Skip to content
naulon
Get started

No retraction, correction or concern found when last checked on Oct 21, 2026.

LATE-NC staging in routine neuropathologic diagnosis: an update

Peter T. Nelson, Edward B. Lee, Matthew D. Cykowski and 47 more

Acta Neuropathologica · 2022 · CC BY

doi:10.1007/s00401-022-02524-2

Abstract

Supplementary Information. The online version contains supplementary material available at 10.1007/s00401-022-02524-2.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 21, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Transactive response DNA-binding protein of 43 kDa (TDP-43) pathology is prevalent in aging brains and is often associated with cognitive impairment or dementia. Age-related TDP-43 pathology and associated clinical features have been described by many investigators over past decades, but a consensus nomenclature was lacking until recently. In 2019, a multidisciplinary consensus group suggested terminology for age-related TDP-43 pathologic changes associated with cognitive impairment. The disease was designated “limbic-predominant age-related TDP-43 encephalopathy” (LATE), and guidelines were suggested for post-mortem evaluation and staging of LATE neuropathologic changes (LATE-NC). This terminology has been adopted widely. However, diagnostic ambiguities and criticisms of the staging scheme have emerged.

At least four shortcomings have been identified in the 2019 LATE-NC guidelines: (1) anatomic regions for sampling were recommended, but the implications of TDP-43 immunopositivity in subregions were not precisely defined; (2) it was not clear how additional information on genetic findings and other pathologies should be incorporated into reports of LATE-NC; (3) there was minimal guidance on how to separate LATE-NC from other TDP-43 proteinopathies; and (4) some cases with TDP-43 pathology in aging could not be readily classified into LATE-NC stages.

The aims of the present paper are to remedy these shortcomings, to provide data to clarify the proper use of the LATE-NC staging system, and to indicate where the diagnosis of LATE-NC may not be appropriate. The overarching goal is to provide additional precision about LATE-NC diagnosis for neuropathologists. These goals are important, since brain autopsy remains the gold-standard for neurodegenerative disease diagnoses. New recommendations and clarifications are proposed for the LATE-NC staging system, guided by published data, findings reported at the LATE 2022 Conference and diagnostic experience.

LATE-NC: recommendations for anatomic sampling and staining

Regarding brain tissue collected at autopsy to assess LATE-NC, this update does not propose additional sampling relative to the 2019 consensus recommendations. However, there is a need to clarify the implications of the immunostaining results within specific regions of interest. Three anatomical regions are recommended for sampling, with the following suggestions (Fig. 1):Amygdala region: this refers to the amygdala and surrounding structures at the level of the uncus, including adjacent entorhinal [Brodmann area (BA) 28], transentorhinal (BA35), anterior temporal (BA36) cortices and anterior parts of the hippocampus and the subiculum/presubiculum, sub-pial, subependymal regions, and white matter. The pathology is scored as positive in this region if aberrant TDP-43 immunoreactivity is seen anywhere on the section that contains amygdala and uncus (not just within amygdala proper).Hippocampus region: this refers to the hippocampus and associated medial temporal cortical structures at the level of the lateral geniculate nucleus. Areas of interest may include fornix, sub-pial region, periventricular region, dentate granule cells, mid-level temporal cortex (BA36), and white matter. This region is considered to be positive if any part of the section has TDP-43 immunoreactive pathology.Middle frontal gyrus (corresponding roughly to BA46). TDP-43 immunoreactive cytoplasmic inclusions in any part of this section is considered to be positive.

Amygdala region: this refers to the amygdala and surrounding structures at the level of the uncus, including adjacent entorhinal [Brodmann area (BA) 28], transentorhinal (BA35), anterior temporal (BA36) cortices and anterior parts of the hippocampus and the subiculum/presubiculum, sub-pial, subependymal regions, and white matter. The pathology is scored as positive in this region if aberrant TDP-43 immunoreactivity is seen anywhere on the section that contains amygdala and uncus (not just within amygdala proper).

Hippocampus region: this refers to the hippocampus and associated medial temporal cortical structures at the level of the lateral geniculate nucleus. Areas of interest may include fornix, sub-pial region, periventricular region, dentate granule cells, mid-level temporal cortex (BA36), and white matter. This region is considered to be positive if any part of the section has TDP-43 immunoreactive pathology.

Middle frontal gyrus (corresponding roughly to BA46). TDP-43 immunoreactive cytoplasmic inclusions in any part of this section is considered to be positive.

Supplemental File 1 (online resource) provides additional detail on the specific anatomical regions and subregions of interest, as pertains to LATE-NC staging.

The LATE-NC staging guidelines suggested that TDP-43 immunohistochemistry should be performed as part of the neuropathologic evaluation of all older individuals’ brains, but there was no specific recommendation on the staining methods used. The antibody used for pathologic diagnosis and associated protocols may affect the ability to detect TDP-43 inclusions. Phosphorylation-specific antibodies, with those against pS409/410 being the most commonly used, robustly label pathologic TDP-43 inclusions and do not stain normal (nonphosphorylated) nuclear TDP-43 protein, thereby facilitating identification of aggregates but precluding the visualization of the loss of normal nuclear TDP-43 protein in inclusion bearing cells and nuclear staining as internal positive control. Antibodies that are phosphorylation independent allow for labeling of inclusions (albeit slightly less sensitively), while also enabling assessment of normal nuclear TDP-43 protein. In an informal survey of U.S. Alzheimer’s Disease Research Centers, approximately 2/3rd of the neuropathologists depended on antibodies against the phosphorylated Ser409/Ser410 TDP-43 epitope. More standardization may be achievable in the future, but there is still not a current consensus on a prescribed set of reagents for TDP-43 detection.

LATE-NC: recommendations for pathological staging

LATE-NC staging, like other neurodegenerative disease staging systems, is based on anatomical regions affected by the neuropathologic changes. Following prior studies which incorporated analyses of TDP-43 immunohistochemical data from more anatomical regions, the 2019 consensus guidelines for LATE-NC suggested that TDP-43 pathology progressed in a stereotypical pattern: LATE-NC Stage 1 corresponds to TDP-43 pathology in the amygdala, Stage 2 corresponds to TDP-43 pathology in the amygdala and hippocampus, and Stage 3 corresponds to TDP-43 pathology in the amygdala, hippocampus, and middle frontal gyrus. If other neocortical regions (orbitofrontal cortex, or temporal neocortex) are stained and show neuronal cytoplasmic inclusions (NCIs), but NCIs are not seen in the middle frontal gyrus, this would not represent LATE-NC Stage 3. Some such LATE-NC Stage 2 cases would be expected, because orbitofrontal cortex and temporal neocortex (as well as some other regions) are affected earlier than middle frontal gyrus in the anatomical progression of LATE-NC. While most cases can be readily assigned to a given LATE-NC stage using those criteria, recent reports have described cases that depart from the staging scheme for one or more reasons. Below are described strategies to address various diagnostic challenges in a data-driven and standardized manner.

Brains with TDP-43 + NCI detected in the hippocampal region, but not in the amygdala region

In recently published studies from five separate autopsy series, a small subset of cases from each cohort was reported with TDP-43 pathology in the hippocampal formation, but not in the amygdala. This pattern is not accounted for in the original LATE-NC staging guidelines. LATE-NC cases with hippocampal TDP-43 + NCIs, but none in amygdala region, are unusual (< 2% of LATE-NC cases), and the TDP-43 pathology usually involves the anterior hippocampus. These cases lacking detectable amygdala TDP-43 pathology may be due in part to sampling issues, and the clinical implications are unclear. More work is required to confirm that hippocampus-only TDP-43 pathology is appropriately diagnosed as LATE-NC. At present, because such cases have a low burden of TDP-43 pathology overall, and we do not know of an example of an individual with cognitive impairment lacking other pathologies, we recommend that this pattern of TDP-43 pathology be designated LATE-NC Stage 1.

To account for the varied pathologic patterns in LATE-NC Stage 1 cases, a system for differentiating subtypes of LATE-NC Stage 1 cases is now recommended. This classification may be most suitable for academic research centers, and should be considered optional for diagnosticians. In this system, a “conventional” case with TDP-43 immunoreactive NCI(s) in amygdala but not hippocampus would be diagnosed as LATE-NC Stage 1a, whereas an unusual case with NCI(s) in hippocampus but none detected in the amygdala region would be diagnosed as LATE-NC Stage 1b (Table 1).

Brains with TDP-43 + cell processes, but no TDP-43 + neuronal cytoplasmic inclusions (NCI)

In LATE-NC, TDP-43 proteinopathy is often detected in cellular compartments outside of the neuronal cell body. A recent study focusing on cases with minimal or incipient LATE-NC described cases without NCI, but with short, non-branching TDP-43 immunoreactive structures that frequently localized around corpora amylacea, and/or in aging-related tau astrogliopathy (ARTAG) pathology. Because of the apparent astroglial derivation of some TDP-43 pathology outside of neuronal cell bodies, we use the term “processes”, as opposed to “neurites”, for these common TDP-43-immunoreactive structures. TDP-43-positive processes were detected in the sub-pial zone overlying the corticomedial region of the amygdala and/or in the periventricular white matter subjacent to amygdala. This pattern was common—aberrant TDP-43 was found only in cellular processes in approximately one-third of LATE-NC cases. Another recent study confirmed that there are cases with TDP-43 + processes but lacking TDP-43 + NCIs.

We propose that cases with only TDP-43-positive processes, and no NCI in the amgydala and hippocampus regions, should be diagnosed as LATE-NC Stage 1. It is emphasized that LATE-NC Stage 2 requires at least a single NCI to be present in each of both the amygdala and hippocampal regions. In the context of the optional LATE-NC Stage 1 subtyping system as described above, any case with TDP-43 immunoreactive processes only (no NCI) would be LATE-NC Stage 1c, even if the TDP-43 + processes are in the hippocampus region. The various possible neuropathologic changes seen in LATE-NC Stage 1, and their relevant diagnoses, are shown in detail in Table 1. This staging scheme will help clarify diagnostic practice, but we also recognize that more work is required to understand the implications of aberrant TDP-43 protein in processes but not NCIs.

Brains with comorbid Alzheimer’s disease neuropathologic changes (ADNC), Lewy bodies, and/or granulovacuolar degeneration

It has been recognized for over a decade that TDP-43 pathology is often comorbid with ADNC, Lewy body pathology, or both. However, these pathologic features also are commonly seen—even when quite severe—in the absence of each other, so they are at least partly independent. Many studies have demonstrated that LATE-NC is associated with additive cognitive impairment for a given amount of other pathologic changes. Therefore, we recommend that descriptions of the individual diseases (and their neuropathologic stages) be rendered as separate line diagnoses on autopsy reports. A potential pitfall for the assessment of LATE-NC is the fact that some phospho-TDP-43 antibodies also detect granulovacuolar degeneration (GVD)—this staining is not considered to represent LATE-NC. For more data and discussion related to immunostaining of GVD, see Refs.

Differentiating LATE-NC Stage 3 from FTLD-TDP

TDP-43 was initially identified as a protein that forms abnormal intracellular aggregates in the most common pathology associated with clinical frontotemporal dementia (FTD) syndromes, now termed frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) and in ALS. The defining feature of FTLD-TDP is the presence of NCIs and dystrophic TDP-43 immunoreactive processes in affected frontotemporal cortices. Differences in the morphologic features, abundance, and laminar distribution of TDP-43 pathology in the cerebral neocortex allow for recognition of at least five subtypes of FTLD-TDP, each with relatively specific clinical and genetic correlations and increasingly recognized molecular differences in the nature of the TDP-43 aggregates. In addition, each FTLD-TDP subtype has a fairly distinct pattern of limbic and subcortical involvement that is helpful in their classification. Nevertheless, potential pitfalls in the FTLD-TDP subtyping have been discussed due to the presence of mixed subtypes (usually FTLD-TDP types A + B), and overall low inter-rater agreement in separating FTLD-TDP types A and B.

Cases with TDP-43 pathology mostly restricted to the medial temporal lobes (LATE-NC Stages 1 or 2) do not fulfill criteria for FTLD-TDP and should be classified as LATE-NC. By contrast, boundaries between LATE-NC Stage 3 and FTLD-TDP are more challenging (~ 11% of LATE-NC cases in community-based cohorts were Stage 3). Ancillary measures, such as neuronal loss and gliosis, as well as superficial laminar spongiosis, involvement of further cortices and subcortical nuclei and white matter in FTLD-TDP, and the morphology of inclusions may help differentiate genuine FTLD-TDP from LATE-NC Stage 3. More work is needed to delineate aspects of biological overlap and differences between LATE-NC and FTLD-TDP, particularly for FTLD-TDP in advanced old age.

Based on current knowledge, our recommendations are as follows:TDP-43 pathology in LATE-NC has histomorphologic features that may be similar to FTLD-TDP type A or less commonly type B. By contrast, all cases with FTLD-TDP types C, D, or E patterns should be classified as FTLD-TDP and not LATE-NC.The severity of TDP-43 pathology in the middle frontal gyrus has been described as a useful indicator to differentiate LATE-NC Stage 3 from FTLD-TDP. Specifically, more than 15 TDP-43 immunoreactive inclusions (NCIs and/or threads) per high power (40 × objective) microscopic field in the middle frontal gyrus had a high sensitivity and specificity in differentiating FTLD-TDP from LATE-NC. More than 15 TDP-43-immunoreactive pathological structures per 40 × microscopic field in the middle frontal gyrus favor a diagnosis of FTLD-TDP or a descriptive diagnosis of the pathologies observed, rather than LATE-NC.In cases with substantial TDP-43 pathology in the middle frontal gyrus, it is recommended to expand regions sampled for TDP-43 pathology and to include regions more typically affected in FTLD-TDP, such as subcortical structures, including basal ganglia, medulla (hypoglossal nucleus), and spinal cord. TDP-43 pathology in these regions supports a diagnosis of FTLD-TDP or ALS.Cases with known pathogenetic mutations in FTLD-TDP-related genes (e.g., GRN, C9orf72, VCP, and others) should not be classified as LATE-NC. Notably, to identify C9orf72 repeat expansion carriers, immunohistochemistry of cerebellum with antibodies against p62 or dipeptide repeat proteins can be used as surrogate markers. This method is recommended in standard histopathologic screening if genetic analyses are not available.Cases with comorbid FTLD-TDP and LATE-NC may exist, but there currently is no consensus about how to definitively diagnose such cases as distinct from FTLD-TDP alone.

TDP-43 pathology in LATE-NC has histomorphologic features that may be similar to FTLD-TDP type A or less commonly type B. By contrast, all cases with FTLD-TDP types C, D, or E patterns should be classified as FTLD-TDP and not LATE-NC.

The severity of TDP-43 pathology in the middle frontal gyrus has been described as a useful indicator to differentiate LATE-NC Stage 3 from FTLD-TDP. Specifically, more than 15 TDP-43 immunoreactive inclusions (NCIs and/or threads) per high power (40 × objective) microscopic field in the middle frontal gyrus had a high sensitivity and specificity in differentiating FTLD-TDP from LATE-NC. More than 15 TDP-43-immunoreactive pathological structures per 40 × microscopic field in the middle frontal gyrus favor a diagnosis of FTLD-TDP or a descriptive diagnosis of the pathologies observed, rather than LATE-NC.

In cases with substantial TDP-43 pathology in the middle frontal gyrus, it is recommended to expand regions sampled for TDP-43 pathology and to include regions more typically affected in FTLD-TDP, such as subcortical structures, including basal ganglia, medulla (hypoglossal nucleus), and spinal cord. TDP-43 pathology in these regions supports a diagnosis of FTLD-TDP or ALS.

Cases with known pathogenetic mutations in FTLD-TDP-related genes (e.g., GRN, C9orf72, VCP, and others) should not be classified as LATE-NC. Notably, to identify C9orf72 repeat expansion carriers, immunohistochemistry of cerebellum with antibodies against p62 or dipeptide repeat proteins can be used as surrogate markers. This method is recommended in standard histopathologic screening if genetic analyses are not available.

Cases with comorbid FTLD-TDP and LATE-NC may exist, but there currently is no consensus about how to definitively diagnose such cases as distinct from FTLD-TDP alone.

Differentiating LATE-NC from amyotrophic lateral sclerosis (ALS)

Another important disease associated with TDP-43 proteinopathy is ALS. A four-tiered staging system of TDP-43 neuropathologic changes in ALS has been described by Brettschneider et al. based on an autopsy cohort of ALS patients with average age at death of 63 years. TDP-43 pathology in the hippocampus region was designated stage 4 and was found in ~ 30% of cases. While, in this study, no significant differences regarding age at disease onset, or age at death, were observed between different stages of TDP-43 pathology, a recent study found medial temporal lobe TDP-43 pathology in 8/8 older ALS cases (> 75 years of age at death), suggesting that in ALS, there may be pathology overlapping with LATE-NC. Yet, the TDP-43 neuropathologic changes in ALS differ from LATE-NC: motor neuron TDP-43 pathology has not been reported in LATE-NC, but is an early site of TDP-43 pathology in ALS, and is even seen in some FTLD-TDP cases without clinical ALS. Until methods are available to distinguish TDP-43 pathology associated with LATE-NC from limbic pathology in ALS, we recommend avoiding the term LATE-NC in the context of sporadic and familial ALS.

Brains with unusual TDP-43 pathologies

Research continues to find expanding implications of aberrant TDP-43 protein in human diseases. TDP-43 pathology is now known to occur in more than 20 different conditions spanning neurodegenerative, developmental, trauma-related, myopathic, and even neoplastic disease categories. For example, TDP-43 pathology is often seen in corticobasal degeneration, Perry syndrome, Alexander disease, and the Parkinsonism–dementia complex diseases of Guam and Kii. However, the morphology and anatomical patterns of the TDP-43 pathology in those conditions often differ from that in LATE-NC, so the diagnosis of LATE-NC should be avoided in these conditions. For persons with a clinical history of brain trauma—traumatic brain injury (TBI) and/or chronic traumatic encephalopathy (CTE)–TDP-43 pathologic changes may be seen, but not necessarily related to LATE-NC. More work is required to develop a data-driven consensus of best practices for diagnosing brain trauma-related TDP-43 pathology.

Guidance in autopsy reports

Brain autopsy reports of individuals across the spectrum of dementias convey complex information reflecting the (often multifactorial) nature of the underlying diseases. That complexity, along with technical nomenclatures, can make it difficult, especially for patients’ families and loved ones, to understand the implications of TDP-43 pathology. It may be helpful for practicing neuropathologists to provide interpretive summaries, but we emphasize that this should be a separate comment with a focus on interpretation of findings in nontechnical language.

What are the implications of LATE-NC staging results? Clinical–pathological studies demonstrated that LATE-NC is associated with cognitive impairment (often with amnestic features), independent of other disease processes. For example, in an attributable risk analysis based on all observed pathologic changes that may contribute to cognitive impairment in a large community cohort, LATE-NC accounted for more than 15% of identified amnestic dementia risk. Similar to other age-related neurodegenerative disease processes, it is not possible to confidently predict clinical implications of LATE-NC in a given individual, especially if there are multiple concurrent pathologies.

The following are possible text templates to complement the diagnostic findings in cases with LATE-NC:LATE-NC Stage 1 indicates the early/incipient stage of LATE-NC, analogous to early stages of other brain and systemic diseases where pathologies are present before outward clinical signs/symptoms (e.g., Braak NFT Stages I–II in Alzheimer’s disease Neuropathologic Changes). The presence of LATE-NC Stage 1 may be compatible with normal cognition or may have only a relatively small additive impact on cognitive function.LATE-NC Stage 2 indicates that TDP-43 neuronal cytoplasmic inclusions are detected more broadly in the brain. LATE-NC Stage 2 is usually associated with some impairment of memory or global cognition or both, with more cognitive impairment in cases with comorbid hippocampal sclerosis.LATE-NC Stage 3 indicates the most advanced stage of LATE-NC in terms of neuroanatomic distribution of TDP-43 pathologic burden in the brain. LATE-NC Stage 3 is usually associated with some degree of impairment of memory or global cognitive impairment, and with more cognitive impairment in cases with comorbid hippocampal sclerosis.

LATE-NC Stage 1 indicates the early/incipient stage of LATE-NC, analogous to early stages of other brain and systemic diseases where pathologies are present before outward clinical signs/symptoms (e.g., Braak NFT Stages I–II in Alzheimer’s disease Neuropathologic Changes). The presence of LATE-NC Stage 1 may be compatible with normal cognition or may have only a relatively small additive impact on cognitive function.

LATE-NC Stage 2 indicates that TDP-43 neuronal cytoplasmic inclusions are detected more broadly in the brain. LATE-NC Stage 2 is usually associated with some impairment of memory or global cognition or both, with more cognitive impairment in cases with comorbid hippocampal sclerosis.

LATE-NC Stage 3 indicates the most advanced stage of LATE-NC in terms of neuroanatomic distribution of TDP-43 pathologic burden in the brain. LATE-NC Stage 3 is usually associated with some degree of impairment of memory or global cognitive impairment, and with more cognitive impairment in cases with comorbid hippocampal sclerosis.

Future directions and knowledge gaps related to LATE-NC

Considering the major public health impact of LATE-NC, there are many aspects of this disorder that merit further research. Of greatest urgency is the need for a sensitive and specific method to diagnose LATE during life, ideally at early stages of disease, to enable focused recruitment into clinical trials. The involvement of aberrant TDP-43 in a wider range of brain areas, and the role(s) of astrocytes in pathogenesis could also be foci of further scholarship. Systematic neuropathological and clinicopathological studies will inform if the staging system needs modifications to include intermediate stages. Additional pressing research is needed to define and stratify risk factors and interactions with other diseases, including various neurodegenerative and neurovascular disorders (see, for example, Refs). Observations in more diverse communities are critical, since socioeconomic, cultural, and/or ancestral aspects may influence clinical–pathological correlation. (Some recent scholarship has evaluated LATE-NC in cohorts other than Whites.)

It may be possible to discover molecular subtypes of LATE-NC using immunophenotyping, transcriptome profiling, and genotyping or other approaches, which has potential implications for prognosis and therapy. Indeed, there has already been significant progress along these lines. In particular, pathologic heterogeneity in LATE-NC has been demonstrated particularly in the early phases of LATE-NC, which occurs in different patterns and appears to originate at one of several different anatomic locations in the amygdala region. Certain parameters and features (e.g., comorbid Lewy body disease) have been associated with differing patterns of LATE-NC. A genetic risk factor for LATE-NC is TMEM106B. Notably, the TMEM106B risk allele frequency was elevated in all identified LATE-NC patterns, and the different TDP-43 pathologic patterns observed in cases with mild pathology tended to converge in more severely affected brains. We conclude that cases meeting criteria for LATE-NC encompass both heterogeneity and meaningful commonalities, but there currently is no agreement on means to differentiate LATE-NC subtypes.

Another area of uncertainty is the relation of LATE-NC to hippocampal sclerosis (HS). HS in the elderly is strongly associated with LATE-NC, with 75–90% of HS cases in aging being seen in cases with LATE-NC. The presence or absence of comorbid HS pathology does not affect LATE-NC staging. Further, HS is a diagnostic term that refers to distinctly different disease processes. For example, the diagnosis of HS is commonly applied in the context of persons with epilepsy, where the pathogenesis is very different (and lacks TDP-43 proteinopathy) in comparison to LATE-NC. At autopsy, sensitive detection of HS requires bilateral sampling, because HS in LATE-NC is often unilateral. In hippocampi affected by severe HS, pyramidal cell dropout is extensive, and hippocampal atrophy can be extreme; however, in some individuals with LATE-NC, cell loss is segmental (neuronal loss in some portions of the hippocampus and/or subiculum, but not others). These factors increase the likelihood of poor inter-rater agreement on the neuropathologic diagnosis of HS, and help explain the differing frequencies of HS reported in various autopsy series. To fully standardize the pathologic diagnosis of HS, especially as it relates to differentiating LATE-NC + HS from other distinct disease processes (e.g., anoxic–ischemic episodes or seizures), will require additional work. Prior studies of HS-related histomorphology, and the recent work by Hokkanen et al., provided methodologies to study HS pathologic features systematically.

In conclusion, despite challenges associated with a fast-moving research field, we found opportunities for recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience. We emphasize that TDP-43 immunohistochemical assessment should be performed in all brain autopsies of older persons. The diagnosis of LATE-NC Stages requires sampling from three specific brain regions (Fig. 1, and Supplemental File 1, online resource). A specific rubric is presented in Table 1 and overall recommendations in Table 2. Recent literature indicates the scope of the challenge, even for this relatively simple pathologic staging system, as a wide variation of results was reported in the proportion of subjects with LATE-NC Stage 1 in a survey of community-based autopsy cohorts. We hope that the present update will assist in efforts to increase standardization in the diagnosis of LATE-NC. As more observations are made across diverse autopsy cohorts, gathering detailed information on each case, including clinical, radiologic, laboratory, neuropathology, and genetic data, may facilitate future refinements of the classification and staging of LATE-NC.

Below is the link to the electronic supplementary material.

References 162

  1. 1.

    (2022) LATE 2022 Webinar, 11 February https://www.nia.nih.gov/research/dn/late-2022. Accessed 1 Nov 2022

    Not in our library

  2. 2.

    Agirre-Beitia G, Moreno-Estebanez A, Gonzalez-Pinto Gonzalez T, Melgar Jimenez B, Campos Rodriguez I, Cabral Martinez L, et al. FOSMN: a possible TDP-43 proteinopathy to consider in a patient with facial sensory symptoms. Neurol Clin Pract. 2020;10:e47-e50.

    Not in our library10.1212/cpj.0000000000000753

  3. 3.

    Agrawal S, Leurgans SE, James BD, Barnes LL, Mehta RI, Dams-O'Connor K, et al. Association of traumatic brain injury with and without loss of consciousness with neuropathologic outcomes in community-dwelling older persons. JAMA Netw Open. 2022;5:e229311.

    Not in our library10.1001/jamanetworkopen.2022.9311

  4. 4.

    Agrawal S, Yu L, Nag S, Arfanakis K, Barnes LL, Bennett DA, et al. The association of Lewy bodies with limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes and their role in cognition and Alzheimer’s dementia in older persons. Acta Neuropathol Commun. 2021;9:156.

    Not in our library10.1186/s40478-021-01260-0

  5. 5.

    Alafuzoff I, Pikkarainen M, Neumann M, Arzberger T, Al-Sarraj S, Bodi I, et al. Neuropathological assessments of the pathology in frontotemporal lobar degeneration with TDP43-positive inclusions: an inter-laboratory study by the BrainNet Europe consortium. J Neural Transm (Vienna). 2015;122:957-972.

    Not in our library10.1007/s00702-014-1304-1

  6. 6.

    Amador-Ortiz C, Ahmed Z, Zehr C, Dickson DW. Hippocampal sclerosis dementia differs from hippocampal sclerosis in frontal lobe degeneration. Acta Neuropathol (Berl). 2007;113:245-252.

    Not in our library10.1007/s00401-006-0183-4

  7. 7.

    Amador-Ortiz C, Lin WL, Ahmed Z, Personett D, Davies P, Duara R, et al. TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer’s disease. Ann Neurol. 2007;61:435-445.

    Not in our library10.1002/ana.21154

  8. 8.

    Aoki N, Murray ME, Ogaki K, Fujioka S, Rutherford NJ, Rademakers R, et al. Hippocampal sclerosis in Lewy body disease is a TDP-43 proteinopathy similar to FTLD-TDP type A. Acta Neuropathol. 2015;129:53-64.

    Not in our library10.1007/s00401-014-1358-z

  9. 9.

    Arai T. Significance and limitation of the pathological classification of TDP-43 proteinopathy. Neuropathology. 2014;34:578-588.

    Not in our library10.1111/neup.12138

  10. 10.

    Arai T, Mackenzie IR, Hasegawa M, Nonoka T, Niizato K, Tsuchiya K, et al. Phosphorylated TDP-43 in Alzheimer’s disease and dementia with Lewy bodies. Acta Neuropathol. 2009;117:125-136.

    Not in our library10.1007/s00401-008-0480-1

  11. 11.

    Arnold SJ, Dugger BN, Beach TG. TDP-43 deposition in prospectively followed, cognitively normal elderly individuals: correlation with argyrophilic grains but not other concomitant pathologies. Acta Neuropathol. 2013;126:51-57.

    Not in our library10.1007/s00401-013-1110-0

  12. 12.
    Neuropathological consensus criteria for the evaluation of Lewy pathology in post-mortem brains: a multi-centre study · 2021
    No notice
  13. 13.

    Ayaki T, Murata K, Kanazawa N, Uruha A, Ohmura K, Sugie K, et al. Myositis with sarcoplasmic inclusions in Nakajo-Nishimura syndrome: a genetic inflammatory myopathy. Neuropathol Appl Neurobiol. 2020;46:579-587.

    Not in our library10.1111/nan.12614

  14. 14.

    Barker WW, Luis CA, Kashuba A, Luis M, Harwood DG, Loewenstein D, et al. Relative frequencies of Alzheimer disease, Lewy body, vascular and frontotemporal dementia, and hippocampal sclerosis in the State of Florida Brain Bank. Alzheimer Dis Assoc Disord. 2002;16:203-212.

    Not in our library10.1097/00002093-200210000-00001

  15. 15.

    Blevins BL, Vinters HV, Love S, Wilcock DM, Grinberg LT, Schneider JA, et al. Brain arteriolosclerosis. Acta Neuropathol. 2020.

    Not in our library10.1007/s00401-020-02235-6

  16. 16.

    Boyle PA, Wang T, Yu L, Wilson RS, Dawe R, Arfanakis K, et al. To what degree is late life cognitive decline driven by age-relatedneuropathologies? Brain. 2021.

    Not in our library10.1093/brain/awab092

  17. 17.

    Boyle PA, Yu L, Leurgans SE, Wilson RS, Brookmeyer R, Schneider JA, et al. Attributable risk of Alzheimer’s dementia attributed to age-related neuropathologies. Ann Neurol. 2019;85:114-124.

    Not in our library10.1002/ana.25380

  18. 18.

    Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K. Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res. 2004;318:121-134.

    Not in our library10.1007/s00441-004-0956-9

  19. 19.

    Braak H, Thal DR, Ghebremedhin E, Del Tredici K. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J Neuropathol Exp Neurol. 2011;70:960-969.

    Not in our library10.1097/nen.0b013e318232a379

  20. 20.

    Brettschneider J, Del Tredici K, Toledo JB, Robinson JL, Irwin DJ, Grossman M, et al. Stages of pTDP-43 pathology in amyotrophic lateral sclerosis. Ann Neurol. 2013;74:20-38.

    Not in our library10.1002/ana.23937

  21. 21.

    Buciuc M, Martin PR, Tosakulwong N, Murray ME, Petrucelli L, Senjem ML, et al. TDP-43-associated atrophy in brains with and without frontotemporal lobar degeneration. Neuroimage Clin. 2022;34:102954.

    Not in our library10.1016/j.nicl.2022.102954

  22. 22.

    Buciuc M, Whitwell JL, Baker MC, Rademakers R, Dickson DW, Josephs KA. Old age genetically confirmed frontotemporal lobar degeneration with TDP-43 has limbic predominant TDP-43 deposition. Neuropathol Appl Neurobiol:. 2021.

    Not in our library10.1111/nan.12727

  23. 23.

    Cairns NJ, Bigio EH, Mackenzie IR, Neumann M, Lee VM, Hatanpaa KJ, et al. Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol. 2007;114:5-22.

    Not in our library10.1007/s00401-007-0237-2

  24. 24.

    Carlos AF, Tosakulwong N, Weigand SD, Boeve BF, Knopman DS, Petersen RC, et al. Frequency and distribution of TAR DNA-binding protein 43 (TDP-43) pathology increase linearly with age in a large cohort of older adults with and without dementia. Acta Neuropathol. 2022.

    Not in our library10.1007/s00401-022-02434-3

  25. 25.

    Cho SH, Choi SM, Kim BC, Song WY, Kim HS, Lee KH. An autopsy-proven case of limbic-predominant age-related TDP-43 encephalopathy. Yonsei Med J. 2020;61:731-735.

    Not in our library10.3349/ymj.2020.61.8.731

  26. 26.

    Chompoopong P, Milone M, Niu Z, Cui G, Mer G, Liewluck T. A novel missense HNRNPA1 variant in the PY-NLS domain in a patient with late-onset distal myopathy. Neuromuscul Disord. 2022;32:521-526.

    Not in our library10.1016/j.nmd.2022.03.009

  27. 27.

    Chornenkyy Y, Fardo DW, Nelson PT. Tau and TDP-43 proteinopathies: kindred pathologic cascades and genetic pleiotropy. Lab Invest. 2019;99:993-1007.

    Not in our library10.1038/s41374-019-0196-y

  28. 28.

    Corey-Bloom J, Sabbagh MN, Bondi MW, Hansen L, Alford MF, Masliah E, et al. Hippocampal sclerosis contributes to dementia in the elderly. Neurology. 1997;48:154-160.

    Not in our library10.1212/wnl.48.1.154

  29. 29.

    Cykowski MD, Arumanayagam AS, Powell SZ, Rivera AL, Abner EL, Roman GC, et al. Patterns of amygdala region pathology in LATE-NC: subtypes that differ with regard to TDP-43 histopathology, genetic risk factors, and comorbid pathologies. Acta Neuropathol. 2022.

    Not in our library10.1007/s00401-022-02416-5

  30. 30.

    Davidson YS, Raby S, Foulds PG, Robinson A, Thompson JC, Sikkink S, et al. TDP-43 pathological changes in early onset familial and sporadic Alzheimer’s disease, late onset Alzheimer’s disease and Down’s syndrome: association with age, hippocampal sclerosis and clinical phenotype. Acta Neuropathol. 2011;122:703-713.

    Not in our library10.1007/s00401-011-0879-y

  31. 31.

    Dickson DW, Davies P, Bevona C, Van Hoeven KH, Factor SM, Grober E, et al. Hippocampal sclerosis: a common pathological feature of dementia in very old (> or = 80 years of age) humans. Acta Neuropathol. 1994;88:212-221.

    Not in our library10.1007/bf00293396

  32. 32.

    Dickson DW, Josephs KA, Amador-Ortiz C. TDP-43 in differential diagnosis of motor neuron disorders. Acta Neuropathol. 2007;114:71-79.

    Not in our library10.1007/s00401-007-0234-5

  33. 33.

    Dickson DW, Rademakers R, Nicholson AM, Schneider JA, Yu L, Bennett DA. The TMEM106B locus and TDP-43 pathology in older persons without FTLD. Neurology. 2015;85:1354-1355.

    Not in our library10.1212/01.wnl.0000472918.79256.a9

  34. 34.
    Analysis of genes (TMEM106B, GRN, ABCC9, KCNMB2, and APOE) implicated in risk for LATE-NC and hippocampal sclerosis provides pathogenetic insights: a retrospective genetic association study · 2021
    Not checked
  35. 35.

    Fearon C, Koch M-L, Hefferman J, Heeney C, Lorigan J, Beausang A, et al. Phosphorylation-dependent TDP-43 antibodies: validation in a neurodegenerative brain bank cohort. J Alzheimer’s Parkinsonism Dement. 2019;3:1-4.

    Not in our library

  36. 36.

    Flanagan ME, Cholerton B, Latimer CS, Hemmy LS, Edland SD, Montine KS, et al. TDP-43 neuropathologic associations in the nun study and the honolulu-asia aging study. J Alzheimers Dis. 2018;66:1549-1558.

    Not in our library10.3233/jad-180162

  37. 37.

    Forrest SL, Wagner S, Kim A, Kovacs GG. Association of glial tau pathology and LATE-NC in the ageing brain. Neurobiol Aging. 2022;119:77-88.

    Not in our library10.1016/j.neurobiolaging.2022.07.010

  38. 38.

    Gauthreaux KM, Teylan MA, Katsumata Y, Mock C, Culhane JE, Chen YC, et al. Limbic-predominant age-related TDP-43 encephalopathy: medical and pathologic factors associated with comorbid hippocampal sclerosis. Neurology. 2022;98:e1422-e1433.

    Not in our library10.1212/wnl.0000000000200001

  39. 39.

    Geser F, Robinson JL, Malunda JA, Xie SX, Clark CM, Kwong LK, et al. Pathological 43-kDa transactivation response DNA-binding protein in older adults with and without severe mental illness. Arch Neurol. 2010;67:1238-1250.

    Not in our library10.1001/archneurol.2010.254

  40. 40.

    Goossens J, Vanmechelen E, Trojanowski JQ, Lee VM, Van Broeckhoven C, van der Zee J, et al. TDP-43 as a possible biomarker for frontotemporal lobar degeneration: a systematic review of existing antibodies. Acta Neuropathol Commun. 2015;3:15.

    Not in our library10.1186/s40478-015-0195-1

  41. 41.

    Grothe MJ, Moscoso A, Silva-Rodriguez J, Lange C, Nho K, Saykin AJ, et al. Differential diagnosis of amnestic dementia patients based on an FDG-PET signature of autopsy-confirmed LATE-NC. Alzheimers Dement. 2022.

    Not in our library10.1002/alz.12763

  42. 42.

    Harrison WT, Lusk JB, Liu B, Ervin JF, Johnson KG, Green CL, et al. Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is independently associated with dementia and strongly associated with arteriolosclerosis in the oldest-old. Acta Neuropathol. 2021.

    Not in our library10.1007/s00401-021-02360-w

  43. 43.

    Hasegawa M, Arai T, Akiyama H, Nonaka T, Mori H, Hashimoto T, et al. TDP-43 is deposited in the Guam parkinsonism-dementia complex brains. Brain. 2007;130:1386-1394.

    Not in our library10.1093/brain/awm065

  44. 44.

    Hasegawa M, Arai T, Nonaka T, Kametani F, Yoshida M, Hashizume Y, et al. Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Ann Neurol. 2008;64:60-70.

    Not in our library10.1002/ana.21425

  45. 45.

    Hatanpaa KJ, Raisanen JM, Herndon E, Burns DK, Foong C, Habib AA, et al. Hippocampal sclerosis in dementia, epilepsy, and ischemic injury: differential vulnerability of hippocampal subfields. J Neuropathol Exp Neurol. 2014;73:136-142.

    Not in our library10.1097/opx.0000000000000170

  46. 46.

    Higashi S, Iseki E, Yamamoto R, Minegishi M, Hino H, Fujisawa K, et al. Concurrence of TDP-43, tau and alpha-synuclein pathology in brains of Alzheimer’s disease and dementia with Lewy bodies. Brain Res. 2007;1184:284-294.

    Not in our library10.1016/j.brainres.2007.09.048

  47. 47.

    Hokkanen SRK, Hunter S, Polvikoski TM, Keage HAD, Minett T, Matthews FE, Group CCS, et al. Hippocampal sclerosis, hippocampal neuron loss patterns and TDP-43 in the aged population. Brain Pathol. 2018;28:548-559.

    Not in our library10.1111/bpa.12556

  48. 48.

    Hokkanen SRK, Kero M, Kaivola K, Hunter S, Keage HAD, Kiviharju A, et al. Putative risk alleles for LATE-NC with hippocampal sclerosis in population-representative autopsy cohorts. Brain Pathol. 2020;30:364-372.

    Not in our library10.1111/bpa.12773

  49. 49.

    Hu WT, Josephs KA, Knopman DS, Boeve BF, Dickson DW, Petersen RC, et al. Temporal lobar predominance of TDP-43 neuronal cytoplasmic inclusions in Alzheimer disease. Acta Neuropathol. 2008;116:215-220.

    Not in our library10.1007/s00401-008-0400-4

  50. 50.

    Huang W, Zhou Y, Tu L, Ba Z, Huang J, Huang N, et al. TDP-43: from Alzheimer’s disease to limbic-predominant age-related TDP-43 encephalopathy. Front Mol Neurosci. 2020;13:26.

    Not in our library10.3389/fnmol.2020.00026

  51. 51.

    Hunter S, Hokkanen SRK, Keage HAD, Fleming J, Minett T, Polvikoski T, Cambridge City over 75s Cohort c, et al. TDP-43 related neuropathologies and phosphorylation state: associations with age and clinical Dementia in the Cambridge city over-75s cohort. J Alzheimers Dis. 2020;75:337-350.

    Not in our library10.3233/jad-191093

  52. 52.

    Ichimata S, Yoshida K, Visanji NP, Lang AE, Nishida N, Kovacs GG. Patterns of mixed pathologies in Down syndrome. J Alzheimers Dis. 2022;87:595-607.

    Not in our library10.3233/jad-215675

  53. 53.

    Igaz LM, Kwong LK, Xu Y, Truax AC, Uryu K, Neumann M, et al. Enrichment of C-terminal fragments in TAR DNA-binding protein-43 cytoplasmic inclusions in brain but not in spinal cord of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Am J Pathol. 2008;173:182-194.

    Not in our library10.2353/ajpath.2008.080003

  54. 54.

    Ighodaro ET, Jicha GA, Schmitt FA, Neltner JH, Abner EL, Kryscio RJ, et al. Hippocampal sclerosis of aging can be segmental: two cases and review of the literature. J Neuropathol Exp Neurol. 2015;74:642-652.

    Not in our library10.1097/nen.0000000000000204

  55. 55.

    Ighodaro ET, Nelson PT, Kukull WA, Schmitt FA, Abner EL, Caban-Holt A, et al. Challenges and considerations related to studying dementia in blacks/African Americans. J Alzheimers Dis. 2017;60:1-10.

    Not in our library10.3233/jad-170242

  56. 56.

    Ihara R, Vincent BD, Baxter MR, Franklin EE, Hassenstab JJ, Xiong C, et al. Relative neuron loss in hippocampal sclerosis of aging and Alzheimer’s disease. Ann Neurol. 2018;84:741-753.

    Not in our library10.1002/ana.25344

  57. 57.

    Jamerlan A, An SSA. The influence of Abeta-dependent and independent pathways on TDP-43 proteinopathy in Alzheimer’s disease: a possible connection to LATE-NC. Neurobiol Aging. 2020;95:161-167.

    Not in our library10.1016/j.neurobiolaging.2020.06.020

  58. 58.

    James BD, Wilson RS, Boyle PA, Trojanowski JQ, Bennett DA, Schneider JA. TDP-43 stage, mixed pathologies, and clinical Alzheimer’s-type dementia. Brain. 2016;139:2983-2993.

    Not in our library10.1093/brain/aww224

  59. 59.

    Jellinger KA. Hippocampal sclerosis: a common pathological feature of dementia in very old humans. Acta Neuropathol. 1994;88:599.

    Not in our library10.1007/bf00296500

  60. 60.

    Johnson VE, Stewart W, Trojanowski JQ, Smith DH. Acute and chronically increased immunoreactivity to phosphorylation-independent but not pathological TDP-43 after a single traumatic brain injury in humans. Acta Neuropathol. 2011;122:715-726.

    Not in our library10.1007/s00401-011-0909-9

  61. 61.

    Josephs KA, Mackenzie I, Frosch MP, Bigio EH, Neumann M, Arai T, et al. LATE to the PART-y. Brain. 2019;142:e47.

    Not in our library10.1093/brain/awz224

  62. 62.

    Josephs KA, Murray ME, Tosakulwong N, Weigand SD, Serie AM, Perkerson RB, et al. Pathological, imaging and genetic characteristics support the existence of distinct TDP-43 types in non-FTLD brains. Acta Neuropathol. 2019;137:227-238.

    Not in our library10.1007/s00401-018-1951-7

  63. 63.

    Josephs KA, Murray ME, Whitwell JL, Parisi JE, Petrucelli L, Jack CR, et al. Staging TDP-43 pathology in Alzheimer’s disease. Acta Neuropathol. 2014;127:441-450.

    Not in our library10.1007/s00401-013-1211-9

  64. 64.

    Josephs KA, Murray ME, Whitwell JL, Tosakulwong N, Weigand SD, Petrucelli L, et al. Updated TDP-43 in Alzheimer’s disease staging scheme. Acta Neuropathol. 2016;131:571-585.

    Not in our library10.1007/s00401-016-1537-1

  65. 65.

    Josephs KA, Stroh A, Dugger B, Dickson DW. Evaluation of subcortical pathology and clinical correlations in FTLD-U subtypes. Acta Neuropathol. 2009;118:349-358.

    Not in our library10.1007/s00401-009-0547-7

  66. 66.

    Josephs KA, Whitwell JL, Knopman DS, Hu WT, Stroh DA, Baker M, et al. Abnormal TDP-43 immunoreactivity in AD modifies clinicopathologic and radiologic phenotype. Neurology. 2008;70:1850-1857.

    Not in our library10.1212/01.wnl.0000304041.09418.b1

  67. 67.

    Josephs KA, Whitwell JL, Tosakulwong N, Weigand SD, Murray ME, Liesinger AM, et al. TAR DNA-binding protein 43 and pathological subtype of Alzheimer’s disease impact clinical features. Ann Neurol. 2015;78:697-709.

    Not in our library10.1002/ana.24493

  68. 68.

    Josephs KA, Whitwell JL, Weigand SD, Murray ME, Tosakulwong N, Liesinger AM, et al. TDP-43 is a key player in the clinical features associated with Alzheimer’s disease. Acta Neuropathol. 2014;127:811-824.

    Not in our library10.1007/s00401-014-1269-z

  69. 69.

    Kadokura A, Yamazaki T, Kakuda S, Makioka K, Lemere CA, Fujita Y, et al. Phosphorylation-dependent TDP-43 antibody detects intraneuronal dot-like structures showing morphological characters of granulovacuolar degeneration. Neurosci Lett. 2009;463:87-92.

    Not in our library10.1016/j.neulet.2009.06.024

  70. 70.

    Kadokura A, Yamazaki T, Lemere CA, Takatama M, Okamoto K. Regional distribution of TDP-43 inclusions in Alzheimer disease (AD) brains: their relation to AD common pathology. Neuropathology. 2009;29:566-573.

    Not in our library10.1111/j.1440-1789.2009.01017.x

  71. 71.
    Dichotomous scoring of TDP-43 proteinopathy from specific brain regions in 27 academic research centers: associations with Alzheimer’s disease and cerebrovascular disease pathologies · 2018
    Not checked
  72. 72.

    Keage HA, Hunter S, Matthews FE, Ince PG, Hodges J, Hokkanen SR, et al. TDP-43 pathology in the population: prevalence and associations with dementia and age. J Alzheimers Dis. 2014;42:641-650.

    Not in our library10.3233/jad-132351

  73. 73.

    Kero M, Raunio A, Polvikoski T, Tienari PJ, Paetau A, Myllykangas L. Hippocampal sclerosis in the oldest old: a finnish population-based study. J Alzheimers Dis. 2018;63:263-272.

    Not in our library10.3233/jad-171068

  74. 74.
    Characterization of mitochondrial DNA quantity and quality in the human aged and Alzheimer’s disease brain · 2021
    Not checked
  75. 75.

    Kokubo Y, Morimoto S, Sasaki R, Hasegawa M, Ishiura H, Tsuji S, et al. An immigrant family with Kii amyotrophic lateral sclerosis/parkinsonism-dementia complex. Neurol Sci. 2022;43:1423-1425.

    Not in our library10.1007/s10072-021-05737-7

  76. 76.

    Koper MJ, Tome SO, Gawor K, Belet A, Van Schoor E, Schaeverbeke J, et al. LATE-NC aggravates GVD-mediated necroptosis in Alzheimer’s disease. Acta Neuropathol Commun. 2022;10:128.

    Not in our library10.1186/s40478-022-01432-6

  77. 77.

    Koper MJ, Van Schoor E, Ospitalieri S, Vandenberghe R, Vandenbulcke M, von Arnim CAF, et al. Necrosome complex detected in granulovacuolar degeneration is associated with neuronal loss in Alzheimer’s disease. Acta Neuropathol. 2020;139:463-484.

    Not in our library10.1007/s00401-019-02103-y

  78. 78.

    Koyano S, Yagishita S, Tada M, Doi H, Uchihara T, Tanaka F. Parallel appearance of polyglutamine and transactivation-responsive DNA-binding protein 43 and their complementary subcellular localization in brains of patients with spinocerebellar ataxia type 2. J Neuropathol Exp Neurol. 2022;81:535-544.

    Not in our library10.1093/jnen/nlac032

  79. 79.

    Kwong LK, Irwin DJ, Walker AK, Xu Y, Riddle DM, Trojanowski JQ, et al. Novel monoclonal antibodies to normal and pathologically altered human TDP-43 proteins. Acta Neuropathol Commun. 2014;2:33.

    Not in our library10.1186/2051-5960-2-33

  80. 80.

    Lachner C, Day GS, Camsari GB, Kouri N, Ertekin-Taner N, Boeve BF et al (2022) Cancer and Vascular Comorbidity Effects on Dementia Risk and Neuropathology in the Oldest- Old. J Alzheimers Dis. 90(1):405-417. 10.3233/JAD-220440

    Not in our library10.3233/jad-220440

  81. 81.

    Latimer CS, Burke BT, Liachko NF, Currey HN, Kilgore MD, Gibbons LE, et al. Resistance and resilience to Alzheimer's disease pathology are associated with reduced cortical pTau and absence of limbic-predominant age-related TDP-43 encephalopathy in a community-based cohort. Acta Neuropathol Commun. 2019;7:91.

    Not in our library10.1186/s40478-019-0743-1

  82. 82.

    Lee EB. Integrated neurodegenerative disease autopsy diagnosis. Acta Neuropathol. 2018;135:643-646.

    Not in our library10.1007/s00401-018-1827-x

  83. 83.

    Lee EB, Lee VM, Trojanowski JQ, Neumann M. TDP-43 immunoreactivity in anoxic, ischemic and neoplastic lesions of the central nervous system. Acta Neuropathol. 2008;115:305-311.

    Not in our library10.1007/s00401-007-0331-5

  84. 84.

    Lee EB, Porta S, Michael Baer G, Xu Y, Suh E, Kwong LK, et al. Expansion of the classification of FTLD-TDP: distinct pathology associated with rapidly progressive frontotemporal degeneration. Acta Neuropathol. 2017;134:65-78.

    Not in our library10.1007/s00401-017-1679-9

  85. 85.

    Leverenz JB, Agustin CM, Tsuang D, Peskind ER, Edland SD, Nochlin D, et al. Clinical and neuropathological characteristics of hippocampal sclerosis: a community-based study. Arch Neurol. 2002;59:1099-1106.

    Not in our library10.1001/archneur.59.7.1099

  86. 86.

    Leverenz JB, Lipton AM. Clinical aspects of hippocampal sclerosis. Handb Clin Neurol. 2008;89:565-567.

    Not in our library10.1016/s0072-9752(07)01252-3

  87. 87.

    Lin WL, Castanedes-Casey M, Dickson DW. Transactivation response DNA-binding protein 43 microvasculopathy in frontotemporal degeneration and familial Lewy body disease. J Neuropathol Exp Neurol. 2009;68:1167-1176.

    Not in our library10.1097/nen.0b013e3181baacec

  88. 88.

    Lopez OL, Kofler J, Chang Y, Berman SB, Becker JT, Sweet RA, et al. Hippocampal sclerosis, TDP-43, and the duration of the symptoms of dementia of AD patients. Ann Clin Transl Neurol. 2020;7:1546-1556.

    Not in our library10.1002/acn3.51135

  89. 89.

    Mackenzie IR, Frick P, Neumann M. The neuropathology associated with repeat expansions in the C9ORF72 gene. Acta Neuropathol. 2014;127:347-357.

    Not in our library10.1007/s00401-013-1232-4

  90. 90.

    Mackenzie IR, Neumann M. Reappraisal of TDP-43 pathology in FTLD-U subtypes. Acta Neuropathol. 2017;134:79-96.

    Not in our library10.1007/s00401-017-1716-8

  91. 91.

    Mackenzie IR, Neumann M. Subcortical TDP-43 pathology patterns validate cortical FTLD-TDP subtypes and demonstrate unique aspects of C9orf72 mutation cases. Acta Neuropathol. 2020;139:83-98.

    Not in our library10.1007/s00401-019-02070-4

  92. 92.

    Mackenzie IR, Neumann M, Baborie A, Sampathu DM, Du Plessis D, Jaros E, et al. A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol. 2011;122:111-113.

    Not in our library10.1007/s00401-011-0845-8

  93. 93.

    Mackenzie IR, Neumann M, Bigio EH, Cairns NJ, Alafuzoff I, Kril J, et al. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol. 2010;119:1-4.

    Not in our library10.1007/s00401-009-0612-2

  94. 94.

    Mackenzie IR, Neumann M, Bigio EH, Cairns NJ, Alafuzoff I, Kril J, et al. Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations. Acta Neuropathol. 2009;117:15-18.

    Not in our library10.1007/s00401-008-0460-5

  95. 95.

    McAleese KE, Walker L, Erskine D, Johnson M, Koss D, Thomas AJ, et al. Concomitant LATE-NC in Alzheimer’s disease is not associated with increased tau or amyloid-beta pathological burden. Neuropathol Appl Neurobiol. 2020;46:722-734.

    Not in our library10.1111/nan.12664

  96. 96.
    The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy · 2015
    No notice
  97. 97.

    McKee AC, Gavett BE, Stern RA, Nowinski CJ, Cantu RC, Kowall NW, et al. TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuropathol Exp Neurol. 2010;69:918-929.

    Not in our library10.1097/nen.0b013e3181ee7d85

  98. 98.

    Melikyan ZA, Corrada MM, Leiby AM, Sajjadi SA, Bukhari S, Montine TJ, et al. Cognitive resilience to three dementia-related neuropathologies in an oldest-old man: a case report from the 90+ study. Neurobiol Aging. 2022;116:12-15.

    Not in our library10.1016/j.neurobiolaging.2022.03.009

  99. 99.

    Mol MO, van Rooij JGJ, Wong TH, Melhem S, Verkerk A, Kievit AJA, et al. Underlying genetic variation in familial frontotemporal dementia: sequencing of 198 patients. Neurobiol Aging. 2021;97:148e149-148e116.

    Not in our library10.1016/j.neurobiolaging.2020.07.014

  100. 100.

    Montine TJ, Corrada MM, Kawas C, Bukhari S, White L, Tian L, et al. Association of cognition and dementia with neuropathologic changes of Alzheimer disease and other conditions in the oldest-old. Neurology. 2022.

    Not in our library10.1212/wnl.0000000000200832

  101. 101.

    Murakami A, Koga S, Sekiya H, Oskarsson B, Boylan K, Petrucelli L, et al. Old age amyotrophic lateral sclerosis and limbic TDP-43 pathology. Brain Pathol. 2022.

    Not in our library10.1111/bpa.13100

  102. 102.

    Murray ME, Bieniek KF, Banks Greenberg M, DeJesus-Hernandez M, Rutherford NJ, van Blitterswijk M, et al. Progressive amnestic dementia, hippocampal sclerosis, and mutation in C9ORF72. Acta Neuropathol. 2013;126:545-554.

    Not in our library10.1007/s00401-013-1161-2

  103. 103.

    Murray ME, Cannon A, Graff-Radford NR, Liesinger AM, Rutherford NJ, Ross OA, et al. Differential clinicopathologic and genetic features of late-onset amnestic dementias. Acta Neuropathol. 2014;128:411-421.

    Not in our library10.1007/s00401-014-1302-2

  104. 104.

    Nag S, Barnes LL, Yu L, Wilson RS, Bennett DA, Schneider JA. Limbic-predominant age-related TDP-43 encephalopathy in Black and White decedents. Neurology. 2020;95:e2056-e2064.

    Not in our library10.1212/wnl.0000000000010602

  105. 105.
    TDP-43 pathology in anterior temporal pole cortex in aging and Alzheimer’s disease · 2018
    No notice
  106. 106.

    Nag S, Yu L, Capuano AW, Wilson RS, Leurgans SE, Bennett DA, et al. Hippocampal sclerosis and TDP-43 pathology in aging and Alzheimer disease. Ann Neurol. 2015;77:942-952.

    Not in our library10.1002/ana.24388

  107. 107.

    Nag S, Yu L, Wilson RS, Chen EY, Bennett DA, Schneider JA. TDP-43 pathology and memory impairment in elders without pathologic diagnoses of AD or FTLD. Neurology. 2017;88:653-660.

    Not in our library10.1212/wnl.0000000000003610

  108. 108.

    Nascimento C, Di Lorenzo Alho AT, Bazan Conceicao Amaral C, Leite REP, Nitrini R, Jacob-Filho W, et al. Prevalence of transactive response DNA-binding protein 43 (TDP-43) proteinopathy in cognitively normal older adults: systematic review and meta-analysis. Neuropathol Appl Neurobiol. 2018;44:286-297.

    Not in our library10.1111/nan.12430

  109. 109.

    Nascimento C, Suemoto CK, Rodriguez RD, Alho AT, Leite RP, Farfel JM, et al. Higher prevalence of TDP-43 proteinopathy in cognitively normal asians: a clinicopathological study on a multiethnic sample. Brain Pathol. 2016;26:177-185.

    Not in our library10.1111/bpa.12296

  110. 110.

    Nelson PT, Abner EL, Patel E, Anderson S, Wilcock DM, Kryscio RJ, et al. The amygdala as a locus of pathologic misfolding in neurodegenerative diseases. J Neuropathol Exp Neurol. 2018;77:2-20.

    Not in our library10.1093/jnen/nlx099

  111. 111.

    Nelson PT, Abner EL, Schmitt FA, Kryscio RJ, Jicha GA, Smith CD, et al. Modeling the association between 43 different clinical and pathological variables and the severity of cognitive impairment in a large autopsy cohort of elderly persons. Brain Pathol. 2010;20:66-79.

    Not in our library10.1111/j.1750-3639.2008.00244.x

  112. 112.

    Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol. 2012;71:362-381.

    Not in our library10.1097/nen.0b013e31825018f7

  113. 113.

    Nelson PT, Brayne C, Flanagan ME, Abner EL, Agrawal S, Attems J, et al. Frequency of LATE neuropathologic change across the spectrum of Alzheimer’s disease neuropathology: combined data from 13 community-based or population-based autopsy cohorts. Acta Neuropathol. 2022.

    Not in our library10.1007/s00401-022-02444-1

  114. 114.

    Nelson PT, Dickson DW, Trojanowski JQ, Jack CR, Boyle PA, Arfanakis K, et al. Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report. Brain. 2019.

    Not in our library10.1093/brain/awz099

  115. 115.

    Nelson PT, Dickson DW, Trojanowski JQ, Jack CR, Boyle PA, Arfanakis K, et al. Reply: LATE to the PART-y. Brain. 2019;142:e48.

    Not in our library10.1093/brain/awz226

  116. 116.

    Nelson PT, Gal Z, Wang WX, Niedowicz DM, Artiushin SC, Wycoff S, et al. TDP-43 proteinopathy in aging: Associations with risk-associated gene variants and with brain parenchymal thyroid hormone levels. Neurobiol Dis. 2019;125:67-76.

    Not in our library10.1016/j.nbd.2019.01.013

  117. 117.

    Nelson PT, Schmitt FA, Lin Y, Abner EL, Jicha GA, Patel E, et al. Hippocampal sclerosis in advanced age: clinical and pathological features. Brain. 2011;134:1506-1518.

    Not in our library10.1093/brain/awr053

  118. 118.

    Nelson PT, Smith CD, Abner EL, Wilfred BJ, Wang WX, Neltner JH, et al. Hippocampal sclerosis of aging, a prevalent and high-morbidity brain disease. Acta Neuropathol. 2013;126:161-177.

    Not in our library10.1007/s00401-013-1154-1

  119. 119.

    Neumann M, Frick P, Paron F, Kosten J, Buratti E, Mackenzie IR. Antibody against TDP-43 phosphorylated at serine 375 suggests conformational differences of TDP-43 aggregates among FTLD-TDP subtypes. Acta Neuropathol. 2020;140:645-658.

    Not in our library10.1007/s00401-020-02207-w

  120. 120.

    Neumann M, Kwong LK, Lee EB, Kremmer E, Flatley A, Xu Y, et al. Phosphorylation of S409/410 of TDP-43 is a consistent feature in all sporadic and familial forms of TDP-43 proteinopathies. Acta Neuropathol. 2009;117:137-149.

    Not in our library10.1007/s00401-008-0477-9

  121. 121.

    Neumann M, Lee EB, Mackenzie IR. Frontotemporal lobar degeneration TDP-43-immunoreactive pathological subtypes: clinical and mechanistic significance. Adv Exp Med Biol. 2021;1281:201-217.

    Not in our library10.1007/978-3-030-51140-1_13

  122. 122.

    Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314:130-133.

    Not in our library10.1126/science.1134108

  123. 123.
    Neuropathology studies of dementia in US persons other than non-Hispanic whites · 2022
    Not checked
  124. 124.

    Nishihira Y, Gefen T, Mao Q, Appin C, Kohler M, Walker J, et al. Revisiting the utility of TDP-43 immunoreactive (TDP-43-ir) pathology to classify FTLD-TDP subtypes. Acta Neuropathol. 2019;138:167-169.

    Not in our library10.1007/s00401-019-02024-w

  125. 125.

    Pao WC, Dickson DW, Crook JE, Finch NA, Rademakers R, Graff-Radford NR. Hippocampal sclerosis in the elderly: genetic and pathologic findings, some mimicking Alzheimer disease clinically. Alzheimer Dis Assoc Disord. 2011;25:364-368.

    Not in our library10.1097/wad.0b013e31820f8f50

  126. 126.

    Postupna N, Rose SE, Gibbons LE, Coleman NM, Hellstern LL, Ritchie K, et al. The delayed neuropathological consequences of traumatic brain injury in a community-based sample. Front Neurol. 2021;12:624696.

    Not in our library10.3389/fneur.2021.624696

  127. 127.

    Power MC, Mormino E, Soldan A, James BD, Yu L, Armstrong NM, et al. Combined neuropathological pathways account for age-related risk of dementia. Ann Neurol. 2018;84:10-22.

    Not in our library10.1002/ana.25246

  128. 128.

    Prater KE, Latimer CS, Jayadev S. Glial TDP-43 and TDP-43 induced glial pathology, focus on neurodegenerative proteinopathy syndromes. Glia. 2022;70:239-255.

    Not in our library10.1002/glia.24096

  129. 129.

    Riku Y, Iwasaki Y, Ishigaki S, Akagi A, Hasegawa M, Nishioka K, et al. Motor neuron TDP-43 proteinopathy in progressive supranuclear palsy and corticobasal degeneration. Brain. 2022.

    Not in our library10.1093/brain/awac091

  130. 130.

    Robinson JL, Corrada MM, Kovacs GG, Dominique M, Caswell C, Xie SX, et al. Non-Alzheimer’s contributions to dementia and cognitive resilience in the 90+ study. Acta Neuropathol. 2018.

    Not in our library10.1007/s00401-018-1872-5

  131. 131.

    Robinson JL, Porta S, Garrett FG, Zhang P, Xie SX, Suh E, et al. Limbic-predominant age-related TDP-43 encephalopathy differs from frontotemporal lobar degeneration. Brain. 2020;143:2844-2857.

    Not in our library10.1093/brain/awaa219

  132. 132.

    Robinson JL, Richardson H, Xie SX, Suh E, Van Deerlin VM, Alfaro B, et al. The development and convergence of co-pathologies in Alzheimer’s disease. Brain. 2021;144:953-962.

    Not in our library10.1093/brain/awaa438

  133. 133.

    Sakuwa M, Adachi T, Suzuki Y, Yoshida K, Fukuda H, Miura H, et al. First Japanese autopsy case showing LRRK2 mutation G2019S and TDP-43 proteinopathy. Parkinsonism Relat Disord. 2021;91:85-87.

    Not in our library10.1016/j.parkreldis.2021.09.009

  134. 134.

    Saveri P, Magri S, Maderna E, Balistreri F, Lombardi R, Ciano C, et al. DNAJB2-related Charcot-Marie-Tooth disease type 2: pathomechanism insights and phenotypic spectrum widening. Eur J Neurol. 2022;29:2056-2065.

    Not in our library10.1111/ene.15326

  135. 135.

    Smirnov DS, Salmon DP, Galasko D, Edland SD, Pizzo DP, Goodwill V, et al. TDP-43 pathology exacerbates cognitive decline in primary age-related tauopathy. Ann neurol. 2022.

    Not in our library10.1002/ana.26438

  136. 136.

    Sommer W. Erkrankung des Ammon’s horn als aetiologis ches moment der epilepsien. Arch Psychiatr Nurs. 1880;10:631-675.

    Not in our library10.1007/bf02224538

  137. 137.

    Tan RH, Kril JJ, Fatima M, McGeachie A, McCann H, Shepherd C, et al. TDP-43 proteinopathies: pathological identification of brain regions differentiating clinical phenotypes. Brain. 2015;138:3110-3122.

    Not in our library10.1093/brain/awv220

  138. 138.

    Tazwar M, Evia AM, Tamhane AA, Ridwan AR, Leurgans SE, Bennett DA, et al. Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is associated with lower R2 relaxation rate: an ex-vivo MRI and pathology investigation. Neurobiol Aging. 2022;117:128-138.

    Not in our library10.1016/j.neurobiolaging.2022.05.009

  139. 139.

    Thal DR, Del Tredici K, Ludolph AC, Hoozemans JJ, Rozemuller AJ, Braak H, et al. Stages of granulovacuolar degeneration: their relation to Alzheimer's disease and chronic stress response. Acta Neuropathol. 2011;122:577-589.

    Not in our library10.1007/s00401-011-0871-6

  140. 140.

    Thal DR, Rub U, Orantes M, Braak H. Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology. 2002;58:1791-1800.

    Not in our library10.1212/wnl.58.12.1791

  141. 141.

    Thal DR, von Arnim C, Griffin WS, Yamaguchi H, Mrak RE, Attems J, et al. Pathology of clinical and preclinical Alzheimer’s disease. Eur Arch Psychiatry Clin Neurosci. 2013;263(Suppl 2):S137-145.

    Not in our library10.1007/s00406-013-0449-5

  142. 142.

    Thom M. Hippocampal sclerosis: progress since Sommer. Brain Pathol. 2009;19:565-572.

    Not in our library10.1111/j.1750-3639.2008.00201.x

  143. 143.
    Distinct molecular patterns of TDP-43 pathology in Alzheimer’s disease: relationship with clinical phenotypes · 2020
    Not checked
  144. 144.

    Trieu T, Sajjadi SA, Kawas CH, Nelson PT, Corrada MM. Risk factors of hippocampal sclerosis in the oldest old: the 90+ study. Neurology. 2018;91:e1788-e1798.

    Not in our library10.1212/wnl.0000000000006455

  145. 145.

    Troncoso JC, Kawas CH, Chang CK, Folstein MF, Hedreen JC. Lack of association of the apoE4 allele with hippocampal sclerosis dementia. Neurosci Lett. 1996;204:138-140.

    Not in our library10.1016/0304-3940(96)12331-4

  146. 146.
    Incidence and extent of TDP-43 accumulation in aging human brain · 2015
    No notice
  147. 147.

    Uemura MT, Robinson JL, Cousins KAQ, Tropea TF, Kargilis DC, McBride JD, et al. Distinct characteristics of limbic-predominant age-related TDP-43 encephalopathy in Lewy body disease. Acta Neuropathol. 2021.

    Not in our library10.1007/s00401-021-02383-3

  148. 148.

    Uryu K, Nakashima-Yasuda H, Forman MS, Kwong LK, Clark CM, Grossman M, et al. Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies. J Neuropathol Exp Neurol. 2008;67:555-564.

    Not in our library10.1097/nen.0b013e31817713b5

  149. 149.

    Uryu K, Nakashima-Yasuda H, Forman MS, Kwong LK, Clark CM, Grossman M, et al. Concomitant TAR-DNA-binding in Alzheimer disease and protein 43 pathology is present corticobasal degeneration but not in other tauopathies. J Neuropathol Exp Neurol. 2008;67:555-564.

    Not in our library10.1097/nen.0b013e31817713b5

  150. 150.

    Van Mossevelde S, Engelborghs S, van der Zee J, Van Broeckhoven C. Genotype-phenotype links in frontotemporal lobar degeneration. Nat Rev Neurol. 2018;14:363-378.

    Not in our library10.1038/s41582-018-0009-8

  151. 151.

    Van Schoor E, Koper MJ, Ospitalieri S, Dedeene L, Tome SO, Vandenberghe R, et al. Necrosome-positive granulovacuolar degeneration is associated with TDP-43 pathological lesions in the hippocampus of ALS/FTLD cases. Neuropathol Appl Neurobiol. 2021;47:328-345.

    Not in our library10.1111/nan.12668

  152. 152.

    Walker AK, Daniels CM, Goldman JE, Trojanowski JQ, Lee VM, Messing A. Astrocytic TDP-43 pathology in Alexander disease. J Neurosci. 2014;34:6448-6458.

    Not in our library10.1523/jneurosci.0248-14.2014

  153. 153.

    Wang SJ, Guo Y, Ervin JF, Lusk JB, Luo S. Neuropathological associations of limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) differ between the oldest-old and younger-old. Acta Neuropathol. 2022;144:45-57.

    Not in our library10.1007/s00401-022-02432-5

  154. 154.

    Wegiel J, Flory M, Kuchna I, Nowicki K, Wegiel J, Ma SY, et al. Developmental deficits and staging of dynamics of age associated Alzheimer’s disease neurodegeneration and neuronal loss in subjects with Down syndrome. Acta Neuropathol Commun. 2022;10:2.

    Not in our library10.1186/s40478-021-01300-9

  155. 155.

    White L, Petrovitch H, Hardman J, Nelson J, Davis DG, Ross GW, et al. Cerebrovascular pathology and dementia in autopsied Honolulu-Asia aging study participants. Ann NY Acad Sci. 2002;977:9-23.

    Not in our library10.1111/j.1749-6632.2002.tb04794.x

  156. 156.

    Wider C, Dickson DW, Stoessl AJ, Tsuboi Y, Chapon F, Gutmann L, et al. Pallidonigral TDP-43 pathology in perry syndrome. Parkinsonism Relat Disord. 2009;15:281-286.

    Not in our library10.1016/j.parkreldis.2008.07.005

  157. 157.

    Yamashita R, Beck G, Yonenobu Y, Inoue K, Mitsutake A, Ishiura H, et al. TDP-43 proteinopathy presenting with typical symptoms of Parkinson’s disease. Mov Disord. 2022.

    Not in our library10.1002/mds.29048

  158. 158.

    Zabar Y, Carson KA, Troncoso JC, Kawas CH. Dementia due to hippocampal sclerosis: clinical features and comparison to Alzheimer’s disease. Neurology. 1998;50(4):A59-A60.

    Not in our library

  159. 159.

    Zarow C, Sitzer TE, Chui HC. Understanding hippocampal sclerosis in the elderly: epidemiology, characterization, and diagnostic issues. Curr Neurol Neurosci Rep. 2008;8:363-370.

    Not in our library10.1007/s11910-008-0057-3

  160. 160.

    Zarow C, Vinters HV, Ellis WG, Weiner MW, Mungas D, White L, et al. Correlates of hippocampal neuron number in Alzheimer’s disease and ischemic vascular dementia. Ann Neurol. 2005;57:896-903.

    Not in our library10.1002/ana.20503

  161. 161.

    Zarow C, Weiner MW, Ellis WG, Chui HC. Prevalence, laterality, and comorbidity of hippocampal sclerosis in an autopsy sample. Brain Behav. 2012;2:435-442.

    Not in our library10.1002/brb3.66

  162. 162.

    Zhang X, Sun B, Wang X, Lu H, Shao F, Rozemuller AJM, et al. Phosphorylated TDP-43 staging of primary age-related tauopathy. Neurosci Bull. 2018.

    Not in our library10.1007/s12264-018-0300-0

Cited by papers we hold 1

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.

Are you an author?

Is this your paper?

Claim it to add your note and be paid when agents cite it. Free.