Ageing-Related Neurodegeneration and Cognitive Decline.

Neuropathological assessment was conducted on 1630 subjects, representing 5% of all the deceased that had been sent to the morgue of Uppsala University Hospital during a 15-year-long period. Among the 1630 subjects, 1610 were ≥41 years of age (range 41 to 102 years). Overall, hyperphosphorylated (HP) τ was observed in the brains of 98% of the 1610 subjects, and amyloid ß-protein (Aß) in the brains of 64%. The most common alteration observed was Alzheimer disease neuropathologic change (ADNC) (56%), followed by primary age-related tauopathy (PART) in 26% of the subjects. In 16% of the subjects, HPτ was limited to the locus coeruleus. In 14 subjects (<1%), no altered proteins were observed. In 3 subjects, only Aß was observed, and in 17, HPτ was observed in a distribution other than that seen in ADNC/PART. The transactive DNA-binding protein 43 (TDP43) associated with limbic-predominant age-related TDP encephalopathy (LATE) was observed in 565 (35%) subjects and α-synuclein (αS) pathology, i.e., Lewy body disease (LBD) or multi system atrophy (MSA) was observed in the brains of 21% of the subjects. A total of 39% of subjects with ADNC, 59% of subjects with PART, and 81% of subjects with HPτ limited to the locus coeruleus lacked concomitant pathologies, i.e., LATE-NC or LBD-NC. Of the 293 (18% of the 1610 subjects) subjects with dementia, 81% exhibited a high or intermediate level of ADNC. In 84% of all individuals with dementia, various degrees of concomitant alterations were observed; i.e., MIXED-NC was a common cause of dementia. A high or intermediate level of PART was observed in 10 subjects with dementia (3%), i.e., tangle-predominant dementia. No subjects exhibited only vascular NC (VNC), but in 17 subjects, severe VNC might have contributed to cognitive decline. Age-related tau astrogliopathy (ARTAG) was observed in 37% of the 1610 subjects and in 53% of those with dementia.

The Compartmentalization of Amyloid-ß in Idiopathic Normal Pressure Hydrocephalus Brain Biopsies.

Background: Amyloid-ß (Aß) is one of the hallmark lesions of Alzheimer's disease (AD). During the disease process, Aß undergoes biochemical changes, producing toxic Aß variants, proposed to be detected within the neurons. Idiopathic normal pressure hydrocephalus (iNPH) causes cognitive impairment, gait, and urinary symptoms in elderly, that can be reversed by a ventriculo-peritoneal shunt. Majority of iNPH subjects display different Aß variants in their brain biopsies, obtained during shunting. Objective: To study the cellular compartmentalization of different Aß variants in brain biopsies from iNPH subjects. Methods: We studied the cellular localization of different proteoforms of Aß using antibodies towards different amino acid sequences or post-translational modifications of Aß, including clones 4G8, 6F/3D, unmodified- (7H3D6), pyroglutamylated- (N3pE), phosphorylated-(1E4E11) Aß and Aß protein precursor (AßPP), in brain biopsies from 3 iNPH subjects, using immunohistochemistry and light microscopy (LM), light microscopy on semi-thin sections (LMst), and electron microscopy (EM). Results: In LM all Aß variants were detected. In LMst and EM, the Aß 4G8, 6F/3D, and the pyroglutamylated Aß were detected. The AßPP was visualized by all methods. The Aß labelling was located extracellularly with no specific signal within the intracellular compartment, whereas the AßPP was seen both intra- and extracellularly. Conclusions: The Aß markers displayed extracellular localization when visualized by three assessment techniques, reflecting the pathological extracellular accumulation of Aß in the human brain. No intracellular Aß pathology was seen. AßPP was visualized in intra- and extracellularly, which corresponds to the localization of the protein in the membranes of cells and organelles.

Is islet amyloid polypeptide indeed expressed in the human brain?

AIMS: This study aims to study the association between pancreatic islet amyloid polypeptide (IAPP) and Alzheimer's disease neuropathological change (ADNC) in brain biopsies obtained from subjects with idiopathic normal pressure hydrocephalus (iNPH) and in post-mortem (PM) brain samples obtained from aged individuals. METHODS: For the immunohistochemical (IHC) analyses, two IAPP antibodies (Abs), monoclonal and polyclonal, and Abs directed towards ADNC were applied. RESULTS: The iNPH cohort included 113 subjects. Amyloid-ß (Aß) was detected in 50% and hyperphosphorylated τ (HPτ) in 47% of the cases. Concomitant pathology was seen in 32%. The PM cohort included 77 subjects. Aß was detected in 69% and HPτ in 91% of the cases. Combined Aß/HPτ pathology was seen in 62%. Reactivity for the monoclonal IAPP was not detected in the brain tissue in either of the cohorts. Reactivity for the polyclonal IAPP was observed in all 77 PM brain samples. CONCLUSIONS: There was no specific expression of IAPP in human brain tissue; hence, an association between IAPP and ADNC is not assessable. Of note, the observed reactivity of the polyclonal IAPP Ab was not reproduced with a specific monoclonal Ab; thus, we considered the observed staining with the polyclonal Ab to be unreliable. When using IHC, several pitfalls, especially the choice of an Ab, always need to be considered. Polyclonal Abs cross-react with other epitopes and proteins, thus leading to false-positive results. This seems to be the case for the polyclonal IAPP Abs in the human brain.

LATE-NC staging in routine neuropathologic diagnosis: an update.

An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer's disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.

When is a postmortem examination carried out? A retrospective analysis of all Swedish deaths 1999-2018.

The objective of this study was to assess who is merited an autopsy in Sweden. Data from the Swedish cause of death (COD) registry over a period of 20 years was retrieved and analysed. A multinominal logistic regression analysis was performed to identify the variables that were most strongly associated with the performance of a clinical or forensic autopsy (CA/FA).A definite COD, i.e. a COD based on autopsy findings, was registered in 12.6% of all deceased during the investigated period. In the remaining cases, the COD was presumed by the clinicians. Being male, born in the Nordic region, dying in a private residence, and unnatural death were most strongly associated with the performance of CA/FA. In contrast, being female, dying from dementia, dying at a nursing home, being born outside of Europe, or living in a small city or rural area seldom led to the performance of CA/FA.The above is certainly surprising as an autopsy provides an opportunity to investigate the cause of death, validate clinical diagnoses, detect unexpected aberrations, audit health care, and provide feedback to clinicians to facilitate their continuing education.

Mixed Pathologies in a Subject with a Novel PSEN1 G206R Mutation.

BACKGROUND: There are more than 300 presenilin-1 (PSEN1) mutations identified but a thorough postmortem neuropathological assessment of the mutation carriers is seldom performed. OBJECTIVE: To assess neuropathological changes (NC) in a 73-year-old subject with the novel PSEN1 G206R mutation suffering from cognitive decline in over 20 years. To compare these findings with an age- and gender-matched subject with sporadic Alzheimer's disease (sAD). METHODS: The brains were assessed macro- and microscopically and the proteinopathies were staged according to current recommendations. RESULTS: The AD neuropathological change (ADNC) was more extensive in the mutation carrier, although both individuals reached a high level of ADNC. The transactive DNA binding protein 43 pathology was at the end-stage in the index subject, a finding not previously described in familial AD. This pathology was moderate in the sAD subject. The PSEN1 G206R subject displayed full-blown alpha-synuclein pathology, while this proteinopathy was absent in the sAD case. Additionally, the mutation carrier displayed pronounced neuroinflammation, not previously described in association with PSEN1 mutations. CONCLUSION: Our findings are exceptional, as the PSEN1 G206R subject displayed an end-stage pathology of every common proteinopathy. It is unclear whether the observed alterations are caused by the mutation or are related to a cross-seeding mechanisms. The pronounced neuroinflammation in the index patient can be reactive to the extensive NC or a contributing factor to the proteinopathies. Thorough postmortem neuropathological and genetic assessment of subjects with familial AD is warranted, for further understanding of a dementing illness.

Gastrointestinal Biopsy Obtained During Cancer Screening, a Biological Marker for α-Synucleinopathy?

The hallmark alteration in α-synucleinopathies, α-synuclein, is observed not only in the brain but also in the peripheral tissues, particularly in the intestine. This suggests that endoscopic biopsies performed for colon cancer screening could facilitate the assessment of α-synuclein in the gastrointestinal (GI) tract. Using immunohistochemistry for α-synuclein, we assessed whether GI biopsies could be used to confirm an ongoing α-synucleinopathy. Seventy-four subjects with cerebral α-synucleinopathy in various Braak stages with concomitant GI biopsies were available for study. In 81% of the subjects, α-synuclein was seen in the mucosal/submucosal GI biopsies. Two subjects with severe cerebral α-synucleinopathy and a long delay between biopsy and death displayed no α-synuclein pathology in the gut, and 11 subjects with sparse cerebral α-synucleinopathy displayed GI α-synuclein up to 36 years prior to death. The finding that there was no GI α-synuclein in 19% of the subjects with cerebral α-synucleinopathy, and α-synuclein was observed in the gut of 11 subjects (15%) with sparse cerebral α-synucleinopathy even many years prior to death is unexpected and jeopardizes the use of assessment of α-synuclein in the peripheral tissue for confirmation of an ongoing cerebral α-synucleinopathy.

The Uppsala APP deletion causes early onset autosomal dominant Alzheimer's disease by altering APP processing and increasing amyloid ß fibril formation.

Point mutations in the amyloid precursor protein gene (APP) cause familial Alzheimer's disease (AD) by increasing generation or altering conformation of amyloid ß (Aß). Here, we describe the Uppsala APP mutation (Δ690-695), the first reported deletion causing autosomal dominant AD. Affected individuals have an age at symptom onset in their early forties and suffer from a rapidly progressing disease course. Symptoms and biomarkers are typical of AD, with the exception of normal cerebrospinal fluid (CSF) Aß42 and only slightly pathological amyloid-positron emission tomography signals. Mass spectrometry and Western blot analyses of patient CSF and media from experimental cell cultures indicate that the Uppsala APP mutation alters APP processing by increasing ß-secretase cleavage and affecting α-secretase cleavage. Furthermore, in vitro aggregation studies and analyses of patient brain tissue samples indicate that the longer form of mutated Aß, AßUpp1-42Δ19-24, accelerates the formation of fibrils with unique polymorphs and their deposition into amyloid plaques in the affected brain.

Accumulation of alpha-synuclein within the liver, potential role in the clearance of brain pathology associated with Parkinson's disease.

Alpha-synuclein (α-syn) aggregation is the hallmark pathological lesion in brains of patients with Parkinson's disease (PD) and related neurological disorders characterized as synucleinopathies. Accumulating evidence now indicates that α-syn deposition is also present within the gut and other peripheral organs outside the central nervous system (CNS). In the current study, we demonstrate for the first time that α-syn pathology also accumulates within the liver, the main organ responsible for substance clearance and detoxification. We further demonstrate that cultured human hepatocytes readily internalize oligomeric α-syn assemblies mediated, at least in part, by the gap junction protein connexin-32 (Cx32). Moreover, we identified a time-dependent accumulation of α-syn within the liver of three different transgenic (tg) mouse models expressing human α-syn under CNS-specific promoters, despite the lack of α-syn mRNA expression within the liver. Such a brain-to-liver transmission route could be further corroborated by detection of α-syn pathology within the liver of wild type mice one month after a single striatal α-syn injection. In contrast to the synucleinopathy models, aged mice modeling AD rarely show any amyloid-beta (Aß) deposition within the liver. In human post-mortem liver tissue, we identified cases with neuropathologically confirmed α-syn pathology containing α-syn within hepatocellular structures to a higher degree (75%) than control subjects without α-syn accumulation in the brain (57%). Our results reveal that α-syn accumulates within the liver and may be derived from the brain or other peripheral sources. Collectively, our findings indicate that the liver may play a role in the clearance and detoxification of pathological proteins in PD and related synucleinopathies.

In vivo Characterization of Biochemical Variants of Amyloid-ß in Subjects with Idiopathic Normal Pressure Hydrocephalus and Alzheimer's Disease Neuropathological Change.

BACKGROUND: Stepwise occurrence of biochemically modified amyloid-ß (Aß) in the brain of subjects with Alzheimer's disease (AD) has been suggested to be of significance for cognitive impairment. Our previous reports have shown that Aß is observed in 63% of all subjects with idiopathic normal pressure hydrocephalus (iNPH) suggesting that the majority of iNPH subjects with Aß are indeed also suffering from AD. OBJECTIVE: We assessed the occurrence of biochemically modified Aß variants, in vivo, in subjects with iNPH and in a cohort of postmortem brain samples from patients with dementia. METHODS: We assessed Aß proteins in 127 diagnostic brain biopsies obtained from subjects with iNPH and in a cohort of subjects with dementia by means of immunohistochemistry. RESULTS: The pyroglutamylated Aß (pyAß) precedes the aggregation of phosphorylated Aß (pAß) during the AD neuropathological change progression; moreover, these modified variants of Aß correlate with hyperphosphorylated tau in the frontal cortical area of human brain. Our results confirm the existence of the suggested biochemical stages of Aß aggregation that might be of significance for neurodegeneration leading to cognitive impairment. CONCLUSION: The observation that both pyAß and pAß are seen in vivo in iNPH subjects is intriguing. It has been reported that most of the iNPH subjects with Aß in the brain biopsy indeed develop AD with time. Based on our current and previous results, it is clinically merited to obtain a diagnostic biopsy from a subject with iNPH. When Aß is observed in the biopsy, the biochemical characterization is of interest.

Mixed Brain Pathology Is the Most Common Cause of Cognitive Impairment in the Elderly.

BACKGROUND: Systemic diseases, diabetes mellitus (DM), and cardiovascular disease (CaVD) have been suggested being risk factors for cognitive impairment (CI) and/or influence Alzheimer's disease neuropathologic change (ADNC). OBJECTIVE: The purpose was to assess the type and the extent of neuropathological alterations in the brain and to assess whether brain pathology was associated with CaVD or DM related alterations in peripheral organs, i.e., vessels, heart, and kidney. METHODS: 119 subjects, 15% with DM and 24% with CI, age range 80 to 89 years, were chosen and neuropathological alterations were assessed applying immunohistochemistry. RESULTS: Hyperphosphorylated τ (HPτ) was seen in 99%, amyloid-ß (Aß) in 71%, transactive DNA binding protein 43 (TDP43) in 62%, and α-synuclein (αS) in 21% of the subjects. Primary age related tauopathy was diagnosed in 29% (more common in females), limbic predominant age-related TDP encephalopathy in 4% (14% of subjects with CI), and dementia with Lewy bodies in 3% (14% of subjects with CI) of the subjects. High/intermediate level of ADNC was seen in 47% and the extent of HPτ increased with age. The extent of ADNC was not associated with the extent of pathology observed in peripheral organs, i.e., DM or CaVD. Contrary, brain alterations such as pTDP43 and cerebrovascular lesions (CeVL) were influenced by DM, and CeVL correlated significantly with the extent of vessel pathology. CONCLUSION: In most (66%) subjects with CI, the cause of impairment was "mixed pathology", i.e., ADNC combined with TDP43, αS, or vascular brain lesions. Furthermore, our results suggest that systemic diseases, DM and CaVD, are risk factors for CI but not related to ADNC.

Modeling SHH-driven medulloblastoma with patient iPS cell-derived neural stem cells.

Medulloblastoma is the most common malignant brain tumor in children. Here we describe a medulloblastoma model using Induced pluripotent stem (iPS) cell-derived human neuroepithelial stem (NES) cells generated from a Gorlin syndrome patient carrying a germline mutation in the sonic hedgehog (SHH) receptor PTCH1. We found that Gorlin NES cells formed tumors in mouse cerebellum mimicking human medulloblastoma. Retransplantation of tumor-isolated NES (tNES) cells resulted in accelerated tumor formation, cells with reduced growth factor dependency, enhanced neurosphere formation in vitro, and increased sensitivity to Vismodegib. Using our model, we identified LGALS1 to be a GLI target gene that is up-regulated in both Gorlin tNES cells and SHH-subgroup of medulloblastoma patients. Taken together, we demonstrate that NES cells derived from Gorlin patients can be used as a resource to model medulloblastoma initiation and progression and to identify putative targets.

Cause of death and significant disease found at autopsy.

The use of clinical autopsy has been in decline for many years throughout healthcare systems of developed countries despite studies showing substantial discrepancies between autopsy results and pre-mortal clinical diagnoses. We conducted a study to evaluate over time the use and results of clinical autopsies in Sweden. We reviewed the autopsy reports and autopsy referrals of 2410 adult (age > 17) deceased patients referred to two University hospitals in Sweden during two plus two years, a decade apart. There was a decline in the number of autopsies performed over time, however, mainly in one of the two hospitals. The proportion of autopsy referrals from the emergency department increased from 9 to 16%, while the proportion of referrals from regular hospital wards was almost halved. The autopsies revealed a high prevalence of cardiovascular disease, with myocardial infarction and cerebrovascular lesion found in 40% and 19% of all cases, respectively. In a large proportion of cases (> 30%), significant findings of disease were not anticipated before autopsy, as judged from the referral document and additional data obtained in some but not all cases. In accordance with previous research, our study confirms a declining rate of autopsy even at tertiary, academic hospitals and points out factors possibly involved in the decline.

Expression of CMV protein pp65 in cutaneous malignant melanoma.

Human cytomegalovirus (CVM) has been detected by immunohistochemistry (IHC) in brain tumours; however, whether CMV antigen is seen in melanomas has not yet been elucidated. Applying IHC, melanoma tissue was assessed for the expression of pp65, a tegument protein of CMV. Two cohorts were available, cohort-I and II, the latter included also related metastasis. In addition to IHC, in situ hybridisation (ISH) was carried out to assess whether CMV related genetic sequences were detectable in a subset of cases. Seventy per cent of the 142 cases in cohort-I and 50% of the 37 cases in cohort-II displayed immunoreactivity (IR). In both cohorts, the IHC outcome correlated with T-stage (Cohort I: Spearman 0.22, p = 0.01, Cohort II: Fisher exact text 0.04). In 30 of cohort-II cases, when IHC staining was carried out on both the primary tumour and the corresponding metastasis, no change in IR was noted in 53%; in 20%, the IR was lower and in 27% higher in the metastasis when compared with the primary tumour. These results were significant (Fisher exact test 0.03). Applying ISH technique on four tumour cases with detectable pp65 protein, CMV related genetic sequence was not detected. Here, we demonstrate, congruent with observations published for brain tumours, that the protein pp65 is indeed observed in substantial number of melanoma cases with IHC; however, no signal was detected with ISH technique. These findings are in line with previously reported studies, demonstrating that the role of CMV in tumours is still debatable.

Predicting Development of Alzheimer's Disease in Patients with Shunted Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) patients often develop Alzheimer's disease (AD) related brain pathology. Disease State Index (DSI) is a method to combine data from various sources for differential diagnosis and progression of neurodegenerative disorders. OBJECTIVE: To apply DSI to predict clinical AD in shunted iNPH-patients in a defined population. METHODS: 335 shunted iNPH-patients (median 74 years) were followed until death (n = 185) or 6/2015 (n = 150). DSI model (including symptom profile, onset age of NPH symptoms, atrophy of medial temporal lobe in CT/MRI, cortical brain biopsy finding, and APOE genotype) was applied. Performance of DSI model was evaluated with receiver operating characteristic (ROC) curve analysis. RESULTS: A total of 70 (21%) patients developed clinical AD during median follow-up of 5.3 years. DSI-model predicted clinical AD with moderate effectiveness (AUC = 0.75). Significant factors were cortical biopsy (0.69), clinical symptoms (0.66), and medial temporal lobe atrophy (0.66). CONCLUSION: We found increased occurrence of clinical AD in previously shunted iNPH patients as compared with general population. DSI supported the prediction of AD. Cortical biopsy during shunt insertion seems indicated for earlier diagnosis of comorbid AD.

Alzheimer's disease neuropathological change and loss of matrix/neuropil in patients with idiopathic Normal Pressure Hydrocephalus, a model of Alzheimer's disease.

Here, we assessed unique brain tissue samples, obtained from living subjects with idiopathic Normal Pressure Hydrocephalus (iNPH). Our cohort of 95 subjects with age ranging from 75 to 79 years, displayed a high prevalence of ß-amyloid (Aß) and hyperphosphorylated τ (HPτ) pathology (63 and 61%, respectively) in a frontal cortex biopsy obtained during shunt operation. These lesions, i.e., Alzheimer's Disease Neuropathologic Change (ADNC), increased within 5 years and were more frequent in females. The extent of HPτ pathology was sparse, primarily seen as neurites and stained dots. Noteworthy, concomitant pathology was seen in 49% of the whole cohort, indicating a severity of ADNC corresponding to a low/intermediate level following the current recommendations. This observation is predictable as based on previous publications a substantial number of subjects with iNPH over time develop AD. Thus, iNPH can be considered as a model of AD. We noted a surprisingly remarkable neuronal preservation assessing Neuronal Nuclei (NeuN) in parallel with a substantial depletion of matrix/neuropil. This finding is intriguing as it suggests that loss of matrix/neuropil might be one of the first lesion of ADNC but also a hallmark lesion of iNPH. The latter observation is in line with the enlarged ventricles, a cardinal feature of iNPH. Furthermore, a positive correlation was observed between the extent of Aß and NeuN but only in females indicating a neuronal preservation even when Aß pathology is present. The assessment of a surgical biopsy as described here is certainly informative and thus it is surprising that a neuropathologic assessment in the setting of iNPH, while inserting a shunt, is seldom performed. Here, we observed ADNC and surprisingly remarkable neuronal preservation in a substantial number of iNPH subjects. Thus, these subjects allow us to observe the natural course of the disease and give us an opportunity for intervention at the earliest stages of AD, prior to severe neuronal damage.

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-ß 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.

[11C]PIB PET Is Associated with the Brain Biopsy Amyloid-ß Load in Subjects Examined for Normal Pressure Hydrocephalus.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) is frequently associated with concomitant amyloid-ß (Aß) pathology. OBJECTIVE: To compare the [11C]PIB PET uptake in the patients with suspected iNPH to Aß and hyperphosphorylated-tau (HPτ) in the right frontal cortical biopsy, the cerebrospinal fluid (CSF) Aß, the response to a CSF shunt, and the final clinical diagnosis of Alzheimer's disease (AD). METHODS: Patients (n = 21) from Kuopio NPH Registry (http://www.uef.fi/nph) with intraventricular pressure monitoring, immunostaining for Aß and HPτ in the right frontal cortical biopsies, and a Mini-Mental State Examination and a Clinical Dementia Rating underwent [11C]PIB PET. Aß, total tau, and Pτ181 were measured by ELISA from the ventricular (n = 15) and the lumbar (n = 9) CSF. Response to the shunt was seen in 13 out of the 15 shunted patients. AD was diagnosed in 8 patients during a median follow-up of 6 years (mean 7.3±2.4 years, range 3-1). RESULTS: [11C]PIB uptake in the right frontal cortex (ρ= 0.60, p < 0.01) and the combined neocortical [11C]PIB uptake score (ρ= 0.61, p < 0.01) were associated with a higher Aß load in the right frontal cortical biopsy. Excluding one (1/15) outlier, [11C]PIB uptake was also associated with the ventricular CSF Aß (ρ= -0.58, p = 0.03). CONCLUSIONS: The findings show that [11C]PIB PET can reliably detect simultaneous amyloid pathology among the iNPH patients. Further studies will show whether amyloid PET could predict a clinical response to the shunt operation. In addition, the presence of Aß pathology in the patients with iNPH might also warrant treatment with current AD drugs.

Detection of Changes in Immunohistochemical Stains Caused by Postmortem Delay and Fixation Time.

In this study, we have systematically assessed the influence of postmortem delay (PMD) and fixation time (FT) on the immunohistochemical (IHC) staining outcome. The IHC method is frequently applied on surgical and postmortem samples in diagnostics and research. To replicate the routine situation, brain tissues from pigs were exposed to either storage in a refrigerator (+8°C), that is, PMD (1 to 168 h), or fixed in 10% buffered formalin, that is, FT (18 to 94 d). Subsequently, the tissue was routinely processed into paraffin blocks to enable construction of tissue microarrays (TMA). Sections cut from the TMA blocks were stained applying 13 different antibodies directed against neuronal and glial antigens. Immunoreactivity applying 5 antibodies was influenced by prolonged PMD and applying 2 antibodies by prolonged FT. None of the staining outcomes related to the PMD or FT were predictable. Loss of TMA cores during processing was primarily influenced by pretreatment and by tissue characteristics (gray/white matter). The test model described here confirmed that these 2 variables, PMD and FT, indeed influence the IHC outcome. The PMD and FT are particularly of importance while assessing tissue samples obtained at autopsy. The result above is also of importance while comparing the IHC outcomes seen in the postmortem setting (various PMD/FT) with surgical samples or with IHC outcome seen in experimental animal setting (controlled PMD/FT). Thus, we suggest that the test model described here is considered when assessing the reliability of the IHC outcome when analyzing tissues with various characteristics.