Hippocampal Sclerosis Pathology Research Articles

Mesial temporal lobe epilepsy and hippocampal sclerosis associated with BRAFV600E mutant neurons in the Cornu Ammonis: an uncertain pathogenesis and a diagnostic challenge.

Mesial temporal lobe epilepsy (MTLE) is a common cause of seizures, and hippocampal sclerosis (HS) is the predominant subtype. BRAFV600E mutations in MTLE-HS have only been reported infrequently. Herein, we illustrate the neurologic, radiological, and histopathological details of a patient with MTLE-HS and BRAFV600E mutant neurons. A 31-year-old male with medically refractory epilepsy presented with magnetic resonance imaging (MRI) and electroencephalography (EEG) findings typical of mesial temporal sclerosis without a mass lesion. The surgical specimens showed ILAE Type 1 HS with neurons immunopositive for BRAFV600E mutant protein distributed along the Cornu Ammonis (CA) curvature. Instead of the normal mostly perpendicular orientation of pyramidal neurons relative to the hippocampal surface, the BRAF mutant neurons were often oriented in a parallel manner. On CD34 immunostaining, sparse clusters or nodules of CD34+ stellate cells and single immunopositive stellate cells were identified. BRAFV600E or CD34 immunopositive cells were less than 1 % of total cells. The patient responded well to surgery with no further seizures after 2 years and occasional auras. Hippocampal BRAF mutant non-expansive lesion (HBNL) has been used to describe such lesions with preserved cytoarchitecture and without overt tumor mass. Others may argue for the dual pathology of HS with early ganglioglioma. Whether pre-neoplastic lesions or early tumors, these cases are important for understanding early glioneuronal tumorigenesis and suggest that BRAFV600E studies should be routinely performed on MTLE-HS cases in the setting of clinical trials. With next-generation sequencing, a FANCL deletion was detected in almost half of the alleles in our case, suggesting that many of the histologically normal-appearing cells of the hippocampus contain this alteration. FANCL mutations can result in cytogenetic anomalies and defective DNA repair and therefore may underlie the development of a low frequency BRAF alteration.

Antemortem MRI detects atrophy related to hippocampal sclerosis pathology in the oldest‐old but side matters: The 90+ Study

AbstractBackgroundHippocampal sclerosis of aging (HS) is the neuropathological finding of neuronal death and gliosis in the hippocampus. HS is more prevalent, and associated with dementia, in the oldest‐old (those = 90 years), but cannot be diagnosed during life. HS is often unilateral and can be missed if only one brain hemisphere is assessed, which is standard neuropathological practice but may hamper the development of biomarkers for HS. Here we examined hippocampal volumes from antemortem MRI in relation to bilaterally‐assessed HS at autopsy, accounting for side, in oldest‐old participants from The 90+ Study.MethodWe included participants with both autopsy and antemortem MRI data. All participants had neuropathological assessment of HS for both hemispheres. We performed hippocampal segmentation of antemortem 3D‐T1w MRIs using FreeSurfer, adjusting by intracranial volume. We compared total average (average of left and right), left, and right, hippocampal volumes between those with and those without HS. For HS participants we combined the hippocampal volumes from each hemisphere with HS into a single group and from each hemisphere without HS into a separate group, and compared these to the average hippocampal volumes from those without HS. We used Welch’s T‐tests for comparisons and report Cohen’s d effect sizes.ResultParticipant characteristics (N = 89) are shown in Table‐1. All HS was unilateral (Right = 6, Left = 4). Average total hippocampal volume was not significantly different between those with and those without HS (d = 0.51, P = 0.11, Figure‐1a). However, right hippocampal volumes were significantly related to right‐sided HS with a large effect size (P = 0.002, d = 1.02) and left hippocampal volumes had a large effect size for left‐sided HS (P = 0.17, d = 0.90, Figure‐1c), whereas this was not the case when HS was on the opposite side (P>0.3, d<0.4, Figure‐1b,c). Combined HS participant hippocampal volumes for the side with HS (d = 0.98, P = 0.003), but not the side without HS (d = ‐0.14, P = 0.7), were different from volumes in participants without HS (Figure‐1d).ConclusionOur results suggest HS is detectable by atrophy on antemortem MRI, but most strongly when using hippocampal volumes from the same side as HS. Researchers should consider assessing and documenting the presence of HS in both hemispheres to accelerate development of neuroimaging biomarkers for HS.

More extensive structural damage in temporal lobe epilepsy with hippocampal sclerosis type 1

ObjectiveTo explore clinical and structural differences between mesial temporal lobe epilepsy (mTLE) patients with different hippocampal sclerosis (HS) subtypes. MethodsHigh-resolution T1-weighted MRI and diffusion tensor imaging data were obtained in 41 refractory mTLE patients and 52 age- and sex-matched healthy controls. Postoperative histopathological examination confirmed HS type 1 in 30 patients and HS type 2 in eleven patients. Clinical features, postoperative seizure outcomes, hippocampal subfields volumes, fractional anisotropy (FA) values of white matter regions and graph theory parameters were explored and compared between the HS type 1 and HS type 2 groups. ResultsNo significant differences in clinical features and postsurgical seizure outcomes were found between the HS type 1 and type 2 groups. However, the HS type 1 group showed extra atrophy in ipsilateral parasubiculum than healthy controls and more severe atrophy in contralateral hippocampal fissure than the HS type 2 group. More extensive FA decrease were also observed in the HS type 1 group, involving ipsilateral optic radiation, superior fronto-occipital fasciculus, contralateral uncinate fasciculus, tapetum, bilateral hippocampal cingulum, corona radiata, etc. Furthermore, in spite of similar impairments in characteristic path length, global efficiency and local efficiency in two HS groups, the HS type 1 group showed additional decrease of clustering coefficient than healthy controls. ConclusionsHS type 1 and 2 groups had similar clinical characteristics and postoperative seizure outcomes. More widespread neuronal cell loss in the HS type 1 group contributed to more extensive structural damage and connectivity abnormality. These results shed new light on the imaging correlates of different HS pathology.

LATE-NC risk alleles (in TMEM106B, GRN, and ABCC9 genes) among persons with African ancestry.

Limbic-predominant age-related TDP-43 encephalopathy (LATE) affects approximately one-third of older individuals and is associated with cognitive impairment. However, there is a highly incomplete understanding of the genetic determinants of LATE neuropathologic changes (LATE-NC) in diverse populations. The defining neuropathologic feature of LATE-NC is TDP-43 proteinopathy, often with comorbid hippocampal sclerosis (HS). In terms of genetic risk factors, LATE-NC and/or HS are associated with single nucleotide variants (SNVs) in 3 genes-TMEM106B (rs1990622), GRN (rs5848), and ABCC9 (rs1914361 and rs701478). We evaluated these 3 genes in convenience samples of individuals of African ancestry. The allele frequencies of the LATE-associated alleles were significantly different between persons of primarily African (versus European) ancestry: In persons of African ancestry, the risk-associated alleles for TMEM106B and ABCC9 were less frequent, whereas the risk allele in GRN was more frequent. We performed an exploratory analysis of data from African-American subjects processed by the Alzheimer's Disease Genomics Consortium, with a subset of African-American participants (n = 166) having corroborating neuropathologic data through the National Alzheimer's Coordinating Center (NACC). In this limited-size sample, the ABCC9/rs1914361 SNV was associated with HS pathology. More work is required concerning the genetic factors influencing non-Alzheimer disease pathology such as LATE-NC in diverse cohorts.

Multiple gene variants linked to Alzheimer's-type clinical dementia via GWAS are also associated with non-Alzheimer's neuropathologic entities

The classic pathologic hallmarks of Alzheimer's disease (AD) are amyloid plaques and neurofibrillary tangles (AD neuropathologic changes, or ADNC). However, brains from individuals clinically diagnosed with “AD-type” (amnestic) dementia usually harbor heterogeneous neuropathologies in addition to, or other than, ADNC. We hypothesized that some AD-type dementia associated genetic single nucleotide variants (SNVs) identified from large genomewide association studies (GWAS) were associated with non-ADNC neuropathologies. To test this hypothesis, we analyzed data from multiple studies with available genotype and neuropathologic phenotype information. Clinical AD/dementia risk alleles of interest were derived from the very large GWAS by Bellenguez et al. (2022) who reported 83 clinical AD/dementia-linked SNVs in addition to the APOE risk alleles. To query the pathologic phenotypes associated with variation of those SNVs, National Alzheimer's disease Coordinating Center (NACC) neuropathologic data were linked to AD Sequencing Project (ADSP) and AD Genomics Consortium (ADGC) data. Separate data were obtained from the harmonized Religious Orders Study and the Rush Memory and Aging Project (ROSMAP). A total of 4811 European participants had at least ADNC neuropathology data and also genotype data available; data were meta-analyzed across cohorts. As expected, a subset of dementia-associated SNVs were associated with ADNC risk in Europeans—e.g., BIN1, PICALM, CR1, MME, and COX7C. Other gene variants linked to (clinical) AD dementia were associated with non-ADNC pathologies. For example, the associations of GRN and TMEM106B SNVs with limbic-predominant age-related TDP-43 neuropathologic changes (LATE-NC) were replicated. In addition, SNVs in TNIP1 and WNT3 previously reported as AD-related were instead associated with hippocampal sclerosis pathology. Some genotype/neuropathology association trends were not statistically significant at P < 0.05 after correcting for multiple testing, but were intriguing. For example, variants in SORL1 and TPCN1 showed trends for association with LATE-NC whereas Lewy body pathology trended toward association with USP6NL and BIN1 gene variants. A smaller cohort of non-European subjects (n = 273, approximately one-half of whom were African-Americans) provided the basis for additional exploratory analyses. Overall, these findings were consistent with the hypothesis that some genetic variants linked to AD dementia risk exert their affect by influencing non-ADNC neuropathologies.

A possible case of Limbic-predominant age-related TDP-43 encephalopathy (LATE) in a Black Female with caregiver burden and limited resources: A Novel Diagnosis with presentation similar to Alzheimer's

<h3>Introduction</h3> Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a proposed neurodegenerative disorder of older adults (typically >80 years old)⁽¹⁾. It presents primarily as an amnestic dementia and is thought to be due to a TDP-43 proteinopathy in limbic system structures, including the hippocampus. There could be coexisting hippocampal sclerosis pathology in some patients presenting with LATE. In community-based autopsy cohorts, ∼25% of brains had a sufficient burden of LATE-neuropathology changes (LATE- NC) to be associated with discernible cognitive impairment. (ADNC) ⁽³⁾. In a retrospective study described by Kapasi et Al, there exist a class I evidence that LATE-NC and Alzheimer's disease pathologic changes are associated with different trajectories of late-life cognitive decline. Persons with pure LATE-NC follow a slower trajectory compared to those with pure ADNC. LATE-neuropathology changes may be co-morbid with Alzheimer's disease neuropathological changes. Those with mixed LATE/ADNC have a steeper decline than individuals with either pathology alone ⁽⁴⁾. The following is a unique case presentation of a patient with possible LATE or a combination of LATE/AD NC as demonstrated by rapid amnestic dementia and changes in brain MRI. In addition, this case shows how the treatment is tailored based on family preference and available resources <h3>Methods</h3> A single patient case of interest was chosen and verbal consent was obtained from the patient. Our initial review was conducted with a literature search at Pubmed. 57 articles were retrieved which was narrowed down to 10 articles after irrelevant topics were excluded. The clinical presentation of the case was found to be correlated with the relevant reports in the research literature implying a possible rationale for LATE vs ADNC for the patient. <h3>Results</h3> Case presentation: This is a case of a 91-year-old female with no past psychiatric history, a medical history significant of HTN, and stable angina who presented to the memory clinic with a decline in short-term memory in the past 18 months that has progressively worsened over the past 6 -8 months. The patient would forget conversations and has been misplacing items at home. The patient would engage in dangerous behaviors to include forgetting the stove on. Also associated were neuropsychiatric symptoms of agitation, irritability, and insomnia. The patient became easily irritable and would attempt to hit others. These behaviors were all new to this patient and her family was very concerned. Taking care of her became increasingly challenging and they decided to consult professional help. The patient became increasingly dependent on all ADLs except feeding and toileting. She had been unable to perform all IADLS for the past two years. On MMSE, she scored 24/30 with most points lost in immediate recall. Further neuropsychiatric testing revealed deficiency in verbal fluency, clock drawing, delay recall, and word list learning. The MRI of the brain indicated a decrease in Hippocampal volume at 7 percentiles for her age as per NEUROQUANT evaluation; almost 2 standard deviations below the mean. Mild/moderate chronic white matter microvascular ischemic changes were also seen. No acute ischemia was noted. The caregiver burden was extremely high and memory medication was not a priority for the family. The family did not qualify for Medicaid and declined much-needed social services that could provide respite and promote social engagement. Paying out of pocket was a hindering factor. A low-dose second-generation antipsychotic was initiated with good remission of agitative symptoms. <h3>Conclusions</h3> The patient's advanced age, delayed onset of the cognitive impairment, precipitous memory decline, and the findings on brain MRI are suggestive of a possible diagnosis of LATE versus LATE ADNC. However, this diagnosis or other forms of dementia cannot be ruled out without a brain biopsy. This case indicates that further research on diagnosing and targeting patients with TDP-43 might greatly improve the disease burden. Furthermore, the differences in social-economic status can greatly add to disparities in dementia care. <h3>This research was funded by</h3> None

Limbic-Predominant Age-Related TDP-43 Encephalopathy: Medical and Pathologic Factors Associated With Comorbid Hippocampal Sclerosis.

Limbic-predominant age-related Tar DNA binding protein 43 (TDP-43) encephalopathy neuropathologic change (LATE-NC) is present in ≈25% of older persons' brains and is strongly associated with cognitive impairment. Hippocampal sclerosis (HS) pathology is often comorbid with LATE-NC, but the clinical and pathologic correlates of HS in LATE-NC are not well understood. This retrospective autopsy cohort study used data derived from the National Alzheimer's Coordinating Center Neuropathology Data Set, which included neurologic status, medical histories, and neuropathologic results. All autopsies were performed in 2014 or later. Among participants with LATE-NC, those who also had HS pathology were compared with those without HS with regard to candidate risk factors or common underlying diseases. Statistical significance was set at nominal p < 0.05 in this exploratory study. A total of 408 participants were included (n = 221 were LATE-NC+/HS-, n = 145 were LATE-NC+/HS+, and n = 42 were LATE-NC-/HS+). Most of the included LATE-NC+ participants were severely impaired cognitively (83.3% with dementia). Compared to HS- participants, LATE-NC+ participants with HS trended toward having worse cognitive status and scored lower on the Personal Care and Orientation domains (both p = 0.03). Among LATE-NC+ participants with Braak neurofibrillary tangle (NFT) stages 0 to IV (n = 88), HS+ participants were more impaired in the Memory and Orientation domains (both p = 0.02). There were no differences (HS+ compared with HS-) in the proportion with clinical histories of seizures, stroke, cardiac bypass procedures, diabetes, or hypertension. The HS+ group lacking TDP-43 proteinopathy (n = 42) was relatively likely to have had strokes (p = 0.03). When LATE-NC+ participants with or without HS were compared, there were no differences in Alzheimer disease neuropathologies (Thal β-amyloid phases or Braak NFT stages) or Lewy body pathologies. However, the HS+ group was less likely to have amygdala-restricted TDP-43 proteinopathy (LATE-NC stage 1) and more likely to have neocortical TDP-43 proteinopathy (LATE-NC stage 3) (p < 0.001). LATE-NC+ brains with HS also tended to have more severe circle of Willis atherosclerosis and arteriolosclerosis pathologies. In this cohort skewed toward participants with severe dementia, LATE-NC+ HS pathology was not associated with seizures or with Alzheimer-type pathologies. Rather, the presence of comorbid HS pathology was associated with more widespread TDP-43 proteinopathy and with more severe non-β-amyloid vessel wall pathologies.

Prognostic value of histopathologic pattern for long-term surgical outcomes of 198 patients with confirmed mesial temporal lobe epilepsy

Hippocampal sclerosis (HS) is the most common neuropathologic findings in patients with intractable temporal lobe epilepsy (TLE). The international league against epilepsy has proposed a new classification of HS based on pyramidal cell loss on different subfields to facilitate the study of HS pathology in patients after anterior temporal lobectomy (ATL), and the influence of these HS patterns on the prognosis of patients with TLE is contradictory. This study aims to investigate the relationship between different HS subtypes and postoperative seizure outcomes for intractable patients with TLE. From January 2008 to December 2018, we retrospectively reviewed 198 TLE patients with ATL surgery, and all patients had a complete preoperative evaluation, a specimen of hippocampal tissue after surgery, cognitive test after surgery, and more than 2 years of postoperative follow-up. The main findings were as follows: 1) temporal neocortical gray matter heterotopia were more common in the no-HS group; 2) HS type 1 was associated with a longer duration of epilepsy; 3) history of meningitis was the independent predictor of HS type 1; 4) no-HS patients experienced worse postoperative seizure outcomes than those with HS type1 and type 2, whereas no difference in seizure outcomes was obtained between HS type 1 and type 2; 5) no-HS patients were at increased risk for verbal memory decline after left hippocampal resection. The HS subtypes were associated with the prognosis of patients with TLE, and other variables were the predictors of different HS types. `Further study was to identify the HS subtypes by noninvasive evaluation to approve better postoperative outcomes.

Putative risk alleles for LATE-NC with hippocampal sclerosis in population-representative autopsy cohorts.

Limbic‐predominant age‐related TAR‐DNA‐binding protein‐43 (TDP‐43) encephalopathy with hippocampal sclerosis pathology (LATE‐NC + HS) is a neurodegenerative disorder characterized by severe hippocampal CA1 neuron loss and TDP‐43‐pathology, leading to cognitive dysfunction and dementia. Polymorphisms in GRN, TMEM106B and ABCC9 are proposed as LATE‐NC + HS risk factors in brain bank collections. To replicate these results in independent population‐representative cohorts, hippocampal sections from brains donated to three such studies (Cambridge City over 75‐Cohort [CC75C], Cognitive Function and Ageing Study [CFAS], and Vantaa 85+ Study) were stained with hematoxylin–eosin (n = 744) and anti‐pTDP‐43 (n = 713), and evaluated for LATE‐NC + HS and TDP‐43 pathology. Single nucleotide polymorphism genotypes in GRN rs5848, TMEM106B rs1990622 and ABCC9 rs704178 were determined. LATE‐NC + HS (n = 58) was significantly associated with the GRN rs5848 genotype (χ2(2) = 20.61, P < 0.001) and T‐allele (χ2(1) = 21.04, P < 0.001), and TMEM106B rs1990622 genotype (Fisher's exact test, P < 0.001) and A‐allele (χ2(1) = 25.75, P < 0.001). No differences in ABCC9 rs704178 genotype or allele frequency were found between LATE‐NC + HS and non‐LATE‐NC + HS neuropathology cases. Dentate gyrus TDP‐43 pathology associated with GRN and TMEM106B variations, but the association with TMEM106B nullified when LATE‐NC + HS cases were excluded. Our results indicate that GRN and TMEM106B are associated with severe loss of CA1 neurons in the aging brain, while ABCC9 was not confirmed as a genetic risk factor for LATE‐NC + HS. The association between TMEM106B and LATE‐NC + HS may be independent of dentate TDP‐43 pathology.

IMPACT OF TDP-43 AND HIPPOCAMPAL SCLEROSIS ON LATE-LIFE COGNITIVE DECLINE

There is increasing recognition of the role of TAR-DNA binding protein 43kDa (TDP-43) and hippocampal sclerosis (HS) pathology in AD and dementia. We studied TDP-43/HS pathology and the rate of decline in global cognition and 5 specific cognitive domains, and determined the impact of AD mixed with TDP-43 pathology on late-life cognitive decline Data came from 1,374 community-based older persons from the Religious Orders Study and the Rush Memory and Aging Project who completed detailed annual cognitive testing and systematic neuropathological examination to identify AD, TDP-43, HS, and other age-related pathologies. To assess distinct rates of cognitive decline in single and mixed pathology profiles, persons were categorized into 4 groups; (1) a group without TDP, HS, or AD pathology (n=378), (2) TDP with or without HS, and no AD (TDP/HS) (n=91), (3) AD without TDP/HS (n=535), and (4) AD with TDP/HS (AD/TDP or AD/TDP/HS) (n=352). Rates of cognitive decline by pathologic groupings were examined using mixed-effect models adjusted for age, sex, education, and other pathologies, followed by post-hoc comparisons. Compared to those without TDP, HS, or AD, those with TDP/HS and no AD had a faster decline in global cognition (p=0.007) and episodic memory (p<0.001); however compared to persons with isolated AD, the TDP/HS without AD group had slower decline in global cognition (p=0.02) and episodic memory (p=0.01). The mixed AD with TDP/HS group had faster decline in global cognition and all 5 cognitive domains, compared to the AD alone and TDP/HS groups. In subsequent analyses, persons with mixed AD/TDP/HS had significantly faster decline in global cognition (p=0.02) and individual cognitive domains, specifically episodic (p=0.01) and semantic memory (p=0.006), than those with mixed AD/TDP. These data show that TDP/HS without AD pathology contributes to late-life memory decline but this decline is slower than that seen in those with AD only. Mixed AD and TDP pathologies show an additive effect on decline, with mixed AD/TDP/HS showing faster decline in memory and language. These findings have important implications for the development of biomarkers and for prognosis of late-life cognitive decline.

Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report.

We describe a recently recognized disease entity, limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE neuropathological change (LATE-NC) is defined by a stereotypical TDP-43 proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer's-type dementia in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiology (LATE generally affects older subjects), and relatively restricted neuroanatomical distribution of TDP-43 proteinopathy. In community-based autopsy cohorts, ∼25% of brains had sufficient burden of LATE-NC to be associated with discernible cognitive impairment. Many subjects with LATE-NC have comorbid brain pathologies, often including amyloid-β plaques and tauopathy. Given that the 'oldest-old' are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognized impact on public health. For these reasons, a working group was convened to develop diagnostic criteria for LATE, aiming both to stimulate research and to promote awareness of this pathway to dementia. We report consensus-based recommendations including guidelines for diagnosis and staging of LATE-NC. For routine autopsy workup of LATE-NC, an anatomically-based preliminary staging scheme is proposed with TDP-43 immunohistochemistry on tissue from three brain areas, reflecting a hierarchical pattern of brain involvement: amygdala, hippocampus, and middle frontal gyrus. LATE-NC appears to affect the medial temporal lobe structures preferentially, but other areas also are impacted. Neuroimaging studies demonstrated that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex, and other brain regions. Genetic studies have thus far indicated five genes with risk alleles for LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, and APOE. The discovery of these genetic risk variants indicate that LATE shares pathogenetic mechanisms with both frontotemporal lobar degeneration and Alzheimer's disease, but also suggests disease-specific underlying mechanisms. Large gaps remain in our understanding of LATE. For advances in prevention, diagnosis, and treatment, there is an urgent need for research focused on LATE, including in vitro and animal models. An obstacle to clinical progress is lack of diagnostic tools, such as biofluid or neuroimaging biomarkers, for ante-mortem detection of LATE. Development of a disease biomarker would augment observational studies seeking to further define the risk factors, natural history, and clinical features of LATE, as well as eventual subject recruitment for targeted therapies in clinical trials.

Dichotomous scoring of TDP-43 proteinopathy from specific brain regions in 27 academic research centers: associations with Alzheimer\u2019s disease and cerebrovascular disease pathologies

TAR-DNA binding protein 43 (TDP-43) proteinopathy is a common brain pathology in elderly persons, but much remains to be learned about this high-morbidity condition. Published stage-based systems for operationalizing disease severity rely on the involvement (presence/absence) of pathology in specific anatomic regions. To examine the comorbidities associated with TDP-43 pathology in aged individuals, we studied data from the National Alzheimer’s Coordinating Center (NACC) Neuropathology Data Set. Data were analyzed from 929 included subjects with available TDP-43 pathology information, sourced from 27 different American Alzheimer’s Disease Centers (ADCs). Cases with relatively unusual diseases including autopsy-proven frontotemporal lobar degeneration (FTLD-TDP or FTLD-tau) were excluded from the study. Our data provide new information about pathologic features that are and are not associated with TDP-43 pathologies in different brain areas—spinal cord, amygdala, hippocampus, entorhinal cortex/inferior temporal cortex, and frontal neocortex. Different research centers used cite-specific methods including different TDP-43 antibodies. TDP-43 pathology in at least one brain region was common (31.4%) but the pathology was rarely observed in spinal cord (1.8%) and also unusual in frontal cortex (5.3%). As expected, TDP-43 pathology was positively associated with comorbid hippocampal sclerosis pathology and with severe AD pathology. TDP-43 pathology was also associated with comorbid moderate-to-severe brain arteriolosclerosis. The association between TDP-43 pathology and brain arteriolosclerosis appears relatively specific since there was no detected association between TDP-43 pathology and microinfarcts, lacunar infarcts, large infarcts, cerebral amyloid angiopathy (CAA), or circle of Willis atherosclerosis. Together, these observations provide support for the hypothesis that many aged brains are affected by a TDP-43 proteinopathy that is more likely to be seen in brains with AD pathology, arteriolosclerosis pathology, or both.

Risk factors of hippocampal sclerosis in the oldest old: The 90+ Study.

To examine the risk factors and comorbidities of hippocampal sclerosis (HS) in the oldest-old. A total of 134 participants with dementia from The 90+ Study with longitudinal evaluations and autopsy were included in this investigation. Participants were divided into 2 groups, one with and one without HS pathology, and differences in clinical and pathologic characteristics were compared. Persons with HS tended to have a longer duration of dementia compared to participants without HS (mean 4.0 years vs 6.7 years, odds ratio [OR] 1.26; 95% confidence interval [CI] 1.11-1.42; p < 0.001). HS was more likely in participants with a history of autoimmune diseases (rheumatoid arthritis or thyroid disease, OR 3.15; 95% CI 1.30-7.62; p = 0.011), high thyroid-stimulating hormone (OR 4.94; 95% CI 1.40-17.46; p = 0.013), or high thyroid antibodies (OR 3.45; 95% CI 1.09-10.88; p = 0.035). Lewy body disease (LBD) pathology was also associated with an increased likelihood of HS (OR 5.70; 95% CI 1.22-26.4; p = 0.027). We identified autoimmune conditions (rheumatoid arthritis and thyroid disease) as potential risk factors for HS in our cohort. LBD was the only pathology that was associated with increased odds of HS and those harboring HS pathology had a longer duration of dementia. This suggests multiple pathways of HS pathology among the oldest-old.

Combined neuropathological pathways account for age-related risk of dementia.

Our objectives were to characterize the inter-relation of known dementia-related neuropathologies in one comprehensive model and quantify the extent to which accumulation of neuropathologies accounts for the association between age and dementia. We used data from 1,362 autopsied participants of three community-based clinicopathological cohorts: the Religious Orders Study, the Rush Memory and Aging Project, and the Minority Aging Research Study. We estimated a series of structural equation models summarizing a priori hypothesized neuropathological pathways between age and dementia risk individually and collectively. At time of death (mean age, 89 years), 44% of our sample had a clinical dementia diagnosis. When considered individually, our vascular, amyloid/tau, neocortical Lewy body, and TAR DNA-binding protein 43 (TDP-43)/hippocampal sclerosis pathology pathways each accounted for a substantial proportion of the association between age and dementia. When considered collectively, the four pathways fully accounted for all variance in dementia risk previously attributable to age. Pathways involving amyloid/tau, neocortical Lewy bodies, and TDP-43/hippocampal sclerosis were interdependent, attributable to the importance of amyloid beta plaques in all three. The importance of the pathways varied, with the vascular pathway accounting for 32% of the association between age and dementia, wheraes the remaining three inter-related degenerative pathways together accounted for 68% (amyloid/tau, 24%; the Lewy body, 1%; and TDP-43/hippocampal sclerosis, 43%). Age-related increases in dementia risk can be attributed to accumulation of multiple pathologies, each of which contributes to dementia risk. Multipronged approaches may be necessary if we are to develop effective therapies. Ann Neurol 2018;84:10-22.

Review: Neurodegenerative processes in temporal lobe epilepsy with hippocampal sclerosis: Clinical, pathological and neuroimaging evidence.

Cognitive decline is increasingly described as a co-morbidity of temporal lobe epilepsy (TLE). Mechanisms underlying cognitive impairment are not fully understood despite examining clinical factors, such as seizure frequency, and cellular mechanisms of excitotoxicity. We review the neuropsychometry evidence for progressive cognitive decline and examine the pathology and neuroimaging evidence supporting a neurodegenerative process in hippocampal sclerosis (HS)-related TLE. Accelerated cognitive decline is described in groups of adult HS-related TLE patients. Large childhood studies show early onset of seizures result in poor development of verbal memory and a hindrance in achieving cognitive potential. We discuss HS classification according to different patterns of neuronal loss and correlation to post-temporal lobectomy cognitive outcomes in refractory TLE patients. Factors such as lateralization of HS pathology, neuronal density and subtype have correlated to cognitive outcomes with varying significance between different studies. Furthermore, alterations in neuronal maturity, regenerative capacity and aberrant connectivity appear to affect cognitive performance post-operatively suggesting a complex multifactorial process. More recent studies have identified tau pathology being present in HS-related TLE and correlated to post-operative cognitive decline in some patients. A traumatic head injury-related or novel tauopathy has been hypothesized as an underlying process. We discuss the value of prospective and cross-sectional imaging in assessing cognition and review volumetric magnetic resonance studies with progressive ipsilateral hippocampal atrophy identified to correlate with seizure frequency. Finally, we consider the use of positron emission tomography biomarkers, such as tau tracers, and connectivity studies that may examine invivo pathways and further explore cognitive decline in TLE.

Genomics and CSF analyses implicate thyroid hormone in hippocampal sclerosis of aging

We report evidence of a novel pathogenetic mechanism in which thyroid hormone dysregulation contributes to dementia in elderly persons. Two single nucleotide polymorphisms (SNPs) on chromosome 12p12 were the initial foci of our study: rs704180 and rs73069071. These SNPs were identified by separate research groups as risk alleles for non-Alzheimer's neurodegeneration. We found that the rs73069071 risk genotype was associated with hippocampal sclerosis (HS) pathology among people with the rs704180 risk genotype (National Alzheimer's Coordinating Center/Alzheimer's Disease Genetic Consortium data; n=2113, including 241 autopsy-confirmed HS cases). Furthermore, both rs704180 and rs73069071 risk genotypes were associated with widespread brain atrophy visualized by MRI (Alzheimer's Disease Neuroimaging Initiative data; n=1239). In human brain samples from the Braineac database, both rs704180 and rs73069071 risk genotypes were associated with variation in expression of ABCC9, a gene which encodes a metabolic sensor protein in astrocytes. The rs73069071 risk genotype was also associated with altered expression of a nearby astrocyte-expressed gene, SLCO1C1. Analyses of human brain gene expression databases indicated that the chromosome 12p12 locus may regulate particular astrocyte-expressed genes induced by the active form of thyroid hormone, triiodothyronine (T3). This is informative biologically, because the SLCO1C1 protein transports thyroid hormone into astrocytes from blood. Guided by the genomic data, we tested the hypothesis that altered thyroid hormone levels could be detected in cerebrospinal fluid (CSF) obtained from persons with HS pathology. Total T3 levels in CSF were elevated in HS cases (p<0.04 in two separately analyzed groups), but not in Alzheimer's disease cases, relative to controls. No change was detected in the serum levels of thyroid hormone (T3 or T4) in a subsample of HS cases prior to death. We conclude that brain thyroid hormone perturbation is a potential pathogenetic factor in HS that may also provide the basis for a novel CSF-based clinical biomarker.

Neuropsychological outcome of seizure-free temporal lobe epilepsy patients after temporal lobe resection with and without antiepileptic drugs

Objective: Temporal lobe epilepsy (TLE) is a common clinical syndrome in adult epilepsy population with most frequently underlying pathology of hippocampal sclerosis. There is a lack of data on influence of antiepileptic drugs (AEDs) on neuropsychological outcome of seizure-free patients. In the present study we compared the neuropsychological outcome of seizure-free patients after temporal lobe resection who were off or on AEDs.

Prevalence of Hippocampal Sclerosis in a Clinicopathologically Characterized Cohort.

Hippocampal sclerosis (HS) is a neuropathological finding that frequently occurs with pathologies, such as Alzheimer's disease (AD). Prevalence estimates of HS in autopsy-confirmed dementia samples have varied between 0.4% and 24.5%. However, the prevalence of HS within other pathologic groups has not been well characterized. Utilizing a sample of 910 prospectively followed and clinicopathologically confirmed dementia cases, we determined the prevalence of HS among the sample and within specific pathologic groups. HS prevalence of the sample was compared to reported HS prevalence rates in other autopsy-confirmed dementia samples. The age range of the sample was 43 to 106 years, with a mean of 81.49±8.45. Of the 910 cases, 505 were male and 405 were female. For the entire sample, the average educational level was 14.59±2.65years. Of the 910 individuals, 47 (5.16%) cases had HS pathology present at autopsy. Among the 561 AD cases, 26 (4.43%) had HS pathology present. The frontotemporal dementia (FTD)/Pick's group had the highest percentage of cases with HS pathology (23.08%) followed by primary progressive aphasia (PPA) (16.67%) and Parkinson's disease with dementia (PDD) (5.34%). The HS prevalence rate of this study was not significantly different from all but 2 studies. The prevalence of HS pathology in this sample of autopsy-confirmed dementia cases was similar to other reported HS prevalence rates. This study is the first to report the presence of HS pathology in PDD cases.

Seizure-free and neuropsychological outcomes after temporal lobectomy with amygdalohippocampectomy in pediatric patients with hippocampal sclerosis

Temporal lobe epilepsy is an uncommon clinical syndrome in the pediatric population. The most common underlying pathologies include low-grade gliomas, cortical dysplasia, and, less commonly, hippocampal sclerosis (HS). There is a paucity of data on neuropsychological and seizure-free outcomes in these patients after temporal lobectomy. In this study, the authors reviewed their seizure-free and neuropsychological outcomes after temporal lobectomy for pediatric HS. The authors retrospectively reviewed the medical records of pediatric patients with HS who underwent anterior temporal lobectomy and amygdalohippocampectomy between 1998 and 2011 at the Cleveland Clinic. Results of neuropsychological assessment before and after surgery and seizure-free outcome at last follow-up were obtained. Forty-five patients met the inclusion criteria. Thirty-four (76%) patients had pathology of HS alone and 10 (22%) had HS and cortical dysplasia. The mean duration of follow-up was 60.2 months. Eighty-four percent of patients had postoperative Engel Class I or II outcomes. Neuropsychological outcomes remained unchanged or minimally improved postoperatively. Seizure-free outcomes in pediatric HS are similar to historical rates in adult HS. Neuropsychological assessments remain stable after temporal lobectomy. Standard temporal lobectomy should be considered in pediatric patients with medically intractable epilepsy secondary to HS.

Hippocampal sclerosis in advanced age: clinical and pathological features

Hippocampal sclerosis is a relatively common neuropathological finding (∼10% of individuals over the age of 85 years) characterized by cell loss and gliosis in the hippocampus that is not explained by Alzheimer's disease. Hippocampal sclerosis pathology can be associated with different underlying causes, and we refer to hippocampal sclerosis in the aged brain as hippocampal sclerosis associated with ageing. Much remains unknown about hippocampal sclerosis associated with ageing. We combined three different large autopsy cohorts: University of Kentucky Alzheimer's Disease Centre, the Nun Study and the Georgia Centenarian Study to obtain a pool of 1110 patients, all of whom were evaluated neuropathologically at the University of Kentucky. We focused on the subset of cases with neuropathology-confirmed hippocampal sclerosis (n=106). For individuals aged≥95 years at death (n=179 in our sample), each year of life beyond the age of 95 years correlated with increased prevalence of hippocampal sclerosis pathology and decreased prevalence of 'definite' Alzheimer's disease pathology. Aberrant TAR DNA protein 43 immunohistochemistry was seen in 89.9% of hippocampal sclerosis positive patients compared with 9.7% of hippocampal sclerosis negative patients. TAR DNA protein 43 immunohistochemistry can be used to demonstrate that the disease is usually bilateral even when hippocampal sclerosis pathology is not obvious by haematoxylin and eosin stains. TAR DNA protein 43 immunohistochemistry was negative on brain sections from younger individuals (n=10) after hippocampectomy due to seizures, who had pathologically confirmed hippocampal sclerosis. There was no association between cases with hippocampal sclerosis associated with ageing and apolipoprotein E genotype. Age of death and clinical features of hippocampal sclerosis associated with ageing (with or without aberrant TAR DNA protein 43) were distinct from previously published cases of frontotemporal lobar degeneration TAR DNA protein 43. To help sharpen our ability to discriminate patients with hippocampal sclerosis associated with ageing clinically, the longitudinal cognitive profile of 43 patients with hippocampal sclerosis associated with ageing was compared with the profiles of 75 controls matched for age, gender, education level and apolipoprotein E genotype. These individuals were followed from intake assessment, with 8.2 (average) longitudinal cognitive assessments. A neuropsychological profile with relatively high-verbal fluency but low word list recall distinguished the hippocampal sclerosis associated with ageing group at intake (P<0.015) and also 5.5-6.5 years before death (P<0.005). This may provide a first step in clinical differentiation of hippocampal sclerosis associated with ageing versus pure Alzheimer's disease in their earliest stages. In summary, in the largest series of autopsy-verified patients with hippocampal sclerosis to date, we characterized the clinical and pathological features associated with hippocampal sclerosis associated with ageing.