Early Selective Vulnerability of the CA2 Hippocampal Subfield in Primary Age-Related Tauopathy

Abstract Primary age-related tauopathy (PART) is a neurodegenerative entity defined as Alzheimer-type neurofibrillary degeneration primarily affecting the medial temporal lobe with minimal to absent amyloid-β (Aβ) plaque deposition. The extent to which PART can be differentiated pathoanatomically from Alzheimer disease (AD) is unclear. Here, we examined the regional distribution of tau pathology in a large cohort of postmortem brains (n = 914). We found an early vulnerability of the CA2 subregion of the hippocampus to neurofibrillary degeneration in PART, and semiquantitative assessment of neurofibrillary degeneration in CA2 was significantly greater than in CA1 in PART. In contrast, subjects harboring intermediate-to-high AD neuropathologic change (ADNC) displayed relative sparing of CA2 until later stages of their disease course. In addition, the CA2/CA1 ratio of neurofibrillary degeneration in PART was significantly higher than in subjects with intermediate-to-high ADNC burden. Furthermore, the distribution of tau pathology in PART diverges from the Braak NFT staging system and Braak stage does not correlate with cognitive function in PART as it does in individuals with intermediate-to-high ADNC. These findings highlight the need for a better understanding of the contribution of PART to cognitive impairment and how neurofibrillary degeneration interacts with Aβ pathology in AD and PART.

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Asymmetry of Hippocampal Tau Pathology in Primary Age-Related Tauopathy and Alzheimer Disease

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlab032 ◽

2021 ◽

Author(s):

Jamie M Walker ◽

Yelena Fudym ◽

Kurt Farrell ◽

Megan A Iida ◽

Kevin F Bieniek ◽

...

Keyword(s):

Alzheimer Disease ◽

Neurofibrillary Degeneration ◽

Temporal Region ◽

Braak Stage ◽

Neuritic Plaques ◽

Tau Pathology ◽

Age Related ◽

Significant Difference ◽

Left And Right ◽

The Right

Abstract Primary age-related tauopathy (PART) is a neurodegenerative entity defined as neurofibrillary degeneration generally restricted to the medial temporal region (Braak stage I–IV) with complete or near absence of diffuse and neuritic plaques. Symptoms range in severity but are generally milder and later in onset than in Alzheimer disease (AD). Recently, an early predilection for neurofibrillary degeneration in the hippocampal CA2 subregion has been demonstrated in PART, whereas AD neuropathologic change (ADNC) typically displays relative sparing of CA2 until later stages. In this study, we utilized a semiquantitative scoring system to evaluate asymmetry of neurofibrillary degeneration between left and right hippocampi in 67 PART cases and 17 ADNC cases. 49% of PART cases demonstrated asymmetric findings in at least one hippocampal subregion, and 79% of the asymmetric cases displayed some degree of CA2 asymmetry. Additionally, 19% of cases revealed a difference in Braak score between the right and left hippocampi. There was a significant difference in CA2 neurofibrillary degeneration (p = 0.0006) and CA2/CA1 ratio (p < 0.0001) when comparing the contralateral sides, but neither right nor left was more consistently affected. These data show the importance of analyzing bilateral hippocampi in the diagnostic evaluation of PART and potentially of other neurodegenerative diseases.

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Quantitative Assessment of Hippocampal Tau Pathology in AD and PART

Journal of Molecular Neuroscience ◽

10.1007/s12031-020-01573-0 ◽

2020 ◽

Vol 70 (11) ◽

pp. 1808-1811 ◽

Cited By ~ 1

Author(s):

Lei Zhang ◽

Yankai Jiang ◽

Jie Zhu ◽

Huazheng Liang ◽

Xiangyang He ◽

...

Keyword(s):

Tau Protein ◽

Quantitative Assessment ◽

Hippocampal Formation ◽

Selective Vulnerability ◽

Tau Pathology ◽

Regional Patterns ◽

Mathematical Algorithm ◽

Age Related ◽

Distinguishing Features ◽

Phosphorylated Tau Protein

Abstract To quantitatively assess the distribution pattern of hippocampal tau pathology in Alzheimer’s disease (AD) and primary age-related tauopathy (PART), we investigated the distribution of phosphorylated tau protein (AT8) in 6 anatomically defined subregions of the hippocampal formation and developed a mathematical algorithm to compare the patterns of tau deposition in PART and AD. We demonstrated regional patterns of selective vulnerability as distinguishing features of PART and AD in functionally relevant structures of the hippocampus. In AD cases, tau pathology was high in both CA1 and subiculum, followed by CA2/3, entorhinal cortex (EC), CA4, and dentate gyrus (DG). In PART, the severity of tau pathology in CA1 and subiculum was high, followed by EC, CA2/3, CA4, and DG. There are significant differences between sector DG and CA1, DG and subiculum in both AD and PART.

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Predictors of cognitive impairment in primary age-related tauopathy: an autopsy study

10.1101/2021.06.08.447553 ◽

2021 ◽

Author(s):

Megan A Iida ◽

Kurt Farrell ◽

Jamie M Walker ◽

Timothy E Richardson ◽

Gabe Marx ◽

...

Keyword(s):

Cognitive Impairment ◽

Medial Temporal Lobe ◽

Neurofibrillary Tangle ◽

Lewy Bodies ◽

Brain Regions ◽

Braak Stage ◽

Autopsy Study ◽

Factors Affecting ◽

Braak Staging ◽

Age Related

Primary age-related tauopathy (PART) is a form of Alzheimer-type neurofibrillary degeneration occurring in the absence of amyloid-beta (Aβ) plaques. While PART shares some features with Alzheimer disease (AD), such as progressive accumulation of neurofibrillary tangle pathology in the medial temporal lobe and other brain regions, it does not progress extensively to neocortical regions. Given this restricted pathoanatomical pattern and variable symptomatology, there is a need to reexamine and improve upon how PART is neuropathologically assessed and staged. We performed a retrospective autopsy study in a collection (n=174) of post-mortem PART brains and used logistic regression to determine the extent to which a set of clinical and neuropathological features predict cognitive impairment. We compared Braak staging, which focuses on hierarchical neuroanatomical progression of AD tau and Aβ pathology, with quantitative assessments of neurofibrillary burden using computer-derived positive pixel counts on digitized whole slide images of sections stained immunohistochemically with antibodies targeting abnormal hyperphosphorylated tau (p-tau) in the entorhinal region and hippocampus. We also assessed other factors affecting cognition, including aging-related tau astrogliopathy (ARTAG) and atrophy. We found no association between Braak stage and cognitive impairment when controlling for age (p=0.76). In contrast, p-tau burden was significantly correlated with cognitive impairment even when adjusting for age (p=0.03). The strongest correlate of cognitive impairment was cerebrovascular disease, a well-known risk factor (p<0.0001), but other features including ARTAG (p=0.03) and hippocampal atrophy (p=0.04) were also associated. In contrast, sex, APOE, psychiatric illness, education, argyrophilic grains, and incidental Lewy bodies were not. These findings support the hypothesis that comorbid pathologies contribute to cognitive impairment in subjects with PART. Quantitative approaches beyond Braak staging are critical for advancing our understanding of the extent to which age-related tauopathy changes impact cognitive function.

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Visuospatial memory impairment as a potential neurocognitive marker to predict tau pathology in Alzheimer’s continuum

Alzheimer s Research & Therapy ◽

10.1186/s13195-021-00909-1 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Eun Hyun Seo ◽

Ho Jae Lim ◽

Hyung-Jun Yoon ◽

Kyu Yeong Choi ◽

Jang Jae Lee ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Medial Temporal Lobe ◽

Memory Impairment ◽

Prediction Models ◽

Characteristic Curve ◽

Amyloid Β ◽

Tau Pathology ◽

Discrimination Ability

Abstract Background Given that tau accumulation, not amyloid-β (Aβ) burden, is more closely connected with cognitive impairment in Alzheimer’s disease (AD), a detailed understanding of the tau-related characteristics of cognitive function is critical in both clinical and research settings. We investigated the association between phosphorylated tau (p-Tau) level and cognitive impairment across the AD continuum and the mediating role of medial temporal lobe (MTL) atrophy. We also developed a prediction model for abnormal tau accumulation. Methods We included participants from the Gwangju Alzheimer’s Disease and Related Dementia Cohort in Korea, who completed cerebrospinal fluid analysis and clinical evaluation, and corresponded to one of three groups according to the biomarkers of A and T profiles based on the National Institute on Aging and Alzheimer’s Association research framework. Multiple linear and logistic regression analyses were performed to examine the association between p-Tau and cognition and to develop prediction models. Receiver operating characteristic curve analysis was performed to examine the discrimination ability of the models. Results Among 185 participants, 93 were classified as A-T-, 23 as A+T-, and 69 as A+T+. There was an association between decreased visuospatial delayed memory performance and p-Tau level (B = − 0.754, β = − 0.363, p < 0.001), independent of other relevant variables (e.g., Aβ). MTL neurodegeneration was found to mediate the association between the two. Prediction models with visuospatial delayed memory alone (area under the curve [AUC] = 0.872) and visuospatial delayed memory and entorhinal thickness (AUC = 0.921) for abnormal tau accumulation were suggested and they were validated in an independent sample (AUC = 0.879 and 0.891, respectively). Conclusion It is crucial to identify sensitive cognitive measures that capture subtle cognitive impairment associated with underlying pathological changes. Preliminary findings from the current study might suggest that abnormal tau accumulation underlies episodic memory impairment, particularly visuospatial modality, in the AD continuum. Suggested models are potentially useful in predicting tau pathology, and might be utilized practically in the field.

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Downstream effects of polypathology on neurodegeneration of medial temporal lobe subregions

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01225-3 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

L. E. M. Wisse ◽

S. Ravikumar ◽

R. Ittyerah ◽

S. Lim ◽

J. Lane ◽

...

Keyword(s):

Temporal Lobe ◽

Medial Temporal Lobe ◽

Strong Association ◽

Amyloid Β ◽

Stratum Radiatum ◽

Post Mortem ◽

Age Related ◽

Important Region ◽

Cornu Ammonis ◽

Mri Scans

AbstractThe medial temporal lobe (MTL) is a nidus for neurodegenerative pathologies and therefore an important region in which to study polypathology. We investigated associations between neurodegenerative pathologies and the thickness of different MTL subregions measured using high-resolution post-mortem MRI. Tau, TAR DNA-binding protein 43 (TDP-43), amyloid-β and α-synuclein pathology were rated on a scale of 0 (absent)—3 (severe) in the hippocampus and entorhinal cortex (ERC) of 58 individuals with and without neurodegenerative diseases (median age 75.0 years, 60.3% male). Thickness measurements in ERC, Brodmann Area (BA) 35 and 36, parahippocampal cortex, subiculum, cornu ammonis (CA)1 and the stratum radiatum lacunosum moleculare (SRLM) were derived from 0.2 × 0.2 × 0.2 mm3 post-mortem MRI scans of excised MTL specimens from the contralateral hemisphere using a semi-automated approach. Spearman’s rank correlations were performed between neurodegenerative pathologies and thickness, correcting for age, sex and hemisphere, including all four proteinopathies in the model. We found significant associations of (1) TDP-43 with thickness in all subregions (r = − 0.27 to r = − 0.46), and (2) tau with BA35 (r = − 0.31) and SRLM thickness (r = − 0.33). In amyloid-β and TDP-43 negative cases, we found strong significant associations of tau with ERC (r = − 0.40), BA35 (r = − 0.55), subiculum (r = − 0.42) and CA1 thickness (r = − 0.47). This unique dataset shows widespread MTL atrophy in relation to TDP-43 pathology and atrophy in regions affected early in Braak stageing and tau pathology. Moreover, the strong association of tau with thickness in early Braak regions in the absence of amyloid-β suggests a role of Primary Age-Related Tauopathy in neurodegeneration.

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The Significance of Tau Aggregates in the Human Brain

Brain Sciences ◽

10.3390/brainsci10120972 ◽

2020 ◽

Vol 10 (12) ◽

pp. 972

Author(s):

Rudy J. Castellani

Keyword(s):

Clinical Signs ◽

Amyloid Β ◽

Selective Vulnerability ◽

Therapeutic Strategies ◽

Neurofibrillary Degeneration ◽

Phosphorylated Tau ◽

Consensus Guidelines ◽

Disease Pathogenesis ◽

Biological Meaning ◽

Tau Isoforms

Neurofibrillary degeneration has attracted the attention of neuroscientists as both a hallmark of the disease and a subject for experimentation for more than a century. Recent studies implicate phosphorylated tau (p-tau) directly in neurodegenerative disease pathogenesis, although the human data continue to raise questions. P-tau accumulates with age in a roughly hierarchical manner, but avoids abundance in the neocortex unless co-occurring with amyloid-β. Neurodegenerative tauopathies tend to have p-tau morphologies that differ from aging and Alzheimer’s disease. Tau isoforms (3R vs. 4R) have a tendency to vary with tauopathy phenotype for unknown reasons. Selective vulnerability to p-tau and spatial-temporal disconnect from amyloid-β are evident in aging. P-tau assessment at autopsy involves tissue decomposition, which may skew microanatomical observations toward limited biological meaning. Two major consensus guidelines for interpreting p-tau at autopsy emphasize the challenges of clinicopathologic correlation, and reinforce the observation that regional neurodegeneration is a better correlate of clinical signs than is proteinopathy. Despite the proliferation of interesting and novel theories related to tau-mediated pathogenesis, the weight of the human observations suggests that neurofibrillary degeneration is an epiphenomenal hallmark of aging and disease rather than an epicenter of neurotoxicity. This is consistent with numerous tau-targeted therapeutic strategies that have been unsuccessful to date.

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Recognition Memory is Associated with Distinct Patterns of Regional Gray Matter Volumes in Young and Aged Monkeys

Cerebral Cortex ◽

10.1093/cercor/bhab257 ◽

2021 ◽

Author(s):

C’iana P Cooper ◽

Andrea T Shafer ◽

Nicole M Armstrong ◽

Sharyn L Rossi ◽

Jennifer Young ◽

...

Keyword(s):

Prefrontal Cortex ◽

Recognition Memory ◽

Gray Matter ◽

Cognitive Aging ◽

Medial Temporal Lobe ◽

Regional Distribution ◽

Structural Reorganization ◽

Primate Model ◽

Age Related ◽

Multiple Structures

Abstract Cognitive aging varies tremendously across individuals and is often accompanied by regionally specific reductions in gray matter (GM) volume, even in the absence of disease. Rhesus monkeys provide a primate model unconfounded by advanced neurodegenerative disease, and the current study used a recognition memory test (delayed non-matching to sample; DNMS) in conjunction with structural imaging and voxel-based morphometry (VBM) to characterize age-related differences in GM volume and brain-behavior relationships. Consistent with expectations from a long history of neuropsychological research, DNMS performance in young animals prominently correlated with the volume of multiple structures in the medial temporal lobe memory system. Less anticipated correlations were also observed in the cingulate and cerebellum. In aged monkeys, significant volumetric correlations with DNMS performance were largely restricted to the prefrontal cortex and striatum. Importantly, interaction effects in an omnibus analysis directly confirmed that the associations between volume and task performance in the MTL and prefrontal cortex are age-dependent. These results demonstrate that the regional distribution of GM volumes coupled with DNMS performance changes across the lifespan, consistent with the perspective that the aged primate brain retains a substantial capacity for structural reorganization.

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Gram-negative bacteria and their lipopolysaccharides in Alzheimer’s disease: pathologic roles and therapeutic implications

Translational Neurodegeneration ◽

10.1186/s40035-021-00273-y ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Hyeon soo Kim ◽

Sujin Kim ◽

Soo Jung Shin ◽

Yong Ho Park ◽

Yunkwon Nam ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Therapeutic Targets ◽

Amyloid Β ◽

Gram Negative Bacteria ◽

Therapeutic Approaches ◽

Tau Pathology ◽

Gram Negative ◽

Therapeutic Implications ◽

Age Related

AbstractAlzheimer’s disease (AD) is the most serious age-related neurodegenerative disease and causes destructive and irreversible cognitive decline. Failures in the development of therapeutics targeting amyloid-β (Aβ) and tau, principal proteins inducing pathology in AD, suggest a paradigm shift towards the development of new therapeutic targets. The gram-negative bacteria and lipopolysaccharides (LPS) are attractive new targets for AD treatment. Surprisingly, an altered distribution of gram-negative bacteria and their LPS has been reported in AD patients. Moreover, gram-negative bacteria and their LPS have been shown to affect a variety of AD-related pathologies, such as Aβ homeostasis, tau pathology, neuroinflammation, and neurodegeneration. Moreover, therapeutic approaches targeting gram-negative bacteria or gram-negative bacterial molecules have significantly alleviated AD-related pathology and cognitive dysfunction. Despite multiple evidence showing that the gram-negative bacteria and their LPS play a crucial role in AD pathogenesis, the pathogenic mechanisms of gram-negative bacteria and their LPS have not been clarified. Here, we summarize the roles and pathomechanisms of gram-negative bacteria and LPS in AD. Furthermore, we discuss the possibility of using gram-negative bacteria and gram-negative bacterial molecules as novel therapeutic targets and new pathological characteristics for AD.

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Predictors of cognitive impairment in primary age-related tauopathy: an autopsy study

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01233-3 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Megan A. Iida ◽

Kurt Farrell ◽

Jamie M. Walker ◽

Timothy E. Richardson ◽

Gabriel A. Marx ◽

...

Keyword(s):

Cognitive Impairment ◽

Medial Temporal Lobe ◽

Neurofibrillary Tangle ◽

Lewy Bodies ◽

Brain Regions ◽

Braak Stage ◽

Autopsy Study ◽

Factors Affecting ◽

Braak Staging ◽

Age Related

AbstractPrimary age-related tauopathy (PART) is a form of Alzheimer-type neurofibrillary degeneration occurring in the absence of amyloid-beta (Aβ) plaques. While PART shares some features with Alzheimer disease (AD), such as progressive accumulation of neurofibrillary tangle pathology in the medial temporal lobe and other brain regions, it does not progress extensively to neocortical regions. Given this restricted pathoanatomical pattern and variable symptomatology, there is a need to reexamine and improve upon how PART is neuropathologically assessed and staged. We performed a retrospective autopsy study in a collection (n = 174) of post-mortem PART brains and used logistic regression to determine the extent to which a set of clinical and neuropathological features predict cognitive impairment. We compared Braak staging, which focuses on hierarchical neuroanatomical progression of AD tau and Aβ pathology, with quantitative assessments of neurofibrillary burden using computer-derived positive pixel counts on digitized whole slide images of sections stained immunohistochemically with antibodies targeting abnormal hyperphosphorylated tau (p-tau) in the entorhinal region and hippocampus. We also assessed other factors affecting cognition, including aging-related tau astrogliopathy (ARTAG) and atrophy. We found no association between Braak stage and cognitive impairment when controlling for age (p = 0.76). In contrast, p-tau burden was significantly correlated with cognitive impairment even when adjusting for age (p = 0.03). The strongest correlate of cognitive impairment was cerebrovascular disease, a well-known risk factor (p < 0.0001), but other features including ARTAG (p = 0.03) and hippocampal atrophy (p = 0.04) were also associated. In contrast, sex, APOE, psychiatric illness, education, argyrophilic grains, and incidental Lewy bodies were not. These findings support the hypothesis that comorbid pathologies contribute to cognitive impairment in subjects with PART. Quantitative approaches beyond Braak staging are critical for advancing our understanding of the extent to which age-related tauopathy changes impact cognitive function.

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Widespread Reduced Density of Noradrenergic Locus Coeruleus Axons in the App Knock-In Mouse Model of Amyloid-β Amyloidosis

Journal of Alzheimer s Disease ◽

10.3233/jad-210385 ◽

2021 ◽

pp. 1-18

Author(s):

Yasufumi Sakakibara ◽

Yu Hirota ◽

Kyoko Ibaraki ◽

Kimi Takei ◽

Sachie Chikamatsu ◽

...

Keyword(s):

Locus Coeruleus ◽

Somatostatin Receptor ◽

Amyloid Β ◽

Immunohistochemical Method ◽

Noradrenergic Neurons ◽

Tau Pathology ◽

Age Related ◽

Neurotrophin 3 ◽

Underlying Mechanisms ◽

Reduced Density

Background: The locus coeruleus (LC), a brainstem nucleus comprising noradrenergic neurons, is one of the earliest regions affected by Alzheimer’s disease (AD). Amyloid-β (Aβ) pathology in the cortex in AD is thought to exacerbate the age-related loss of LC neurons, which may lead to cortical tau pathology. However, mechanisms underlying LC neurodegeneration remain elusive. Objective: Here, we aimed to examine how noradrenergic neurons are affected by cortical Aβ pathology in AppNL-G-F/NL-G-F knock-in mice. Methods: The density of noradrenergic axons in LC-innervated regions and the LC neuron number were analyzed by an immunohistochemical method. To explore the potential mechanisms for LC degeneration, we also examined the occurrence of tau pathology in LC neurons, the association of reactive gliosis with LC neurons, and impaired trophic support in the brains of AppNL-G-F/NL-G-F mice. Results: We observed a significant reduction in the density of noradrenergic axons from the LC in aged App NL-G-F/NL-G-F mice without neuron loss or tau pathology, which was not limited to areas near Aβ plaques. However, none of the factors known to be related to the maintenance of LC neurons (i.e., somatostatin/somatostatin receptor 2, brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3) were significantly reduced in App NL-G-F/NL-G-F mice. Conclusion: This study demonstrates that cortical Aβ pathology induces noradrenergic neurodegeneration, and further elucidation of the underlying mechanisms will reveal effective therapeutics to halt AD progression.

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