Individuals with biomarker evidence of β-amyloid (Aβ) deposition are increasingly being enrolled in clinical treatment trials but there is a need to identify markers to predict which of these ...individuals will also develop tau deposition. We aimed to determine whether Aβ-positive individuals can remain tau-negative for at least 5 years and identify characteristics that could distinguish between these individuals and those who develop high tau within this period.
Tau PET positivity was defined using a Gaussian mixture model with log-transformed standard uptake value ratio values from 7 temporal and medial parietal regions using all participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) with flortaucipir PET. Tau PET scans were classified as normal if the posterior probability of elevated tau was less than 1%. Aβ PET positivity was defined based on ADNI cutpoints. We identified all Aβ-positive individuals from ADNI who had normal tau PET more than 5 years after their first abnormal Aβ PET (amyloid with low tau ALT group) and all Aβ-positive individuals with abnormal tau PET within 5 years (biomarker AD). In a case-control design, logistic regression was used to model the odds of biomarker AD vs ALT accounting for sex, age,
ε4 carriership, Aβ Centiloid, and hippocampal volume.
We identified 45 individuals meeting criteria for ALT and 157 meeting criteria for biomarker AD. The ALT group had a lower proportion of
ε4 carriers, lower Aβ Centiloid, larger hippocampal volumes, and more preserved cognition, and were less likely to develop dementia, than the biomarker AD group.
ε4, higher Aβ Centiloid, and hippocampal atrophy were independently associated with increased odds of abnormal tau within 5 years. A Centiloid value of 50 effectively discriminated biomarker AD and ALT with 80% sensitivity and specificity. The majority of the ALT participants did not develop dementia throughout the 5-year interval.
Aβ-positive individuals can remain tau-negative for at least 5 years. Baseline characteristics can help identify these ALT individuals who are less likely to develop dementia. Conservative Aβ cutpoints should be utilized for clinical trials to better capture individuals with high risk of developing biomarker AD.
OBJECTIVE:To determine ways to improve diagnostic accuracy of multiple system atrophy (MSA), we assessed the diagnostic process in patients who came to autopsy with antemortem diagnosis of MSA by ...comparing clinical and pathologic features between those who proved to have MSA and those who did not. We focus on likely explanations for misdiagnosis.
METHODS:This is a retrospective review of 134 consecutive patients with an antemortem clinical diagnosis of MSA who came to autopsy with neuropathologic evaluation of the brain. Of the 134 patients, 125 had adequate medical records for review. Clinical and pathologic features were compared between patients with autopsy-confirmed MSA and those with other pathologic diagnoses, including dementia with Lewy bodies (DLB), Parkinson disease (PD), and progressive supranuclear palsy (PSP).
RESULTS:Of the 134 patients with clinically diagnosed MSA, 83 (62%) had the correct diagnosis at autopsy. Pathologically confirmed DLB was the most common misdiagnosis, followed by PSP and PD. Despite meeting pathologic criteria for intermediate to high likelihood of DLB, several patients with DLB did not have dementia and none had significant Alzheimer-type pathology. Autonomic failure was the leading cause of misdiagnosis in DLB and PD, and cerebellar ataxia was the leading cause of misdiagnosis in PSP.
CONCLUSIONS:The diagnostic accuracy for MSA was suboptimal in this autopsy study. Pathologically confirmed DLB, PD, and PSP were the most common diseases to masquerade as MSA. This has significant implications not only for patient care, but also for research studies in MSA cases that do not have pathologic confirmation.
OBJECTIVE:To determine how well the consensus criteria could classify subjects with primary progressive aphasia (PPA) using a quantitative speech and language battery that matches the test ...descriptions provided by the consensus criteria.
METHODS:A total of 105 participants with a neurodegenerative speech and language disorder were prospectively recruited and underwent neurologic, neuropsychological, and speech and language testing and MRI in this case-control study. Twenty-one participants with apraxia of speech without aphasia served as controls. Select tests from the speech and language battery were chosen for application of consensus criteria and cutoffs were employed to determine syndromic classification. Hierarchical cluster analysis was used to examine participants who could not be classified.
RESULTS:Of the 84 participants, 58 (69%) could be classified as agrammatic (27%), semantic (7%), or logopenic (35%) variants of PPA. The remaining 31% of participants could not be classified. Of the unclassifiable participants, 2 clusters were identified. The speech and language profile of the first cluster resembled mild logopenic PPA and the second cluster semantic PPA. Gray matter patterns of loss of these 2 clusters of unclassified participants also resembled mild logopenic and semantic variants.
CONCLUSIONS:Quantitative application of consensus PPA criteria yields the 3 syndromic variants but leaves a large proportion unclassified. Therefore, the current consensus criteria need to be modified in order to improve sensitivity.
In this study, we update the TDP-43 in Alzheimer’s disease staging scheme by assessing the topography of TDP-43 in 193 cases of Alzheimer’s disease, in 14 different brain regions (eight previously ...described plus six newly reported) and use conditional probability to model the spread of TDP-43 across the 14 brain regions. We show that in addition to the eight original regions we previously reported amygdala, entorhinal cortex, subiculum, dentate gyrus of the hippocampus, occipitotemporal cortex, inferior temporal cortex, middle frontal cortex and basal ganglia (putamen/globus pallidum) that TDP-43 is also deposited in the insular cortex, ventral striatum, basal forebrain, substantia nigra, midbrain tectum, and the inferior olive of the medulla oblongata, in Alzheimer’s disease. The conditional probability analysis produced six significantly different stages (
P
< 0.01), and suggests that TDP-43 deposition begins in the amygdala (stage 1), then moves to entorhinal cortex and subiculum (stage 2); to the dentate gyrus of the hippocampus and occipitotemporal cortex (stage 3); insular cortex, ventral striatum, basal forebrain and inferior temporal cortex (stage 4); substantia nigra, inferior olive and midbrain tectum (stage 5); and finally to basal ganglia and middle frontal cortex (stage 6). This updated staging scheme is superior to our previous staging scheme, classifying 100 % of the cases (versus 94 % in the old scheme), based on criteria provided, and shows clinical significance with some regions and with increasing stage. We discuss the relevance of the updated staging scheme, as well as its impact on the prion-like hypothesis of protein spread in neurodegenerative disease. We also address the issue of whether frontotemporal lobar degeneration with TDP-43 could be the primary pathology in stage 6.
It has been approximately 50 years since neurologists were introduced to the entities, “progressive supranuclear palsy” and “corticobasal degeneration”. Since the two seminal publications, there have ...been significant advancements in our understanding of these two neurodegenerative diseases, particularly the fact that both are associated with tau. Recent advances over the past 3 years that are notable to the field are discussed in this review that covers clinical diagnosis, pathological features, neuroimaging and CSF biomarkers, genetic associations and clinical trials related to progressive supranuclear palsy and corticobasal degeneration.
TDP-43 immunoreactivity occurs in 19–57 % of Alzheimer’s disease (AD) cases. Two patterns of TDP-43 deposition in AD have been described involving hippocampus (limbic) or hippocampus and neocortex ...(diffuse), although focal amygdala involvement has been observed. In 195 AD cases with TDP-43, we investigated regional TDP-43 immunoreactivity with the aim of developing a TDP-43 in AD staging scheme. TDP-43 immunoreactivity was assessed in amygdala, entorhinal cortex, subiculum, hippocampal dentate gyrus, occipitotemporal, inferior temporal and frontal cortices, and basal ganglia. Clinical, neuroimaging, genetic and pathological characteristics were assessed across stages. Five stages were identified: stage I showed scant-sparse TDP-43 in the amygdala only (17 %); stage II showed moderate-frequent amygdala TDP-43 with spread into entorhinal and subiculum (25 %); stage III showed further spread into dentate gyrus and occipitotemporal cortex (31 %); stage IV showed further spread into inferior temporal cortex (20 %); and stage V showed involvement of frontal cortex and basal ganglia (7 %). Cognition and medial temporal volumes differed across all stages and progression across stages correlated with worsening cognition and medial temporal volume loss. Compared to 147 AD patients without TDP-43, only the Boston Naming Test showed abnormalities in stage I. The findings demonstrate that TDP-43 deposition in AD progresses in a stereotypic manner that can be divided into five distinct topographic stages which are supported by correlations with clinical and neuroimaging features. Given these findings, we recommend sequential regional TDP-43 screening in AD beginning with the amygdala.
Neurodegenerative tauopathies, of which progressive supranuclear palsy (PSP) is one of the most common, are clinically heterogeneous, reflecting differences in distribution and biochemical ...composition of tau pathology. This review highlights the range of clinical and pathologic presentations of PSP and its variants.
Progressive supranuclear palsy is a 4R tauopathy with neuronal and glial tau-immunoreactive lesions in neuroanatomically specific nuclei in the basal ganglia, diencephalon, brainstem and cerebellum, with restricted involvement of the neocortex. Hierarchical cluster analyses of clinical and pathologic features of PSP indicate that there are distinct clinicopathologic variants of PSP. In variants of PSP presenting with focal cortical syndromes, such as frontotemporal dementia, corticobasal syndrome and apraxia of speech, there is greater cortical pathology than in typical PSP. In variants of PSP presenting with levodopa-responsive Parkinsonism, as well as pure akinesia and gait failure, there is less cortical pathology and more severe degeneration in the cardinal nuclei - globus pallidus, subthalamic nucleus and substantia nigra - than in typical PSP.
Clinical variants in PSP reflect varying anatomical distribution of tau pathology, but they share histopathologic, biochemical and genetic features with typical PSP. The basis for anatomical selective vulnerability in PSP and its variants remains to be determined.
We investigate whether there is any association between the Braak neurofibrillary tangle (NFT) stage and clinical and MRI features in definite primary age-related tauopathy (PART). We analysed 52 ...cases with a Braak NFT tangle stage >0 and ≤IV, and a Thal phase of 0 (no beta-amyloid present). Twenty-nine (56%) were female. Median age at death was 88 years (IQR 82–92 years). Fifteen (29%) were TDP-positive (75% TDP stage I), 16 (31%) had argyrophilic grain disease and three (6%) had alpha-synuclein-positive Lewy bodies. TDP-43 inclusion when present were rare and predominantly perivascular. Of the 15 with TDP-43, three showed a moderate number of inclusions and also had hippocampal sclerosis, neuronal intranuclear inclusions and fine neurites of the CA1 region of the hippocampus. Four cases (8%) had an apolipoprotein epsilon 4 (APOE4) allele. There was a significant correlation between age at death and Braak NFT stage (
r
= 0.32,
p
= 0.02). After accounting for age at clinical examination, there were significant associations between Braak NFT stage, and WAIS-R Block Design and Trail Making Tests A and B, with higher Braak stage associated with poorer performances. Thirty of the 52 cases had completed an antemortem volumetric head MRI. Two separate MRI analyses revealed an association between higher Braak NFT stage and grey matter atrophy in the head of the left hippocampus. There were no significant clinical or radiologic associations with TDP-43. Findings from this study demonstrate that aggregated tau distribution is associated with poorer cognitive performance, as well as atrophy, in the absence of beta-amyloid. These findings support the parcellation of definite PART as a useful construct. The relatively low frequencies of APOE4, TDP-43, Lewy bodies, and hippocampal sclerosis, and the rarity and morphology of TDP-43 lesions are noted contrasts to what is typically observed in Alzheimer’s disease of the old.
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