Progressive supranuclear palsy (PSP) is a 4R-tauopathy predominated by subcortical pathology in neurons, astrocytes, and oligodendroglia associated with various clinical phenotypes. In the present ...international study, we addressed the question of whether or not sequential distribution patterns can be recognized for PSP pathology. We evaluated heat maps and distribution patterns of neuronal, astroglial, and oligodendroglial tau pathologies and their combinations in different clinical subtypes of PSP in postmortem brains. We used conditional probability and logistic regression to model the sequential distribution of tau pathologies across different brain regions. Tau pathology uniformly predominates in the neurons of the pallido-nigro-luysian axis in different clinical subtypes. However, clinical subtypes are distinguished not only by total tau load but rather cell-type (neuronal versus glial) specific vulnerability patterns of brain regions suggesting distinct dynamics or circuit-specific segregation of propagation of tau pathologies. For Richardson syndrome (
n
= 81) we recognize six sequential steps of involvement of brain regions by the combination of cellular tau pathologies. This is translated to six stages for the practical neuropathological diagnosis by the evaluation of the subthalamic nucleus, globus pallidus, striatum, cerebellum with dentate nucleus, and frontal and occipital cortices. This system can be applied to further clinical subtypes by emphasizing whether they show caudal (cerebellum/dentate nucleus) or rostral (cortical) predominant, or both types of pattern. Defining cell-specific stages of tau pathology helps to identify preclinical or early-stage cases for the better understanding of early pathogenic events, has implications for understanding the clinical subtype-specific dynamics of disease-propagation, and informs tau-neuroimaging on distribution patterns.
Apolipoprotein-E (ApoE) has been implicated in Alzheimer's disease, atherosclerosis, and other unresolvable inflammatory conditions but a common mechanism of action remains elusive. We found in ...ApoE-deficient mice that oxidized lipids activated the classical complement cascade (CCC), resulting in leukocyte infiltration of the choroid plexus (ChP). All human ApoE isoforms attenuated CCC activity via high-affinity binding to the activated CCC-initiating C1q protein (K
~140-580 pM) in vitro, and C1q-ApoE complexes emerged as markers for ongoing complement activity of diseased ChPs, Aβ plaques, and atherosclerosis in vivo. C1q-ApoE complexes in human ChPs, Aβ plaques, and arteries correlated with cognitive decline and atherosclerosis, respectively. Treatment with small interfering RNA (siRNA) against C5, which is formed by all complement pathways, attenuated murine ChP inflammation, Aβ-associated microglia accumulation, and atherosclerosis. Thus, ApoE is a direct checkpoint inhibitor of unresolvable inflammation, and reducing C5 attenuates disease burden.
Epigenome-wide association studies (EWAS) based on human brain samples allow a deep and direct understanding of epigenetic dysregulation in Alzheimer's disease (AD). However, strong variation of ...cell-type proportions across brain tissue samples represents a significant source of data noise. Here, we report the first EWAS based on sorted neuronal and non-neuronal (mostly glia) nuclei from postmortem human brain tissues.
We show that cell sorting strongly enhances the robust detection of disease-related DNA methylation changes even in a relatively small cohort. We identify numerous genes with cell-type-specific methylation signatures and document differential methylation dynamics associated with aging specifically in neurons such as CLU, SYNJ2 and NCOR2 or in glia RAI1,CXXC5 and INPP5A. Further, we found neuron or glia-specific associations with AD Braak stage progression at genes such as MCF2L, ANK1, MAP2, LRRC8B, STK32C and S100B. A comparison of our study with previous tissue-based EWAS validates multiple AD-associated DNA methylation signals and additionally specifies their origin to neuron, e.g., HOXA3 or glia (ANK1). In a meta-analysis, we reveal two novel previously unrecognized methylation changes at the key AD risk genes APP and ADAM17.
Our data highlight the complex interplay between disease, age and cell-type-specific methylation changes in AD risk genes thus offering new perspectives for the validation and interpretation of large EWAS results.
The novel tau-PET tracer 18FPI-2620 detects the 3/4-repeat-(R)-tauopathy Alzheimer’s disease (AD) and the 4R-tauopathies corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP). We ...determined whether 18FPI-2620 binding characteristics deriving from non-invasive reference tissue modelling differentiate 3/4R- and 4R-tauopathies. Ten patients with a 3/4R tauopathy (AD continuum) and 29 patients with a 4R tauopathy (CBS, PSP) were evaluated. 18FPI-2620 PET scans were acquired 0-60 min p.i. and the distribution volume ratio (DVR) was calculated. 18FPI-2620-positive clusters (DVR ≥ 2.5 SD vs. 11 healthy controls) were evaluated by non-invasive kinetic modelling. R1 (delivery), k2 & k2a (efflux), DVR, 30-60 min standardized-uptake-value-ratios (SUVR30-60) and the linear slope of post-perfusion phase SUVR (9-60 min p.i.) were compared between 3/4R- and 4R-tauopathies. Cortical clusters of 4R-tau cases indicated higher delivery (R1SRTM: 0.92 ± 0.21 vs. 0.83 ± 0.10, p = 0.0007), higher efflux (k2SRTM: 0.17/min ±0.21/min vs. 0.06/min ± 0.07/min, p < 0.0001), lower DVR (1.1 ± 0.1 vs. 1.4 ± 0.2, p < 0.0001), lower SUVR30-60 (1.3 ± 0.2 vs. 1.8 ± 0.3, p < 0.0001) and flatter slopes of the post-perfusion phase (slope9-60: 0.006/min ± 0.007/min vs. 0.016/min ± 0.008/min, p < 0.0001) when compared to 3/4R-tau cases. 18FPI-2620 binding characteristics in cortical regions differentiate 3/4R- and 4R-tauopathies. Higher tracer clearance indicates less stable binding in 4R tauopathies when compared to 3/4R-tauopathies.
Neuronal intermediate filament inclusion disease (NIFID) is an uncommon neurodegenerative condition that typically presents as early-onset, sporadic frontotemporal dementia (FTD), associated with a ...pyramidal and/or extrapyramidal movement disorder. The neuropathology is characterized by frontotemporal lobar degeneration with neuronal inclusions that are immunoreactive for all class IV intermediate filaments (IF), light, medium and heavy neurofilament subunits and α-internexin. However, not all the inclusions in NIFID are IF-positive and the primary molecular defect remains uncertain. Mutations in the gene encoding the
fused in sarcoma
(FUS) protein have recently been identified as a cause of familial amyotrophic lateral sclerosis (ALS). Because of the recognized clinical, genetic and pathological overlap between FTD and ALS, we investigated the possible role of FUS in NIFID. We found abnormal intracellular accumulation of FUS to be a consistent feature of our NIFID cases (
n
= 5). More neuronal inclusions were labeled using FUS immunohistochemistry than for IF. Several types of inclusions were consistently FUS-positive but IF-negative, including neuronal intranuclear inclusions and glial cytoplasmic inclusions. Double-label immunofluorescence confirmed that many cells had only FUS-positive inclusions and that all cells with IF-positive inclusions also contained pathological FUS. No mutation in the
FUS
gene was identified in a single case with DNA available. These findings suggest that FUS may play an important role in the pathogenesis of NIFID.
Purpose
Second-generation tau radiotracers for use with positron emission tomography (PET) have been developed for visualization of tau deposits in vivo. For several β-amyloid and first-generation ...tau-PET radiotracers, it has been shown that early-phase images can be used as a surrogate of neuronal injury. Therefore, we investigated the performance of early acquisitions of the novel tau-PET radiotracer
18
FPI-2620 as a potential substitute for
18
Ffluorodeoxyglucose (
18
FFDG).
Methods
Twenty-six subjects were referred with suspected tauopathies or overlapping parkinsonian syndromes (Alzheimer’s disease, progressive supranuclear palsy, corticobasal syndrome, multi-system atrophy, Parkinson’s disease, multi-system atrophy, Parkinson's disease, frontotemporal dementia) and received a dynamic
18
FPI-2620 tau-PET (0–60 min p.i.) and static
18
FFDG-PET (30–50 min p.i.). Regional standardized uptake value ratios of early-phase images (single frame SUVr) and the blood flow estimate (R
1
) of
18
FPI-2620-PET were correlated with corresponding quantification of
18
FFDG-PET (global mean/cerebellar normalization). Reduced tracer uptake in cortical target regions was also interpreted visually using 3-dimensional stereotactic surface projections by three more and three less experienced readers. Spearman rank correlation coefficients were calculated between early-phase
18
FPI-2620 tau-PET and
18
FFDG-PET images for all cortical regions and frequencies of disagreement between images were compared for both more and less experienced readers.
Results
Highest agreement with
18
FFDG-PET quantification was reached for
18
FPI-2620-PET acquisition from 0.5 to 2.5 min p.i. for global mean (lowest
R
= 0.69) and cerebellar scaling (lowest
R
= 0.63). Correlation coefficients (summed 0.5–2.5 min SUVr & R
1
) displayed strong agreement in all cortical target regions for global mean (R
SUVr
0.76,
R
R1
= 0.77) and cerebellar normalization (R
SUVr
0.68,
R
R1
= 0.68). Visual interpretation revealed high regional correlations between early-phase tau-PET and
18
FFDG-PET. There were no relevant differences between more and less experienced readers.
Conclusion
Early-phase imaging of
18
FPI-2620 can serve as a surrogate biomarker for neuronal injury. Dynamic imaging or a dual time-point protocol for tau-PET imaging could supersede additional
18
FFDG-PET imaging by indexing both the distribution of tau and the extent of neuronal injury.
Background and purpose
Clinical diagnostic criteria for neurodegenerative diseases have been framed based on clinical phenomenology. However, systematic knowledge about the first reported clinical ...symptoms in neurodegenerative diseases is lacking. Therefore, the aim was to determine the prevalence and clinical implications of the first clinical symptom (FS) as assessed by medical history in neuropathologically proven neurodegenerative diseases.
Methods
Neuropathological diagnoses from the Neurobiobank Munich, Germany, were matched with clinical records for analyses of the diagnostic and prognostic values of FSs.
Results
In all, 301 patients with the neuropathological diagnoses Alzheimer disease (AD), progressive supranuclear palsy (PSP), frontotemporal lobar degeneration (FTLD), Lewy body disease (LBD) including the neuropathologically indistinguishable clinical phenotypes Parkinson disease and dementia with Lewy bodies, multiple system atrophy (MSA) and corticobasal degeneration (CBD) were studied. Memory disturbance was the most common FS in AD (34%), FTLD (19%) and LBD (26%), gait disturbance in PSP (35%) and MSA (27%) and aphasia and personality changes in CBD (20%, respectively). In a model adjusting for prevalence in the general population, AD was predicted by memory disturbance in 79.0%, aphasia in 97.2%, personality changes in 96.0% and by cognitive disturbance in 99.0%. Gait disturbance and tremor predicted LBD in 54.6% and 97.3%, coordination disturbance MSA in 59.4% and dysarthria FTLD in 73.0%. Cognitive FSs were associated with longer survival in AD (12.0 vs. 5.3 years; p < 0.001) and FTLD (8.2 vs. 4.1 years; p = 0.005) and motor FSs with shorter survival in PSP (7.2 vs. 9.7; p = 0.048).
Conclusions
Assessing FSs in neurodegenerative diseases may be beneficial for accuracy of diagnosis and prognosis and thereby may improve clinical care and precision of study recruitment.
In this work, the distribution of first clinical symptoms in neurodegenerative diseases is provided together with a prevalence adjusted model that depicts the probabilities for each neurodegenerative diagnosis if a distinct first symptom occurs in a patient. For clinicians that hover between two neurodegenerative diagnoses, a scheme is given that may facilitate diagnosis using the first clinical symptom. Further, the prognostic value of the first clinical symptom regarding survival in neurodegenerative diseases is analyzed.
Background and purpose
Knowledge about the seizure prevalence in the whole symptomatic course, from disease onset to death, in neurodegenerative diseases (ND) is lacking. Therefore, the aim was to ...investigate seizure prevalence and associated clinical implications in neuropathologically diagnosed ND.
Methods
Clinical records of cases from the Neurobiobank Munich, Germany, were analyzed. Neuropathological diagnoses of the assessed cases included Alzheimer disease (AD), corticobasal degeneration (CBD), frontotemporal lobar degeneration (FTLD), Lewy body disease (LBD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Seizure prevalence during the whole symptomatic disease phase was assessed and compared amongst ND. Associations between first clinical symptom and seizure prevalence and between seizures and disease duration were examined.
Results
In all, 454 patients with neuropathologically diagnosed ND and with available and meaningful clinical records were investigated (AD, n = 144; LBD, n = 103; PSP, n = 93; FTLD, n = 53; MSA, n = 36; CBD, n = 25). Seizure prevalence was 31.3% for AD, 20.0% for CBD, 12.6% for LBD, 11.3% for FTLD, 8.3% for MSA and 7.5% for PSP. Seizure prevalence was significantly higher in AD compared to FTLD (p = 0.005), LBD (p = 0.001), MSA (p = 0.005) and PSP (p < 0.001). No other significant differences regarding seizure prevalence were found between the studied ND. Cognitive first symptoms in ND were associated with an increased seizure prevalence (21.1% vs. 11.0% in patients without cognitive first symptoms) and motor first symptoms with a decreased seizure prevalence (10.3% vs. 20.5% in patients without motor first symptoms). Seizures were associated with a longer disease duration in MSA (12.3 vs. 7.0 years in patients without seizures; p = 0.017).
Conclusions
Seizures are a clinically relevant comorbidity in ND, particularly in AD. Knowledge of the first clinical symptom in ND may allow for estimation of seizure risk.
The current clinical neuropathological correlation study reveals high seizure prevalences in neurodegenerative diseases, particularly in Alzheimer disease. Additionally, this work shows associations between cognitive first symptoms and an increased seizure risk and between motor first symptoms and a decreased seizure risk in neurodegenerative diseases.
Corticotroph macroadenomas are rare but difficult to manage intracranial neoplasms. Mutations in the two Cushing's disease mutational hotspots USP8 and USP48 are less frequent in corticotroph ...macroadenomas and invasive tumors. There is evidence that TP53 mutations are not as rare as previously thought in these tumors. The aim of this study was to determine the prevalence of TP53 mutations in corticotroph tumors, with emphasis on macroadenomas, and their possible association with clinical and tumor characteristics. To this end, the entire TP53 coding region was sequenced in 86 functional corticotroph tumors (61 USP8 wild type; 66 macroadenomas) and the clinical characteristics of patients with TP53 mutant tumors were compared with TP53/USP8 wild type and USP8 mutant tumors. We found pathogenic TP53 variants in 9 corticotroph tumors (all macroadenomas and USP8 wild type). TP53 mutant tumors represented 14% of all functional corticotroph macroadenomas and 24% of all invasive tumors, were significantly larger and invasive, and had higher Ki67 indices and Knosp grades compared to wild type tumors. Patients with TP53 mutant tumors had undergone more therapeutic interventions, including radiation and bilateral adrenalectomy. In conclusion, pathogenic TP53 variants are more frequent than expected, representing a relevant amount of functional corticotroph macroadenomas and invasive tumors. TP53 mutations associated with more aggressive tumor features and difficult to manage disease.
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