Patients with corticobasal degeneration can present with several different clinical syndromes, making ante-mortem diagnosis a challenge. Corticobasal syndrome is the clinical phenotype originally ...described for corticobasal degeneration, characterized by asymmetric rigidity and apraxia, cortical sensory deficits, dystonia and myoclonus. Some patients do not develop these features, but instead have clinical features consistent with the Richardson syndrome presentation of progressive supranuclear palsy, characterized by postural instability, early unexplained falls, vertical supranuclear gaze palsy, symmetric motor disability and dysphagia. The aim of this study was to identify differences in corticobasal degeneration presenting with corticobasal syndrome (n = 11) or Richardson syndrome (n = 15) with respect to demographic, clinical and neuropathological features. Corticobasal degeneration cases were also compared with patients with pathologically proven progressive supranuclear palsy with Richardson syndrome (n = 15). Cases with corticobasal degeneration, regardless of presentation, shared histopathological and tau biochemical characteristics, but they had differing densities of tau pathology in neuroanatomical regions that correlated with their clinical presentation. In particular, those with corticobasal syndrome had greater tau pathology in the primary motor and somatosensory cortices and putamen, while those with Richardson syndrome had greater tau pathology in limbic and hindbrain structures. Compared with progressive supranuclear palsy, patients with corticobasal degeneration and Richardson syndrome had less neuronal loss in the subthalamic nucleus, but more severe neuronal loss in the medial substantia nigra and greater atrophy of the anterior corpus callosum. Clinically, they had more cognitive impairment and frontal behavioural dysfunction. The results suggest that Richardson syndrome can be a clinicopathological presentation of corticobasal degeneration. Atrophy of anterior corpus callosum may be a potential neuroimaging marker to differentiate corticobasal degeneration from progressive supranuclear palsy in patients with Richardson syndrome.
A proteomic signature for dementia with Lewy bodies O'Bryant, Sid E.; Ferman, Tanis J.; Zhang, Fan ...
Alzheimer's & dementia : diagnosis, assessment & disease monitoring,
December 2019, Volume:
11, Issue:
1
Journal Article
Peer reviewed
Open access
We sought to determine if a proteomic profile approach developed to detect Alzheimer's disease would distinguish patients with Lewy body disease from normal controls, and if it would distinguish ...dementia with Lewy bodies (DLB) from Parkinson's disease (PD).
Stored plasma samples were obtained from 145 patients (DLB n = 57, PD without dementia n = 32, normal controls n = 56) enrolled from patients seen in the Behavioral Neurology or Movement Disorders clinics at the Mayo Clinic, Florida. Proteomic assays were conducted and analyzed as per our previously published protocols.
In the first step, the proteomic profile distinguished the DLB-PD group from controls with a diagnostic accuracy of 0.97, sensitivity of 0.91, and specificity of 0.86. In the second step, the proteomic profile distinguished the DLB from PD groups with a diagnostic accuracy of 0.92, sensitivity of 0.94, and specificity of 0.88.
These data provide evidence of the potential utility of a multitiered blood-based proteomic screening method for detecting DLB and distinguishing DLB from PD.
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FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Our primary goal was to examine demographic and clinicopathologic differences across an ethnoracially diverse autopsy-confirmed cohort of Alzheimer's disease cases.
A retrospective study was ...conducted in the Florida Autopsied Multi-Ethnic cohort on 1625 Alzheimer's disease cases, including decedents who self-reported as Hispanic/Latino (n = 67), black/African American (n = 19), and white/European American (n = 1539).
Hispanic decedents had a higher frequency of family history of cognitive impairment (58%), an earlier age at onset (median age of 70 years), longer disease duration (median of 12 years), and lower MMSE proximal to death (median of 4 points) compared with the other ethnoracial groups. Black decedents had a lower Braak tangle stage (stage V) and higher frequency of coexisting hippocampal sclerosis (21%); however, only hippocampal sclerosis differences survived adjustment for sex, age at onset, and disease duration. Neither Thal amyloid phase nor coexisting Lewy body disease differed across ethnoracial groups.
Despite a smaller sample size, Hispanics demonstrated longer disease duration with Alzheimer's disease, but not greater lifespan. Neuropathologic differences across ethnoracial groups supported differences in tau pathology distribution and coexisting hippocampal sclerosis, which may impact biomarker studies.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Alzheimer’s disease (AD) can be classified based on the relative density of neurofibrillary tangles (NFTs) in the hippocampus and association cortices into three subtypes: typical AD, ...hippocampal-sparing AD (HpSp AD), and limbic-predominant AD (LP AD). AD subtypes not only have pathologic, but also demographic, clinical, and genetic differences. Neurofibrillary tangle-predominant dementia (NFTD), a disorder with NFTs relatively restricted to limbic structures, shares this feature with LP AD raising the possibility that NFTD is a variant of AD. The objective criteria for pathologic diagnosis of NFTD are not available. A goal of this study was to design a mathematical algorithm that could diagnose NFTD from NFT and senile plaque (SP) counts in hippocampus and association cortices, analogous to that used to subtype AD. Moreover, we aimed to compare pathologic, demographic, clinical, and genetic features of NFTD (
n
= 18) with LP AD (
n
= 19), as well as the other AD subtypes, typical AD (
n
= 52) and HpSp AD (
n
= 17). Using digital microscopy, we confirmed that burden of phospho-tau (CP13) and of an NFT conformational epitope (Ab39) correlated with NFT densities and showed expected patterns across AD subtypes. HpSp AD had the highest and LP AD had the lowest burden of cortical CP13 and Ab39 immunoreactivity. On the other hand, cortical β-amyloid burden did not significantly differ between AD subtypes. Semi-quantitative assessment of SPs in the basal ganglia did show HpSp AD to have significantly more frequent presence of SPs compared to typical AD, which was more frequent than LP AD. Compared to LP AD, NFTD had an older age at disease onset and shorter disease duration, as well as lower Braak NFT stage. NFTs and SPs on thioflavin-S fluorescent microscopy, as well as CP13, Ab39, and Aβ immunoreactivities were very low in the frontal cortex of NFTD, differentiating NFTD from AD subtypes, including LP AD.
MAPT
H1H1 genotype frequency was high (~70 %) in NFTD and LP AD, and similar to typical AD, while APOE ε4 carrier state was low in NFTD. While it shares clinical similarities with regard to female sex predominance, onset in advanced age, and a slow cognitive decline, NFTD has significant pathologic differences from LP AD, suggesting that it may not merely be a variant of AD.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract Introduction We hypothesized that common Alzheimer's disease (AD)-associated variants within the triggering receptor expressed on myeloid ( TREM ) gene cluster influence disease through gene ...expression. Methods Expression microarrays on temporal cortex and cerebellum from ∼400 neuropathologically diagnosed subjects and two independent RNAseq replication cohorts were used for expression quantitative trait locus analysis. Results A variant within a DNase hypersensitive site 5′ of TREM2 , rs9357347-C, associates with reduced AD risk and increased TREML1 and TREM2 levels (uncorrected P = 6.3 × 10−3 and 4.6 × 10−2 , respectively). Meta-analysis on expression quantitative trait locus results from three independent data sets ( n = 1006) confirmed these associations (uncorrected P = 3.4 × 10−2 and 3.5 × 10−3 , Bonferroni-corrected P = 6.7 × 10−2 and 7.1 × 10−3 , respectively). Discussion Our findings point to rs9357347 as a functional regulatory variant that contributes to a protective effect observed at the TREM locus in the International Genomics of Alzheimer's Project genome-wide association study meta-analysis and suggest concomitant increase in TREML1 and TREM2 brain levels as a potential mechanism for protection from AD.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The ε4 allele of the APOE gene encoding apolipoprotein E (apoE) is a strong genetic risk factor for aging-related cognitive decline as well as late-onset Alzheimer's disease (AD) compared to the ...common ε3 allele. In the central nervous system, apoE is produced primarily by astrocytes and functions in transporting lipids including cholesterol to support neuronal homeostasis and synaptic integrity. Although mouse models and corresponding primary cells have provided valuable tools for studying apoE isoform-dependent functions, recent studies have shown that human astrocytes have a distinct gene expression profile compare with rodent astrocytes. Human induced pluripotent stem cells (iPSCs) derived from individuals carrying specific gene variants or mutations provide an alternative cellular model more relevant to humans upon differentiation into specific cell types. Thus, we reprogramed human skin fibroblasts from cognitively normal individuals carrying APOE ε3/ε3 or ε4/ε4 genotype to iPSC clones and further differentiated them into neural progenitor cells and then astrocytes. We found that human iPSC-derived astrocytes secreted abundant apoE with apoE4 lipoprotein particles less lipidated compared to apoE3 particles. More importantly, human iPSC-derived astrocytes were capable of promoting neuronal survival and synaptogenesis when co-cultured with iPSC-derived neurons with APOE ε4/ε4 astrocytes less effective in supporting these neurotrophic functions than those with APOE ε3/ε3 genotype. Taken together, our findings demonstrate APOE genotype-dependent effects using human iPSC-derived astrocytes and provide novel evidence that the human iPSC-based model system is a strong tool to explore how apoE isoforms contribute to neurodegenerative diseases.
Inclusions of TAR DNA-binding protein 43 kDa (TDP-43) has been designated limbic-predominant, age-related TDP-43 encephalopathy (LATE), with or without co-occurrence of Alzheimer's disease (AD). ...Approximately, 30-70% AD cases present TDP-43 proteinopathy (AD-TDP), and a greater disease severity compared to AD patients without TDP-43 pathology. However, it remains unclear to what extent TDP-43 dysfunction is involved in AD pathogenesis.
To investigate whether TDP-43 dysfunction is a prominent feature in AD-TDP cases, we evaluated whether non-conserved cryptic exons, which serve as a marker of TDP-43 dysfunction in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP), accumulate in AD-TDP brains. We assessed a cohort of 192 post-mortem brains from three different brain regions: amygdala, hippocampus, and frontal cortex. Following RNA and protein extraction, qRT-PCR and immunoassays were performed to quantify the accumulation of cryptic RNA targets and phosphorylated TDP-43 pathology, respectively.
We detected the accumulation of misspliced cryptic or skiptic RNAs of STMN2, KCNQ2, UNC13A, CAMK2B, and SYT7 in the amygdala and hippocampus of AD-TDP cases. The topographic distribution of cryptic RNA accumulation mimicked that of phosphorylated TDP-43, regardless of TDP-43 subtype classification. Further, cryptic RNAs efficiently discriminated AD-TDP cases from controls.
Overall, our results indicate that cryptic RNAs may represent an intriguing new therapeutic and diagnostic target in AD, and that methods aimed at detecting and measuring these species in patient biofluids could be used as a reliable tool to assess TDP-43 pathology in AD. Our work also raises the possibility that TDP-43 dysfunction and related changes in cryptic splicing could represent a common molecular mechanism shared between AD-TDP and FTLD-TDP.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Microtubule-associated protein tau (MAPT) mutations cause frontotemporal lobar degeneration, and novel biomarkers are urgently needed for early disease detection. We used task-free functional ...magnetic resonance imaging (fMRI) mapping, a promising biomarker, to analyze network connectivity in symptomatic and presymptomatic MAPT mutation carriers.
We compared cross-sectional fMRI data between 17 symptomatic and 39 presymptomatic carriers and 81 controls with (1) seed-based analyses to examine connectivity within networks associated with the 4 most common MAPT-associated clinical syndromes (ie, salience, corticobasal syndrome, progressive supranuclear palsy syndrome, and default mode networks) and (2) whole-brain connectivity analyses. We applied K-means clustering to explore connectivity heterogeneity in presymptomatic carriers at baseline. Neuropsychological measures, plasma neurofilament light chain, and gray matter volume were compared at baseline and longitudinally between the presymptomatic subgroups defined by their baseline whole-brain connectivity profiles.
Symptomatic and presymptomatic carriers had connectivity disruptions within MAPT-syndromic networks. Compared to controls, presymptomatic carriers showed regions of connectivity alterations with age. Two presymptomatic subgroups were identified by clustering analysis, exhibiting predominantly either whole-brain hypoconnectivity or hyperconnectivity at baseline. At baseline, these two presymptomatic subgroups did not differ in neuropsychological measures, although the hypoconnectivity subgroup had greater plasma neurofilament light chain levels than controls. Longitudinally, both subgroups showed visual memory decline (vs controls), yet the subgroup with baseline hypoconnectivity also had worsening verbal memory and neuropsychiatric symptoms, and extensive bilateral mesial temporal gray matter decline.
Network connectivity alterations arise as early as the presymptomatic phase. Future studies will determine whether presymptomatic carriers' baseline connectivity profiles predict symptomatic conversion. ANN NEUROL 2023;94:632-646.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Objectives
To investigate whether demographic (age and education) adjustments for the Mini‐Mental State Examination (MMSE) attenuate mean score discrepancies between African‐American and Caucasian ...adults and whether demographically adjusted MMSE scores improve the diagnostic classification accuracy of dementia in African‐American adults over unadjusted MMSE scores.
Design
Cross‐sectional study.
Setting
Community‐dwelling adults participating in the Mayo Clinic Alzheimer's Disease Patient Registry and Alzheimer's Disease Research Center.
Participants
Three thousand two hundred fifty‐four adults (2,819 Caucasian, 435 African American) aged 60 and older.
Measurements
MMSE score at study entry.
Results
African‐American adults had significantly lower unadjusted MMSE scores (23.0 ± 7.4) than Caucasian adults (25.3 ± 5.4). This discrepancy persisted despite adjustment of MMSE scores for age and years of education using established regression weights or newly derived weights. Controlling for dementia severity at baseline and adjusting MMSE scores for age and quality of education attenuated this discrepancy. In African‐American adults, an age‐ and education‐adjusted MMSE cut score of 23/24 provided optimal dementia classification accuracy, but this represented only a modest improvement over an unadjusted MMSE cut score of 22/23. The posterior probability of dementia in African‐American adults is presented for various unadjusted MMSE cut scores and prevalence rates of dementia.
Conclusion
Age, dementia severity at study entry, and quality of educational experience are important explanatory factors in understanding the existing discrepancies in MMSE performance between Caucasian and African‐American adults. These findings support the use of unadjusted MMSE scores when screening older African Americans for dementia, with an unadjusted MMSE cut score of 22/23 yielding optimal classification accuracy.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Multiple system atrophy (MSA) presents with various combinations of autonomic dysfunction, parkinsonism, and cerebellar ataxia. Although clinical diagnostic criteria have been widely used, the ...sensitivity and specificity are suboptimal. This study aims to provide evidence supporting the revision of the current diagnostic criteria for MSA.
Medical records of 171 patients with autopsy-confirmed MSA in the Mayo Clinic brain bank were reviewed with regard to their clinical features and diagnoses. Pathologic features, including concomitant pathologies (i.e., Alzheimer-related and Lewy-related pathologies), were also assessed.
The cohort included 133 MSA-parkinsonian type, 36 MSA-cerebellar type, and 2 unclassified MSA patients who did not show significant motor symptoms. Twenty-three patients (13%) were not clinically diagnosed with MSA, but instead with progressive supranuclear palsy, Parkinson's disease (PD), PD with dementia (PDD), or dementia with Lewy bodies (DLB). Three patients with PDD and DLB also had concomitant Lewy body pathology. Six patients had late-onset MSA, with an age of onset greater than 75 years. Erectile dysfunction was frequent in male patients (60/63; 95%) in all age ranges. REM sleep behavior disorder (RBD) was present in 82 patients (48%) and was the initial symptom in 13 patients. Cognitive impairment was present in 60 patients (35%), but was an initial symptom in only two patients.
Our findings support the conclusion that late-onset presentation should not exclude MSA. The findings of this large autopsy-based cohort provides valuable insights for improving clinical criteria for MSA.
•Some multiple system atrophy (MSA) were clinically diagnosed as PSP, PD, PDD, or DLB.•A small subset of MSA had an older symptomatic onset (>75-years).•Current diagnostic criteria for MSA need a revision for improving diagnostic accuracy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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