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Background: Despite the presence of significant cortical pTDP-43 inclusions of heterogeneous morphologies in patients diagnosed with amyotrophic lateral sclerosis (ALS), pathological subclassification is routinely performed in the minority of patients with concomitant frontotemporal dementia (FTD)., Objective: In order to improve current understanding of the presence and relevance of pathological pTDP-43 subtypes in ALS, the present study examined the pattern of cortical pTDP-43 aggregates in 61 ALS cases without FTD., Results: Based on the presence, morphology and composition of pTDP-43 pathology, three distinct ALS-TDP subtypes were delineated: (1) A predominant pattern of pTDP-43 granulofilamentous neuronal inclusions (GFNIs) and grains that were immuno-negative for p62 was identified in 18% of cases designated ALS-TDP type E; (2) neuronal cytoplasmic inclusions (NCIs) that were immuno-positive for both pTDP-43 and p62 were observed in 67% of cases assigned ALS-TDP type B; and (3) scarce cortical pTDP-43 and p62 aggregates were identified in 15% of cases coined ALS-TDP type SC (scarce cortical). Quantitative analyses revealed a significantly greater burden of pTDP-43 GFNI and grains in ALS-TDP type E. Principal component analysis demonstrated significant relationships between GFNIs, grains and ALS-TDP subtypes to support the distinction of subtypes E and B. No significant difference in age at death or disease duration was found between ALS-TDP subgroups to suggest that these subtypes represent earlier or later stages of the same disease process. Instead, a significantly higher ALS-TDP stage, indicating greater topographical spread of pTDP-43, was identified in ALS-TDP type E. Alzheimer's disease neuropathological change (ABC score ≥ intermediate) and Lewy body disease (Braak stage ≥ IV) was more prevalent in the ALS-TDP type SC cohort, which also demonstrated a significantly lower overall cognitive score., Conclusion: In summary, the present study demonstrates that ALS-TDP does not represent a single homogenous neuropathology. We propose the subclassification of ALS-TDP into three distinct subtypes using standard immuno-stains for pTDP-43 and p62 in the motor cortex, which is routinely sampled and evaluated for diagnostic neuropathological characterisation of ALS. We propose that future studies specify both clinicopathological group and pTDP-43 subtype to advance current understanding of the pathogenesis of clinical phenotypes in pTDP-43 proteinopathies, which will have significant relevance to the development of targeted therapies for this heterogeneous disorder., (© 2023. The Author(s).)

Molecular mechanisms that define patterns of neuropeptide expression are essential for the formation and rewiring of neural circuits. The prodynorphin gene (PDYN) gives rise to dynorphin opioid peptides mediating depression and substance dependence. We here demonstrated that PDYN is expressed in neurons in human dorsolateral prefrontal cortex (dlPFC), and identified neuronal differentially methylated region in PDYN locus framed by CCCTC-binding factor binding sites. A short, nucleosome size human-specific promoter CpG island (CGI), a core of this region may serve as a regulatory module, which is hypomethylated in neurons, enriched in 5-hydroxymethylcytosine, and targeted by USF2, a methylation-sensitive E-box transcription factor (TF). USF2 activates PDYN transcription in model systems, and binds to nonmethylated CGI in dlPFC. USF2 and PDYN expression is correlated, and USF2 and PDYN proteins are co-localized in dlPFC. Segregation of activatory TF and repressive CGI methylation may ensure contrasting PDYN expression in neurons and glia in human brain.

Age is a critical factor in the prevalence of tauopathies, including Alzheimer's disease. To observe how an aging phenotype interacts with and affects the pathological intracellular accumulation of hyperphosphorylated tau, the tauopathy mouse model pR5 (expressing P301L mutant human tau) was back-crossed more than ten times onto a senescence-accelerated SAMP8 background to establish the new strain, SApT. Unlike SAMP8 mice, pR5 mice are characterized by a robust tau pathology particularly in the amygdala and hippocampus. Analysis of age-matched SApT mice revealed that pathological tau phosphorylation was increased in these brain regions compared to those in the parental pR5 strain. Moreover, as revealed by immunohistochemistry, phosphorylation of critical tau phospho-epitopes (P-Ser202/P-Ser205 and P-Ser235) was significantly increased in the amygdala of SApT mice in an age-dependent manner, suggesting an age-associated effect of tau phosphorylation. Anxiety tests revealed that the older cohort of SApT mice (10 months vs. 8 months) exhibited a behavioural pattern similar to that observed for age-matched tau transgenic pR5 mice and not the SAMP8 parental mice. Learning and memory, however, appeared to be governed by the accelerated aging background of the SAMP8 strain, as at both ages investigated, SAMP8 and SApT mice showed a decreased learning capacity compared to pR5 mice. We therefore conclude that accelerated aging exacerbates pathological tau phosphorylation, leading to changes in normal behaviour. These findings further suggest that SApT mice may be a useful novel model in which to study the role of a complex geriatric phenotype in tauopathy., (© 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Brain banks continue to make a major contribution to the study of neurological and psychiatric disorders. The current complexity and scope of research heighten the need for well-characterized cases and the demand for larger cohorts and necessitate strategies, such as the establishment of bank networks based in regional areas. While individual brain banks have developed protocols that meet researchers' needs within the confines of resources and funding, to further promote collaboration, standardization and scientific validity and understanding of the current protocols of participating banks are required. A survey was sent to brain banks, identified by an Internet search, to investigate operational protocols, case characterization, cohort management, data collection, standardization, and degree of collaboration between banks. The majority of the 24 banks that returned the survey have been established for more than 20 years, and most are affiliated with a regional network. While prospective donor programs were the primary source of donation, the data collected on donors varied. Longitudinal information assists case characterization and enhances the analysis capabilities of research. However, acquiring this information depended on the availability of qualified staff. Respondents indicated a high level of importance for standardization, but only 8 of 24 considered this occurred between banks. Standard diagnostic criteria were not achieved in the classification of controls, and some banks relied on the researcher to indicate the criteria for classification of controls. Although the capacity to collaborate with other banks was indicated by 16 of 24 banks, this occurred infrequently. Engagement of all brain banks to participate toward a consensus of diagnostic tools, especially for controls, will strengthen collaboration., Competing Interests: Author Disclosure Statement No conflicting financial interests exist.

Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.

Background: The greatest genetic risk factor for late-onset Alzheimer's disease (AD) is the ϵ4 allele of Apolipoprotein E (ApoE). ApoE regulates secretion of the potent neuroprotective signaling lipid Sphingosine 1-phosphate (S1P). S1P is derived by phosphorylation of sphingosine, catalysed by sphingosine kinases 1 and 2 (SphK1 and 2), and SphK1 positively regulates glutamate secretion and synaptic strength in hippocampal neurons. S1P and its receptor family have been subject to intense pharmacological interest in recent years, following approval of the immunomodulatory drug Fingolimod, an S1P mimetic, for relapsing multiple sclerosis., Results: We quantified S1P levels in six brain regions that are differentially affected by AD pathology, in a cohort of 34 post-mortem brains, divided into four groups based on Braak neurofibrillary tangle staging. S1P declined with increasing Braak stage, and this was most pronounced in brain regions most heavily affected by AD pathology. The S1P/sphingosine ratio was 66% and 64% lower in Braak stage III/IV hippocampus (p = 0.010) and inferior temporal cortex (p = 0.014), respectively, compared to controls. In accordance with this change, both SphK1 and SphK2 activity declined with increasing Braak pathology in the hippocampus (p = 0.032 and 0.047, respectively). S1P/sphingosine ratio was 2.5-fold higher in hippocampus of ApoE2 carriers compared to ApoE4 carriers, and multivariate regression showed a significant association between APOE genotype and hippocampal S1P/sphingosine (p = 0.0495), suggesting a new link between APOE genotype and pre-disposition to AD., Conclusions: This study demonstrates loss of S1P and sphingosine kinase activity early in AD pathogenesis, and prior to AD diagnosis. Our findings establish a rationale for further exploring S1P receptor pharmacology in the context of AD therapy.

The nuclear protein fused in sarcoma (FUS) is found in cytoplasmic inclusions in a subset of patients with the neurodegenerative disorder frontotemporal lobar degeneration (FTLD-FUS). FUS contains a methylated arginine-glycine-glycine domain that is required for transport into the nucleus. Recent findings have shown that this domain is hypomethylated in patients with FTLD-FUS. To determine whether the cause of hypomethylation is the result of mutations in protein N-arginine methyltransferases (PRMTs), we selected 3 candidate genes (PRMT1, PRMT3, and PRMT8) and performed complete sequencing analysis and real-time polymerase chain reaction mRNA expression analysis in 20 FTLD-FUS cases. No mutations or statistically significant changes in expression were observed in our patient samples, suggesting that defects in PRMTs are not the cause of FTLD-FUS., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Behavioural variant frontotemporal dementia can present with episodic memory deficits as severe as those in Alzheimer's disease. Little is known of the integrity of grey matter areas and white matter tracts of the Papez memory circuit in these diseases. The integrity of the Papez circuit (hippocampus, fornix, mammillary bodies, anterior thalamus, cingulate cortex) was investigated in vivo and at post-mortem in behavioural variant frontotemporal dementia and Alzheimer's disease cohorts using voxel-based morphometry, diffusion tensor imaging and manual volumetric tracing. Our findings indicate that behavioural variant frontotemporal dementia and Alzheimer's disease show similar degrees of hippocampal atrophy in vivo, but patients with behavioural variant frontotemporal dementia show greater hippocampal atrophy at post-mortem, with the frontotemporal lobar degeneration with TDP-43 inclusions subtype being particularly affected. Cingulate cortex findings show an expected atrophy pattern with behavioural variant frontotemporal dementia being affected more anteriorly and Alzheimer's disease showing more posterior atrophy. More importantly, subcortical Papez circuit regions (fornix and anterior thalamus) were affected in behavioural variant frontotemporal dementia only, with atrophy in these regions determining the degree of amnesia in behavioural variant frontotemporal dementia. Hippocampal atrophy does not appear to be an efficient diagnostic marker for underlying behavioural variant frontotemporal dementia or Alzheimer's disease pathology, although for behavioural variant frontotemporal dementia, episodic memory deficits in conjunction with marked hippocampal atrophy emerge as potential biomarkers for frontotemporal lobar degeneration with TDP-43 inclusions pathology. Sub-regions of the Papez circuit were differentially affected in behavioural variant frontotemporal dementia and Alzheimer's disease with subcortical regions determining the degree of episodic memory deficits in behavioural variant frontotemporal dementia. Subcortical atrophy should be taken into account when establishing whether the severe amnesia observed in a patient is likely to be due to behavioural variant frontotemporal dementia or Alzheimer's disease pathology.

The neuropathological correlates of suicide in older persons have received little research attention. Our recent study of elderly suicide victims from an Australian forensic medicine department (n = 143), unlike a previous case-control study, did not find an increased prevalence of Alzheimer's disease (AD) in older persons who committed suicide despite a history of dementia in 6.3%. Both studies were limited to the examination of AD-related pathology by the availability of tissue. We present clinicopathological data on three cases from our study for whom autopsy findings were available. These cases included: a community-dwelling male in his early eighties with dementia who was found to have multiple cortical and striatal lacunes and glial scars, small vessel cerebrovascular disease (SVD) and AD-related pathology; a community-dwelling male in his mid-seventies with depression and loss of concentration, with brainstem predominant Lewy body disease (LBD) and AD-related pathology; and a female nursing home resident in her nineties with a history of stroke and prior suicide attempts who was found to have infarcts and SVD in frontal regions. Neuropathological findings in elderly suicide victims may include multiple neurodegenerative pathologies. The burden and distribution of neurodegenerative diseases apart from AD, including SVD and LBD, should be assessed as possible pathophysiological factors contributing to late life suicide.

Maps of cytoarchitectonically defined cortical areas have proven to be a valuable tool for anatomic localization of activated brain regions revealed by functional imaging studies. However, architectonic data require observations in a sample of postmortem brains. They can only be used reliably for comparison with functional data as probabilistic maps after spatial normalization to a common reference space. The complete architectonic analysis of an individual living brain has not been achievable to date, because the relationship remains unclear between laminar gray value changes of cerebral cortex in magnetic resonance (MR) images and those of cyto- and myeloarchitectonic histologic sections. We examined intensity profiles through the cortex in five imaging modalities: in vivo T1 and postmortem T2 MRI, one cell body stain, and two myelin stains. After visualizing the dissimilarities in the shapes of these profiles using a canonical analysis, differences between the profiles from the different image modalities were compared quantitatively. Subsequently, the profiles extracted from the in vivo T1-weighted images were estimated from profiles extracted from cyto- and myeloarchitectonic sections using linear combinations. We could verify statistically the mixed nature of the cortical T1 signal obtained in vivo: The MR intensity profiles were significantly more similar to myeloarchitectonic than to cytoarchitectonic profiles, but a weighted sum of both fitted the T1 profiles best., (Copyright 2004 Wiley-Liss, Inc.)

Early and severe memory impairment is generally held to be an exclusion criterion for the clinical diagnosis of frontotemporal dementia (FTD). However, clinical experience suggests that some patients with otherwise typical FTD can be amnesic from presentation, or even present solely with amnesia. A review of severe amnesia at presentation in patients with pathologically proven FTD is therefore warranted. The present study examined the records of all patients in the joint Cambridge-Sydney neuropathological series of patients with dementia and a pathological diagnosis of FTD to identify those for whom memory complaints were dominant at presentation. Eight of 71 patients met these criteria. For two patients, memory loss was the only complaint; for one patient, memory loss was accompanied by personality change; for two patients, memory loss was accompanied by prominent dysexecutive symptoms; and for three patients, memory loss was accompanied by apathy but no other behavioural changes. In seven patients local specialist teams initially diagnosed Alzheimer's disease; four patients entered anticholinesterase drug trials. All eight later developed behavioural features: in four, the diagnosis was revised to FTD, while in four the diagnosis of FTD was made only on neuropathological examination after death. In conclusion, severe amnesia at presentation in FTD is commoner than previously thought and the clinical consensus criteria for the diagnosis of FTD may need to be revised. The underlying basis of the memory impairments in patients with FTD may be heterogeneous, with different explanations in different subgroups.

The main unifying feature of cases with frontotemporal dementia (FTD) is the pattern of brain atrophy. Surprisingly, there are a variety of underlying histopathologies in cases with the clinical features and typical pattern of atrophy characterizing FTD. This suggests that the degenerative mechanism(s) associated with pyramidal cell loss and gliosis in FTD is likely to be similar in the different histopathological forms of the disease. In this study we tested this hypothesis by analysing a common cell death mechanism, apoptosis, in cases of FTD with either Pick's disease (PiD) (n = 9) or frontotemporal lobar degeneration (FTLD) (n = 7) compared with normal controls (n = 10). Tissue sections from previously analysed cases were stained using anti-activated caspase-3 immunohistochemistry, TUNEL, propidium iodide, and cell- and pathology-specific labels. These markers of apoptosis identified both astrocytes and neurons in regions vulnerable to degeneration in all cases of FTD. However, neuronal apoptosis was rare (<2% of neurons), even at early disease stages where there is considerably less frontotemporal atrophy or pyramidal cell loss. This suggests that other cell death mechanisms account for the progressive neuronal loss in FTD. In contrast, astrocytes with beaded processes and other apoptotic features were very frequent in both PiD and FTLD, with the severity of astrocytosis and astrocytic apoptosis correlating with both the degree of neuronal loss and the stage of disease. These findings provide evidence that astrocytic apoptosis occurs as an early event in different histopathological forms of FTD. Furthermore, this astrocytic apoptosis directly relates to the degree of degeneration in FTD, and becomes the overwhelming pathological feature as the disease progresses.

Plasminogen knock-out (PG(-/-)) mice provide an unique opportunity for the study of alternative mediators of fibrinolysis. Polymorpho-nuclear leucocytes (PMNs) contain non-plasmin fibrinolytic proteases, however the degree to which these cells contribute to fibrin(ogen) degradation in these animals is not known. Thrombi were generated in carotid arteries and jugular veins of PG(-/-) and wild type (PG(+/+)) mice following adventitial application of a 20% ferric chloride solution. PMNs, identified histologically on H&E staining and by immunohistochemistry using anti-mouse PMN RB6-8C5 antibody, accumulated within the thrombus by 6 h after the injury and peaked at 24 h. There was significantly greater retention of PMNs within the thrombi of PG(-/-) mice from 48 to 72 h than in the PG(+/+) controls (at 72 h: PG(-/-)255 +/- 41 cell/mm(2) (n = 5), PG(+/+) 61 +/- 10 cell/mm(2) (n = 5), p<0.01 in the arterial thrombi; PG(-/-) 252 +/- 50 cell/mm(2) (n = 5), PG(+/+) 100 +/- 36 cell/mm(2) (n = 5), p<0.05 in the venous thrombi), providing potential for more PMN derived fibrinolytic enzymes to be present at late times after a thrombotic challenge in PG(-/-) mice relative to the PG(+/+) controls. Intact PMNs were elicited from the peritoneal cavities of PG(-/-) and PG(+/+) mice following 4% thioglycolate stimulation. In vitro studies showed PMNs from PG(-/-) mice to release greater quantities of 10% trichloroacetic acid (TCA)-soluble fibrinopeptides from I(125)-labeled fibrinogen, than cells from PG(+/+) controls although these differences did not become apparent until after 24 h of incubation (at 72 h incubation: PG(-/-) 918 n/10 x 10(6) cells/0.5 ml, PG(+/+) 589 ng/10 10(6) cells/0.5 ml p = 0.005). Furthermore, autoradiographic analysis of the I(125)-labeled fibrinogen degradation products showed the cleavage pattern by PG(-/-) PMNs to be distinct from that produced by PG(+/+) PMNs. These data suggest that a relatively greater role for PMNs-initiated fibrinolysis exists in the setting of plasminogen deficiency, although this prominence only becomes evident more than 24 h after the thrombotic insult. In addition, mechanisms responsible for the process in PG(-/-) mice may be distinct from those primarily responsible for the process in PMNs from PG(+/+) mice.