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Tauopathies, a group of neurodegenerative disorders characterized by tau protein aggregation, encompass diseases such as progressive supranuclear palsy, and corticobasal degeneration. While the development of disease-modifying therapies remains a primary research focus, current pharmacological interventions are predominantly directed towards symptomatic management. This review aims to summarize the evidence-based approaches for addressing the motor, autonomic, and systemic manifestations of tauopathies, highlighting both their therapeutic benefits and limitations. For motor dysfunction, dopaminergic agents and muscle relaxants are explored, though their benefits in PSP and CBS are often modest. Sleep disturbances and autonomic dysfunction, which are prevalent but underrecognized in tauopathies, can be managed using targeted pharmacological strategies, with emerging evidence supporting the use of melatonin and other agents. We will discuss the current significant gaps in optimizing these treatments to meet the complex needs of patients and their family. The potential for repurposing existing drugs and the role of novel symptomatic therapies is currently under investigation. By providing an updated synthesis of pharmacological management strategies, clinicians attending this session will get the evidence-based, patient-centered care skills for treatment of PSP and CBS.

Alzheimer’s disease (AD) is characterized by progressive memory loss and cognitive function deficits. There are two major pathological hallmarks that contribute to the pathogenesis of AD which are the presence of extracellular amyloid plaques composed of amyloid-β (Aβ) and intracellular neurofibrillary tangles composed of hyperphosphorylated tau. Despite extensive research that has been done on Aβ in the last two decades, therapies targeting Aβ were not very fruitful at treating AD as the efficacy of Aβ therapies observed in animal models is not reflected in human clinical trials. Hence, tau-directed therapies have received tremendous attention as the potential treatments for AD. Tauopathies are closely correlated with dementia and immunotherapy has been effective at reducing tau pathology and improving cognitive deficits in animal models. Thus, in this review article, we discussed the pathological mechanism of tau proteins, the key factors contributing to tauopathies, and therapeutic approaches for tauopathies in AD based on the recent progress in tau-based research.

Sleep disturbances are associated with the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease and primary tauopathies. Here we demonstrate that administration of the dual orexin receptor antagonist lemborexant in the P301S/E4 mouse model of tauopathy improves tau-associated impairments in sleep–wake behavior. It also protects against chronic reactive microgliosis and brain atrophy in male P301S/E4 mice by preventing abnormal phosphorylation of tau. These neuroprotective effects in males were not observed after administration of the nonorexinergic drug zolpidem that similarly promoted nonrapid eye movement sleep. Furthermore, both genetic ablation of orexin receptor 2 and lemborexant treatment reduced wakefulness and decreased seeding and spreading of phosphorylated tau in the brain of wild-type mice. These findings raise the therapeutic potential of targeting sleep by orexin receptor antagonism to prevent abnormal tau phosphorylation and limit tau-induced damage. Parhizkar et al. show that lemborexant, an orexin receptor antagonist, protects against neurodegeneration in male tau transgenic mice by preventing tau protein build-up and inflammation, highlighting its potential for preventing neurodegeneration.

Introduction The MAPT gene encodes Tau, a protein mainly expressed by neurons. Tau protein plays an important role in cerebral microtubule polymerization and stabilization, in axonal transport and synaptic plasticity. Heterozygous pathogenic variation in MAPT are involved in a spectrum of autosomal dominant neurodegenerative diseases known as taupathies, including Alzheimer's disease, Pick’s disease, fronto-temporal dementia, cortico-basal degeneration and progressive supranuclear palsy. Taupathies are characterized by the constant presence of neuronal and/or glial aberrant Tau inclusions leading to atrophy and subsequent neuronal loss resulting in central nervous system degeneration. We report here two unrelated families in which segregates a MAPT -related neurodegenerative disorder marked by respiratory failure in the foreground. Results Nine individuals from two unrelated families were affected by a neurodegenerative disorder. Respiratory features were progressively worsening dyspnea-orthopnea with episodes of acute respiratory decompensation leading to hypercapnic coma or sudden death. A diaphragmatic paralysis was shown in three cases. Associated neurological signs were gait disturbances, bulbar signs including swallowing disorders and dysarthria, pyramidal signs, cognitive and behavioral disorders. ENMG inconstantly found signs of mild denervation. Post-mortem brain immuno-histochemical analysis in one patient revealed unusual composite neuronal Tau inclusions, significant neuronal loss and reactive gliosis, in cortical and subcortical regions, cranial nerves and anterior horn of spinal cord. The heterozygous missense variant c.2041C > T, p. (Pro681Ser) in MAPT was identified in both families by gene panel or exome sequencing. Discussion In the literature, four additional related patients carrying the same MAPT variant, in heterozygous state, also presented rapidly progressive respiratory failure and unusual composite neuronal Tau inclusions in anterior horn of spinal cord. Conclusion Our observation allows to extend the phenotypic spectrum associated with MAPT variants describing a rapidly progressive respiratory failure, with episodes of exacerbations and premature death.

Corticobasal degeneration (CBD) is a clinically heterogeneous tauopathy, which has overlapping clinicopathologic and genetic characteristics with progressive supranuclear palsy (PSP). This study aimed to elucidate whether transactive response DNA-binding protein of 43 kDa (TDP-43) pathology contributes to clinicopathologic heterogeneity of CBD. Paraffin-embedded sections of the midbrain, pons, subthalamic nucleus, and basal forebrain from 187 autopsy-confirmed CBD cases were screened with immunohistochemistry for phospho-TDP-43. In cases with TDP-43 pathology, additional brain regions (i.e., precentral, cingulate, and superior frontal gyri, hippocampus, medulla, and cerebellum) were immunostained. Hierarchical clustering analysis was performed based on the topographical distribution and severity of TDP-43 pathology, and clinicopathologic and genetic features were compared between the clusters. TDP-43 pathology was observed in 45% of CBD cases, most frequently in midbrain tegmentum (80% of TDP-43-positive cases), followed by subthalamic nucleus (69%). TDP-43-positive CBD was divided into TDP-limited (52%) and TDP-severe (48%) by hierarchical clustering analysis. TDP-severe patients were more likely to have been diagnosed clinically as PSP compared to TDP-limited and TDP-negative patients (80 vs 32 vs 30%, P  < 0.001). The presence of downward gaze palsy was the strongest factor for the antemortem diagnosis of PSP, and severe TDP-43 pathology in the midbrain tectum was strongly associated with downward gaze palsy. In addition, tau burden in the olivopontocerebellar system was significantly greater in TDP-positive than TDP-negative CBD. Genetic analyses revealed that MAPT H1/H1 genotype frequency was significantly lower in TDP-severe than in TDP-negative and TDP-limited CBD (65 vs 89 vs 91%, P  < 0.001). The homozygous minor allele frequencies in GRN rs5848 and TMEM106B rs3173615 were not significantly different between the three groups. In conclusion, the present study indicates that CBD with severe TDP-43 pathology is a distinct clinicopathologic subtype of CBD, characterized by PSP-like clinical presentations, severe tau pathology in the olivopontocerebellar system, and low frequency of MAPT H1 haplotype.

Primary age-related tauopathy (PART) has been associated with milder degrees of cognitive impairment, but the role of PART-related tangles, from the hippocampus, nearby inferior temporal neocortex, and the role of co-existing pathologies on cognitive decline are underappreciated. We used three harmonized community-based clinicopathologic studies to investigate the association of regional distributions of tangles and co-existing pathologies with cognitive decline. At autopsy, PART was defined by a Braak NFT stage of I–IV in the absence or with limited amyloid-β (Thal ≤ 2). Tau tangle density from the hippocampus and inferior temporal cortex were evaluated by AT8-immunohistochemistry. Other brain pathologies (LATE-NC, Lewy bodies (LBs), and vascular pathologies) were also evaluated. Linear mixed effect models were employed to examine the associations between regional tau tangles and other brain pathologies with decline in global cognition and 5 cognitive domains. Among 1,859 participants, 527 (28%) had neuropathologically confirmed PART: 385 had possible PART and 142 had definite PART, with an average age at death of 88 ± 6.9 years and 63% being female. Nearly all PART participants ( N  = 524) had hippocampal tangles and 449 also exhibited tangles in the inferior temporal neocortex. After controlling demographics and other brain pathologies, hippocampal and inferior temporal neocortical tangle burden were each associated with decline in global cognition and episodic memory; however, the effect of inferior temporal neocortical tangles on decline was 3.2 times stronger than that of hippocampal tangles. In further analyses, when included together in the same model, only the association of inferior temporal neocortical tangle burden persisted. However, using Braak staging alone, we did not find a clinical–pathological relationship between tangles and cognitive decline. Additionally, LATE-NC, LBs, atherosclerosis, and cerebral infarcts were each independently associated with cognitive decline. Our data also indicated that LATE-NC may have stronger impact on cognitive decline in PART than tau tangles. Overall, this study provides evidence that both extension of tangles to the nearby neocortex, specifically the inferior temporal, along with other co-pathologies, particularly LATE-NC, play a key role in cognitive decline in PART.

PurposeTraumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) have emerged as independent risk factors for an earlier onset of Alzheimer’s disease (AD), although the pathophysiology underlying this risk is unclear. Postmortem studies have revealed extensive cerebral accumulation of tau following multiple and single TBI incidents. We hypothesized that a history of TBI and/or PTSD may induce an AD-like pattern of tau accumulation in the brain of nondemented war veterans.MethodsVietnam War veterans (mean age 71.4 years) with a history of war-related TBI and/or PTSD underwent [18F]AV145 PET as part of the US Department of Defense Alzheimer’s Disease Neuroimaging Initiative. Subjects were classified into the following four groups: healthy controls (n = 21), TBI (n = 10), PTSD (n = 32), and TBI+PTSD (n = 17). [18F]AV1451 reference tissue-normalized standardized uptake value (SUVr) maps, scaled to the cerebellar grey matter, were tested for differences in tau accumulation between groups using voxel-wise and region of interest approaches, and the SUVr results were correlated with neuropsychological test scores.ResultsCompared to healthy controls, all groups showed widespread tau accumulation in neocortical regions overlapping with typical and atypical patterns of AD-like tau distribution. The TBI group showed higher tau accumulation than the other clinical groups. The extent of tauopathy was positively correlated with the neuropsychological deficit scores in the TBI+PTSD and PTSD groups.ConclusionA history of TBI and/or PTSD may manifest in neurocognitive deficits in association with increased tau deposition in the brain of nondemented war veterans decades after their trauma. Further investigation is required to establish the burden of increased risk of dementia imparted by earlier TBI and/or PTSD.

Abnormally hyperphosphorylated tau aggregated as intraneuronal neurofibrillary tangles is one of the two neuropathological hallmarks of Alzheimer’s disease (AD). The majority of AD cases are sporadic with numerous environmental, biological and genetic risks factors. Interestingly, insulin dysfunction and hyperglycaemia are both risk factors for sporadic AD. However, how hyperglycaemia and insulin dysfunction affect tau pathology, is not well understood. In this study, we examined the effects of insulin deficiency on tau pathology in transgenic hTau mice by injecting different doses of streptozotocin (STZ), a toxin that destroys insulin-producing cells in the pancreas. One high dose of STZ resulted in marked diabetes, and five low doses led to a milder diabetes. Both groups exhibited brain tau hyperphosphorylation but no increased aggregation. Tau hyperphosphorylation correlated with inhibition of Protein Phosphatase 2A (PP2A), the main tau phosphatase. Interestingly, insulin injection 30 minutes before sacrifice partially restored tau phosphorylation to control levels in both STZ-injected groups. Our results confirm a link between insulin homeostasis and tau phosphorylation, which could explain, at least in part, a higher incidence of AD in diabetic patients.

ABSTRACTExtensive tau-immunoreactive neurons and glial cells associated with chronic traumatic encephalopathy (CTE) have been documented in the brains of some professional athletes and others with a history of repetitive mild traumatic brain injury (r-mTBI). The neuropathology and tau involvement in mTBI have not been extensively studied in animal models, particularly in aged animals. We investigated the effects of single mTBI (s-mTBI) and r-mTBI in 18-month-old hTau mice, which express wild-type human tau isoforms on a null murine tau background (n = 3–5 per group). At this age, hTau mice already demonstrate tau pathology, but there was a significant increase in phospho-tau immunoreactivity in response to r-mTBI, but not to s-mTBI,as determined using multiple phospho-tau–specific antibodies. Repetitive mTBI also resulted in a marked increase in astrocyte/microglia activation notably in the superficial layer of the motor/somatosensory cortex and the corpus callosum. We did not observe the perivascular tau pathology, neuritic threads, or astrocytic tangles that are commonly found in human CTE. The increase in phospho-tau in the r-mTBI mice suggests that this may be a useful model for investigating further the link between mTBI, particularly r-mTBI, and tau pathobiology in CTE and in understanding responses of the aged brain to mTBI.