Brain collection, standardized neuropathologic assessment, and comorbidity in Alzheimer's Disease Neuroimaging Initiative 2 participants

Franklin, Erin; Perrin, Richard J.; Vincent, Benjamin D.; Baxter, Michael R. N.; Morris, John C.; Cairns, Nigel J.

doi:10.1016/j.jalz.2015.05.010

Cited by 51 publications

(46 citation statements)

References 21 publications

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“…A common feature in several neurodegenerative diseases affecting memory is the presence of brain amyloidosis, including plaques (Aβ), tangles (tau) and Lewy bodies (α-synuclein), and neuropathological studies have shown that ADD patients often have other concomitant pathologies, besides plaques and tangles [12, 24, 37]. We found increased CSF Ng concentrations with increased Thal, CERAD and Braak scores demonstrating that Ng is linked to the ADD pathology.…”

Section: Discussionmentioning

confidence: 60%

Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology

et al. 2018

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Neurogranin (Ng) is a post-synaptic protein that previously has been shown to be a biomarker for synaptic function when measured in cerebrospinal fluid (CSF). The CSF concentration of Ng is increased in Alzheimer’s disease dementia (ADD), and even in the pre-dementia stage. In this prospective study, we used an enzyme-linked immunosorbent assay that quantifies Ng in CSF to test the performance of Ng as a marker of synaptic function. In 915 patients, CSF Ng was evaluated across several different neurodegenerative diseases. Of these 915 patients, 116 had a neuropathologically confirmed definitive diagnosis and the relation between CSF Ng and topographical distribution of different pathologies in the brain was evaluated. CSF Ng was specifically increased in ADD compared to eight other neurodegenerative diseases, including Parkinson’s disease (p < 0.0001), frontotemporal dementia (p < 0.0001), and amyotrophic lateral sclerosis (p = 0.0002). Similar results were obtained in neuropathologically confirmed cases. Using a biomarker index to evaluate whether CSF Ng contributed diagnostic information to the core AD CSF biomarkers (amyloid β (Aβ), t-tau, and p-tau), we show that Ng significantly increased the discrimination between AD and several other disorders. Higher CSF Ng levels were positively associated with greater Aβ neuritic plaque (Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuritic plaque score, p = 0.0002) and tau tangle pathology (Braak neurofibrillary tangles staging, p = 0.0007) scores. In the hippocampus and amygdala, two brain regions heavily affected in ADD with high expression of Ng, CSF Ng was associated with plaque (p = 0.0006 and p < 0.0001), but not with tangle, α-synuclein, or TAR DNA-binding protein 43 loads. These data support that CSF Ng is increased specifically in ADD, that high CSF Ng concentrations likely reflect synaptic dysfunction and that CSF Ng is associated with β-amyloid plaque pathology.Electronic supplementary materialThe online version of this article (10.1007/s00401-018-1851-x) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 60%

Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology

et al. 2018

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“…Our case suggests that the implementation of gene analysis should be considered when a patient shows presenile‐onset of uncommon psychiatric changes and a family history of neurological diseases cannot be completely denied. In addition, it should be emphasized that, even in the exploration of the relationship between a mutation and its clinical presentation, investigations using autopsy cases may clarify the influence of incidentally coexisting age‐related degenerative diseases that can cause cognitive impairment and psychiatric and behavioral changes . In this context, the accumulation of data regarding clinical features in pathologically confirmed cases bearing MAPT mutations may be required to improve the accuracy of the ante mortem identification of FTLD‐related pathological bases.…”

Section: Discussionmentioning

confidence: 99%

Frontotemporal lobar degeneration due to P301L tau mutation showing apathy and severe frontal atrophy but lacking other behavioral changes: A case report and literature review

et al. 2017

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The clinical features in cases that have mutations in the microtubule-associated protein tau gene but lack prominent behavioral changes remain unclear. Here, we describe detailed clinical and pathological features of a case carrying the P301L tau mutation that showed only apathy until the middle stage of the course. The mother of this case was suspected to have mild cognitive decline at age 46. However, before she was fully examined, she had a subarachnoid hemorrhage at age 49 and died at age 53. An autopsy was not done. The proband of this pedigree, a 60-year-old right-handed Japanese man at the time of death, began to make mistakes at work at the age of 51 years. Until age 54, he showed only mild apathy with bradykinesia. Insight was well spared. Parkinsonism and echolalia developed at age 55, and pyramidal signs and oral tendency at age 57. Personality change, disinhibition, stereotypy, or semantic memory impairment was not found throughout the course. The final neurological diagnosis was unspecified dementia. Pathological examination demonstrated numerous round four-repeat tau-positive three-repeat tau-negative or perinuclear ring-like neuronal cytoplasmic inclusions with many ballooned neurons in the frontal and temporal cortices and hippocampus. Genetic analysis using frozen brain tissue demonstrated a P301L tau mutation. Among 31 previously reported cases bearing the P301L tau mutation for which the data regarding initial symptoms are available, one clinical case showed only apathy with depression in the early stage. Given these findings, clinicians should be aware that a clinical course characterized only by apathy for several years, which can be misdiagnosed as a psychiatric disorder, is one of the clinical presentations associated with P301L tau mutation.

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“…Consistent with our previous work , a key feature of our modeling approach is that it allows the possibility that multiple latent factors are expressed to varying degrees within an individual. This is motivated by an extensive literature suggesting multiple etiologies underlying disease heterogeneity that are not mutually exclusive (Schneider et al, 2007;Schneider et al, 2009;Dickerson and Wolk, 2011;Murray et al, 2011;Franklin et al, 2015;Coutu et al, 2016;Ossenkoppele et al, 2016). For example, the atrophy-cognitive profiles of a patient might be 80% owing to factor 1, 15% to factor 2, and 5% to factor 3, whereas the atrophy-cognitive profiles of another patient might be 30% owing to factor 1, 65% to factor 2, and 5% to factor 3.…”

Section: Figure 1 a Bayesian Model Of Ad Dementia Patients Latent Fmentioning

confidence: 99%

Multi-modal Latent Factor Exploration of Atrophy, Cognitive and Tau Heterogeneity in Alzheimer’s Disease

Sun

Mormino

Chen

et al. 2018

Preprint

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Individuals with Alzheimer's disease (AD) dementia exhibit significant heterogeneity across clinical symptoms, atrophy patterns, and spatial distribution of Tau deposition. Most previous studies of AD heterogeneity have focused on atypical clinical subtypes, defined subtypes with a single modality, or restricted their analyses to a priori brain regions and cognitive tests. Here, we considered a data-driven hierarchical Bayesian model to identify latent factors from atrophy patterns and cognitive deficits simultaneously, thus exploiting the rich dimensionality within each modality. Unlike most previous studies, our model allows each factor to be expressed to varying degrees within an individual, in order to reflect potential multiple co-existing pathologies. By applying our model to ADNI-GO/2 AD dementia participants, we found three atrophy-cognitive factors. The first factor was associated with medial temporal lobe atrophy, episodic memory deficits and disorientation to time/place ("MTL-Memory"). The second factor was associated with lateral temporal atrophy and language deficits ("Lateral Temporal-Language"). The third factor was associated with atrophy in posterior bilateral cortex, and visuospatial executive function deficits ("Posterior Cortical-Executive"). While the MTL-Memory and Posterior Cortical-Executive factors were discussed in previous literature, the Lateral Temporal-Language factor is novel and emerged only by considering atrophy and cognition jointly. Several analyses were performed to ensure generalizability, replicability and stability of the estimated factors. First, the factors generalized to new participants within a 10fold cross-validation of ADNI-GO/2 AD dementia participants. Second, the factors were replicated in an independent ADNI-1 AD dementia cohort. Third, factor loadings of ADNI-GO/2 AD dementia participants were longitudinally stable, suggesting that these factors capture heterogeneity across patients, rather than longitudinal disease progression. Fourth, the model outperformed canonical correlation analysis at capturing associations between atrophy patterns and cognitive deficits.To explore the influence of the factors early in the disease process, factor loadings were estimated in ADNI-GO/2 mild cognitively impaired (MCI) participants. Although the associations between the atrophy patterns and cognitive profiles were weak in MCI compared to AD, we found that factor loadings were associated with inter-individual regional variation in Tau uptake. Taken together, these results suggest that distinct atrophy-cognitive patterns exist in typical Alzheimer's disease, and are associated with distinct patterns of Tau depositions before clinical dementia emerges. Highlights:1. Bayesian model reveals 3 atrophy-cognitive factors in typical AD from ADNI-GO/2 2. Replicated in independent ADNI-1 cohort; longitudinally stable within individuals 3. Triple cognitive dissociations among atrophy patterns suggest subtypes, not stages 4. Outperforms canonical correlation analysis 5. Factor loadings as...

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Brain collection, standardized neuropathologic assessment, and comorbidity in Alzheimer's Disease Neuroimaging Initiative 2 participants

Cited by 51 publications

References 21 publications

Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology

Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology

Frontotemporal lobar degeneration due to P301L tau mutation showing apathy and severe frontal atrophy but lacking other behavioral changes: A case report and literature review

Multi-modal Latent Factor Exploration of Atrophy, Cognitive and Tau Heterogeneity in Alzheimer’s Disease

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