due to differences between insoluble tau in aggregates and soluble tau in body fluids. Here, we demonstrated that tau isoforms differ between tauopathies in insoluble aggregates, but not in soluble brain extracts. We therefore characterized post-translational modifications of both the aggregated and the soluble tau protein obtained from post mortem human brain tissue of patients with Alzheimer's disease, cortico-basal degeneration, Pick's disease, and frontotemporal lobe degeneration. We found specific soluble signatures for each tauopathy and its specific aggregated tau isoforms: including ubiquitination on Lysine 369 for cortico-basal degeneration and acetylation on Lysine 311 for Pick's disease. These findings provide potential targets for future development of fluid-based biomarker assays able to distinguish tauopathies in vivo.

Progressive supranuclear palsy: current approach and challenges to diagnosis and treatment.

PURPOSE OF REVIEW: Since the original description of progressive supranuclear palsy (PSP) by Steele, Richardson and Olszewski, the clinical spectrum of PSP has expanded and now includes multiple phenotypic variants linked by a common disease. In this review, we discuss the evolution of the PSP syndrome and clinical criteria, with a particular focus on the 2017 Movement Disorders Society PSP criteria, its application and limitations. We also discuss our current approach to diagnosis and treatment. RECENT FINDINGS: There is a significant overlap between the different variants of PSP and multiple phenotypes that may be applied to the same patient simultaneously. Variant severity and predominance also evolve throughout the course of the disease. Each variant and level of certainty is associated with different specificity and sensitivity for underlying disease. The differential diagnosis of PSP is continuously evolving and includes other tauopathies, neurodegenerative, genetic, autoimmune and infectious disorders. MRI measurements can aid in the diagnosis. The first guidelines to help with clinical management of those patients have been recently published. SUMMARY: Although much improved, clinical PSP criteria alone remain insufficient and emphasize the need for improved biomarkers to identify patients at early stages to direct appropriate therapeutic strategies and target potential research.

Thioflavin S Staining and Amyloid Formation Are Unique to Mixed Tauopathies.

Tau phosphorylation, aggregation, and toxicity are the main drivers of neurodegeneration in multiple tauopathies, including Alzheimer's disease (AD) and frontotemporal lobar degeneration with tau. Although aggregation and amyloid formation are often assumed to be synonymous, the ability of tau aggregates in different diseases to form amyloids in vivo has not been systematically studied. We used the amyloid dye Thioflavin S to look at tau aggregates in mixed tauopathies such as AD and primary age-related tauopathy, as well as pure 3R or 4R tauopathies such as Pick's disease, progressive supranuclear palsy, and corticobasal degeneration. We found that aggregates of tau protein only form thioflavin-positive amyloids in mixed (3R/4R), but not pure (3R or 4R), tauopathies. Interestingly, neither astrocytic nor neuronal tau pathology was thioflavin-positive in pure tauopathies. As most current positron emission tomography tracers are based on thioflavin derivatives, this suggests that they may be more useful for differential diagnosis than the identification of a general tauopathy. Our findings also suggest that thioflavin staining may have utility as an alternative to traditional antibody staining for distinguishing between tau aggregates in patients with multiple pathologies and that the mechanisms for tau toxicity may differ between different tauopathies.

Retinal photoreceptor layer thickness has disease specificity and distinguishes predicted FTLD-Tau from biomarker-determined Alzheimer's disease.

While Alzheimer's disease (AD) is associated with inner retina thinning (retinal nerve fiber layer and ganglion cell layer), we have observed photoreceptor outer nuclear layer (ONL) thinning in patients with frontotemporal lobar degeneration tauopathy (FTLD-Tau) compared to normal controls. We hypothesized that ONL thinning may distinguish FTLD-Tau from patients with biomarker evidence of AD neuropathologic change (ADNC) and will correlate with FTLD-Tau disease severity. Predicted FTLD-Tau (pFTLD-Tau; n = 21; 33 eyes) and predicted ADNC (pADNC; n = 24; 46 eyes) patients were consecutively enrolled, underwent optical coherence tomography macula imaging, and disease was categorized (pFTLD-Tau vs. pADNC) with cerebrospinal fluid biomarkers, genetic testing, and autopsy data when available. Adjusting for age, sex, and race, pFTLD-Tau patients had a thinner ONL compared to pADNC, while retinal nerve fiber layer and ganglion cell layer were not significantly different. Reduced ONL thickness correlated with worse performance on Folstein Mini-Mental State Examination and clinical dementia rating plus frontotemporal dementia sum of boxes for pFTLD-Tau but not pADNC. Photoreceptor ONL thickness may serve as an important noninvasive diagnostic marker that distinguishes FTLD-Tau from AD neuropathologic change.

Neuroimmune proteins can differentiate between tauopathies.

BACKGROUND: Tauopathies are a group of neurodegenerative diseases where there is pathologic accumulation of hyperphosphorylated tau protein (ptau). The most common tauopathy is Alzheimer's disease (AD), but chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and argyrophilic grain disease (AGD) are significant health risks as well. Currently, it is unclear what specific molecular factors might drive each distinct disease and represent therapeutic targets. Additionally, there is a lack of biomarkers that can differentiate each disease in life. Recent work has suggested that neuroinflammatory changes might be specific among distinct diseases and offers a novel resource for mechanistic targets and biomarker candidates. METHODS: To better examine each tauopathy, a 71 immune-related protein multiplex ELISA panel was utilized to analyze anterior cingulate grey matter from 127 individuals neuropathologically diagnosed with AD, CTE, PSP, CBD, and AGD. A partial least square regression analysis was carried out to perform unbiased clustering and identify proteins that are distinctly correlated with each tauopathy correcting for age and gender. Receiver operator characteristic and binary logistic regression analyses were then used to examine the ability of each candidate protein to distinguish diseases. Validation in postmortem cerebrospinal fluid (CSF) from 15 AD and 14 CTE cases was performed to determine if candidate proteins could act as possible novel biomarkers. RESULTS: Five clusters of immune proteins were identified and compared to each tauopathy to determine if clusters were specific to distinct disease. Each cluster was found to correlate with either CTE, AD, PSP, CBD, or AGD. When examining which proteins were the strongest driver of each cluster, it was observed the most distinctive protein for CTE was CCL21, AD was FLT3L, and PSP was IL13. Individual proteins that were specific to CBD and AGD were not observed. CCL21 was observed to be elevated in CTE CSF compared to AD cases (p = 0.02), further validating the use as possible biomarkers. Sub-analyses for male only cases confirmed the results were not skewed by gender differences. CONCLUSIONS: Overall, these results highlight that different neuroinflammatory responses might underlie unique mechanisms in related neurodegenerative pathologies. Additionally, the use of distinct neuroinflammatory signatures could help differentiate between tauopathies and act as novel biomarker candidate to increase specificity for in-life diagnoses.

Progressive supranuclear palsy and corticobasal degeneration: novel clinical concepts and advances in biomarkers.

BACKGROUND: Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are sporadic adult-onset primary tauopathies clinically classified among the atypical parkinsonian syndromes. They are intrinsically related with regard to their clinical features, pathology, biochemistry, and genetic risk factors. OBJECTIVES: This review highlights the current knowledge on PSP and CBD, focusing on evolving clinical concepts, new diagnostic criteria, and advances in biomarkers. METHODS: We performed a non-systematic literature review through the PubMed database. The search was restricted to articles written in English, published from 1964 to date. RESULTS: Clinicopathologic and in vivo biomarkers studies have broadened PSP and CBD clinical phenotypes. They are now recognized as a range of motor and behavioral syndromes associated with underlying 4R-tauopathy neuropathology. The Movement Disorders Society PSP diagnostic criteria included clinical variants apart from the classical description, increasing diagnostic sensitivity. Meanwhile, imaging biomarkers have explored the complexity of symptoms and pathological processes related to corticobasal syndrome and CBD. CONCLUSIONS: In recent years, several prospective or clinicopathologic studies have assessed clinical, radiological, and fluid biomarkers that have helped us gain a better understanding of the complexity of the 4R-tauopathies, mainly PSP and CBD.

Rainwater Charitable Foundation criteria for the neuropathologic diagnosis of progressive supranuclear palsy.

Neuropathologic criteria for progressive supranuclear palsy (PSP) proposed by a National Institute of Neurological Disorders and Stroke (NINDS) working group were published in 1994 and based on the presence of neurofibrillary tangles in basal ganglia and brainstem. These criteria did not stipulate detection methods or incorporate glial tau pathology. In this study, a group of 14 expert neuropathologists scored digital slides from 10 brain regions stained with hematoxylin and eosin (H&E) and phosphorylated tau (AT8) immunohistochemistry. The cases included 15 typical and atypical PSP cases and 10 other tauopathies. Blinded to clinical and neuropathological information, raters provided a categorical diagnosis (PSP or not-PSP) based upon provisional criteria that required neurofibrillary tangles or pretangles in two of three regions (substantia nigra, subthalamic nucleus, globus pallidus) and tufted astrocytes in one of two regions (peri-Rolandic cortices, putamen). The criteria showed high sensitivity (0.97) and specificity (0.91), as well as almost perfect inter-rater reliability for diagnosing PSP and differentiating it from other tauopathies (Fleiss kappa 0.826). Most cases (17/25) had 100% agreement across all 14 raters. The Rainwater Charitable Foundation criteria for the neuropathologic diagnosis of PSP feature a simplified diagnostic algorithm based on phosphorylated tau immunohistochemistry and incorporate tufted astrocytes as an essential diagnostic feature.

Caspase-6-cleaved tau is relevant in Alzheimer's disease and marginal in four-repeat tauopathies: Diagnostic and therapeutic implications.

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 monoclonal antibodies against tr-tau sites (D402 and D13) targeted by aCasp-6. Then, we used five-plex immunofluorescence to quantify the neuronal and astroglial burden of aCasp-6, tr-tau, p-tau and their co-occurrence in healthy controls, AD and primary tauopathies. RESULTS: Casp-6 activation was strongest in AD and Pick's disease (PiD) but almost absent in 4-repeat (4R) tauopathies. In neurons, the tr-tau burden was much more abundant in AD and PiD than in 4R tauopathies and disproportionally higher when normalising by p-tau pathology. Tr-tau astrogliopathy was detected in low numbers in 4R tauopathies. Unexpectedly, about half of tr-tau positive neurons in AD and PiD lacked p-tau aggregates, a finding we confirmed using several p-tau antibodies. CONCLUSIONS: Early modulation of aCasp-6 to reduce tr-tau pathology is a promising therapeutic strategy for AD and PiD but is unlikely to benefit 4R tauopathies. The large percentage of tr-tau-positive neurons lacking p-tau suggests that many vulnerable neurons to tau pathology go undetected when using conventional p-tau antibodies. Therapeutic strategies against tr-tau pathology could be necessary to modulate the extent of tau abnormalities in AD. The disproportionally higher burden of tr-tau in AD and PiD supports the development of biofluid biomarkers against tr-tau to detect AD and PiD and differentiate them from 4R tauopathies at a patient level.

Deep learning-based model for diagnosing Alzheimer's disease and tauopathies.

AIMS: This study aimed to develop a deep learning-based model for differentiating tauopathies, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and Pick's disease (PiD), based on tau-immunostained digital slide images. METHODS: We trained the YOLOv3 object detection algorithm to detect five tau lesion types: neuronal inclusions, neuritic plaques, tufted astrocytes, astrocytic plaques and coiled bodies. We used 2522 digital slide images of CP13-immunostained slides of the motor cortex from 10 cases each of AD, PSP and CBD for training. Data augmentation was performed to increase the size of the training dataset. We next constructed random forest classifiers using the quantitative burdens of each tau lesion from motor cortex, caudate nucleus and superior frontal gyrus, ascertained from the object detection model. We split 120 cases (32 AD, 36 PSP, 31 CBD and 21 PiD) into training (90 cases) and test (30 cases) sets to train random forest classifiers. RESULTS: The resultant random forest classifier achieved an average test score of 0.97, indicating that 29 out of 30 cases were correctly diagnosed. A validation study using hold-out datasets of CP13- and AT8-stained slides from 50 cases (10 AD, 17 PSP, 13 CBD and 10 PiD) showed >92% (without data augmentation) and >95% (with data augmentation) diagnostic accuracy in both CP13- and AT8-stained slides. CONCLUSION: Our diagnostic model trained with CP13 also works for AT8; therefore, our diagnostic tool can be potentially used by other investigators and may assist medical decision-making in neuropathological diagnoses of tauopathies.

Tau pathology mediates age effects on medial temporal lobe structure.

Hippocampal atrophy is endemic in 'normal aging' but it is unclear what factors drive age-related changes in medial temporal lobe (MTL) structural measures. We investigated cross-sectional (n = 191) and longitudinal (n = 164) MTL atrophy patterns in cognitively normal older adults from ADNI-GO/2 with no to low cerebral ß-amyloid and assessed whether white matter hyperintensities (WMHs) and cerebrospinal fluid (CSF) phospho tau (p-tau) levels can explain age-related changes in the MTL. Age was significantly associated with hippocampal volumes and Brodmann Area (BA) 35 thickness, regions affected early by neurofibrillary tangle pathology, in the cross-sectional analysis and with anterior and/or posterior hippocampus, entorhinal cortex and BA35 in the longitudinal analysis. CSF p-tau was significantly associated with hippocampal volumes and atrophy rates. Mediation analyses showed that CSF p-tau levels partially mediated age effects on hippocampal atrophy rates. No significant associations were observed for WMHs. These findings point toward a role of tau pathology, potentially reflecting Primary Age-Related Tauopathy, in age-related MTL structural changes and suggests a potential role for tau-targeted interventions in age-associated neurodegeneration and memory decline.

Distinct phosphorylation profiles of tau in brains of patients with different tauopathies.

Tauopathies are neurodegenerative diseases that are characterized by pathological accumulation of tau protein. Tau is hyperphosphorylated in the brain of tauopathy patients, and this phosphorylation is proposed to play a role in disease development. However, it has been unclear whether phosphorylation is different among different tauopathies. Here, we investigated the phosphorylation states of tau in several tauopathies, including corticobasal degeneration, Pick's disease, progressive supranuclear palsy (PSP), argyrophilic grain dementia (AGD) and Alzheimer's disease (AD). Analysis of tau phosphorylation profiles using Phos-tag SDS-PAGE revealed distinct phosphorylation of tau in different tauopathies, whereas similar phosphorylation patterns were found within the same tauopathy. For PSP, we found 2 distinct phosphorylation patterns suggesting that PSP may consist of 2 different related diseases. Immunoblotting with anti-phospho-specific antibodies showed different site-specific phosphorylation in the temporal lobes of patients with different tauopathies. AD brains showed increased phosphorylation at Ser202, Thr231 and Ser235, Pick's disease brains showed increased phospho-Ser202, and AGD brains showed increased phospho-Ser396. The cis conformation of the peptide bond between phospho-Thr231 and Pro232 (cis ptau) was increased in AD and AGD. These results indicate that while tau is differently phosphorylated in tauopathies, a similar pathological mechanism may occur in AGD and AD patients. The present data provide useful information regarding tau pathology and diagnosis of tauopathies.

Sex differences in in vivo tau neuropathology in a multiethnic sample of late middle-aged adults.

It is unclear whether women have higher brain tau pathology. The objective of this study was to examine whether women have higher tau burden than men, and whether tau differences are independent of amyloid ß (Aß) burden. We conducted a cross-sectional analysis of a multiethnic sample of 252 nondemented late middle-aged (mean age: 64.1 years) adults with tau and amyloid Positron Emission Tomography (PET) data. Tau burden was measured as global standardized uptake value ratio (SUVR) in the middle/inferior temporal gyri and medial temporal cortex with 18F-MK-6240 PET. Aß was measured as global SUVR with 18F-Florbetaben PET. Women had higher middle/inferior temporal gyri tau SUVR compared to men. However, no sex differences in the medial temporal cortex were observed. Women had higher brain Aß SUVR compared to men. Continuous Aß SUVR was positively correlated with medial temporal cortex and middle/inferior temporal gyri tau SUVR. However, there was no evidence of effect modification by Aß SUVR on sex and tau. Compared with men, women in late middle age show higher tau burden, independent of Aß.

Broad Kinase Inhibition Mitigates Early Neuronal Dysfunction in Tauopathy.

Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau and cellular dysfunction, especially during the early stages of disease progression. In this study, we treated early stage tau transgenic mice with a multi-target kinase inhibitor to identify novel substrates that contribute to cognitive impairment and exhibit therapeutic potential. Drug treatment significantly ameliorated brain atrophy and cognitive function as determined by behavioral testing and a sensitive imaging technique called manganese-enhanced magnetic resonance imaging (MEMRI) with quantitative R1 mapping. Surprisingly, these benefits occurred despite unchanged hyperphosphorylated tau levels. To elucidate the mechanism behind these improved cognitive outcomes, we performed quantitative proteomics to determine the altered protein network during this early stage in tauopathy and compare this model with the human Alzheimer's disease (AD) proteome. We identified a cluster of preserved pathways shared with human tauopathy with striking potential for broad multi-target kinase intervention. We further report high confidence candidate proteins as novel therapeutically relevant targets for the treatment of tauopathy. Proteomics data are available via ProteomeXchange with identifier PXD023562.

The Role of Neuropsychiatric Symptoms in Research Diagnostic Criteria for Neurodegenerative Diseases.

Neuropsychiatric syndromes and symptoms play increasingly important roles in research diagnostic criteria for neurodegenerative disorders. Diagnostic criteria were reviewed including those for dementia, Alzheimer's disease, mild cognitive impairment, mild behavioral impairment, prodromal Alzheimer's disease, dementia with Lewy bodies, prodromal dementia with Lewy bodies, Parkinson's disease, multiple system atrophy, frontotemporal dementia, primary progressive aphasia, progressive supranuclear palsy, corticobasal degeneration, traumatic encephalopathy syndrome, Huntington' disease, amyotrophic lateral sclerorsis. All contemporary research diagnostic criteria for neurodegenerative disorders expect those for Parkinson's disease, primary progressive aphasia, multisystem atrophy and amyotrophic lateral sclerosis include neuropsychiatric phenomena as core diagnostic criteria. There are no disease-specific neuropsychiatric symptoms; apathy and disinhibition are common in tauopathies, and rapid-eye-movement sleep behavioral disorder occurs almost exclusively in synucleinopathies. Neuropsychiatric symptoms and syndromes are increasingly integrated into research diagnostic criteria for neurodegenerative disorders; they require clinician skills for recognition; their biology is better understood as their relationships to cognitive, motor, and autonomic symptoms of neurodegenerative disorders are studied.