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Neuropathologically defined subtypes of Alzheimer's disease with distinct clinical characteristics: a retrospective study.

ABSTRACT: Neurofibrillary pathology has a stereotypical progression in Alzheimer's disease (AD) that is encapsulated in the Braak staging scheme; however, some AD cases are atypical and do not fit into this scheme. We aimed to compare clinical and neuropathological features between typical and atypical AD cases.AD cases with a Braak neurofibrillary tangle stage of more than IV were identified from a brain bank database. By use of thioflavin-S fluorescence microscopy, we assessed the density and the distribution of neurofibrillary tangles in three cortical regions and two hippocampal sectors. These data were used to construct an algorithm to classify AD cases into typical, hippocampal sparing, or limbic predominant. Classified cases were then compared for clinical, demographic, pathological, and genetic characteristics. An independent cohort of AD cases was assessed to validate findings from the initial cohort.889 cases of AD, 398 men and 491 women with age at death of 37-103 years, were classified with the algorithm as hippocampal sparing (97 cases [11%]), typical (665 [75%]), or limbic predominant (127 [14%]). By comparison with typical AD, neurofibrillary tangle counts per 0.125 mm(2) in hippocampal sparing cases were higher in cortical areas (median 13, IQR 11-16) and lower in the hippocampus (7.5, 5.2-9.5), whereas counts in limbic-predominant cases were lower in cortical areas (4.3, 3.0-5.7) and higher in the hippocampus (27, 22-35). Hippocampal sparing cases had less hippocampal atrophy than did typical and limbic-predominant cases. Patients with hippocampal sparing AD were younger at death (mean 72 years [SD 10]) and a higher proportion of them were men (61 [63%]), whereas those with limbic-predominant AD were older (mean 86 years [SD 6]) and a higher proportion of them were women (87 [69%]). Microtubule-associated protein tau (MAPT) H1H1 genotype was more common in limbic-predominant AD (54 [70%]) than in hippocampal sparing AD (24 [46%]; p=0.011), but did not differ significantly between limbic-predominant and typical AD (204 [59%]; p=0.11). Apolipoprotein E (APOE) ?4 allele status differed between AD subtypes only when data were stratified by age at onset. Clinical presentation, age at onset, disease duration, and rate of cognitive decline differed between the AD subtypes. These findings were confirmed in a validation cohort of 113 patients with AD.These data support the hypothesis that AD has distinct clinicopathological subtypes. Hippocampal sparing and limbic-predominant AD subtypes might account for about 25% of cases, and hence should be considered when designing clinical, genetic, biomarker, and treatment studies in patients with AD.US National Institutes of Health via Mayo Alzheimer's Disease Research Center, Mayo Clinic Study on Aging, Florida Alzheimer's Disease Research Center, and Einstein Aging Study; and State of Florida Alzheimer's Disease Initiative.

SUBMITTER: Murray ME

PROVIDER: S-EPMC3175379 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Neuropathologically defined subtypes of Alzheimer's disease with distinct clinical characteristics: a retrospective study.

Murray Melissa E ME Graff-Radford Neill R NR Ross Owen A OA Petersen Ronald C RC Duara Ranjan R Dickson Dennis W DW

The Lancet. Neurology 20110727 9

<h4>Background</h4>Neurofibrillary pathology has a stereotypical progression in Alzheimer's disease (AD) that is encapsulated in the Braak staging scheme; however, some AD cases are atypical and do not fit into this scheme. We aimed to compare clinical and neuropathological features between typical and atypical AD cases.<h4>Methods</h4>AD cases with a Braak neurofibrillary tangle stage of more than IV were identified from a brain bank database. By use of thioflavin-S fluorescence microscopy, we ...[more]

PMID: 21802369

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Project description: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.

Project description:BackgroundThree subtypes of Alzheimer's disease (AD) have been pathologically defined on the basis of the distribution of neurofibrillary tangles: typical AD, hippocampal-sparing AD, and limbic-predominant AD. Compared with typical AD, hippocampal-sparing AD has more neurofibrillary tangles in the cortex and fewer in the hippocampus, whereas the opposite pattern is seen in limbic-predominant AD. We aimed to determine whether MRI patterns of atrophy differ between these subtypes and whether structural neuroimaging could be a useful predictor of pathological subtype at autopsy.MethodsWe identified patients who had been followed up in the Mayo Clinic Alzheimer's Disease Research Center (Rochester, MN, USA) or in the Alzheimer's Disease Patient Registry (Rochester, MN, USA) between 1992 and 2005. To be eligible for inclusion, participants had to have had dementia, AD pathology at autopsy (Braak stage ≥IV and intermediate to high probability of AD), and an ante-mortem MRI. Cases were assigned to one of three pathological subtypes--hippocampal-sparing, limbic-predominant, and typical AD--on the basis of neurofibrillary tangle counts in hippocampus and cortex and ratio of hippocampal to cortical burden, without reference to neuronal loss. Voxel-based morphometry and atlas-based parcellation were used to compare patterns of grey matter loss between groups and with age-matched control individuals. Neuroimaging was obtained at the time of first presentation. To summarise pair-wise group differences, we report the area under the receiver operator characteristic curve (AUROC).FindingsOf 177 eligible patients, 125 (71%) were classified as having typical AD, 33 (19%) as having limbic-predominant AD, and 19 (11%) as having hippocampal-sparing AD. Most patients with typical (98 [78%]) and limbic-predominant AD (31 [94%]) initially presented with an amnestic syndrome, but fewer patients with hippocampal-sparing AD (eight [42%]) did. The most severe medial temporal atrophy was recorded in patients with limbic-predominant AD, followed by those with typical disease, and then those with hippocampal-sparing AD. Conversely, the most severe cortical atrophy was noted in patients with hippocampal-sparing AD, followed by those with typical disease, and then limbic-predominant AD. The ratio of hippocampal to cortical volumes allowed the best discrimination between subtypes (p<0·0001; three-way AUROC 0·52 [95% CI 0·47-0·52]; ratio of AUROC to chance classification 3·1 [2·8-3·1]). Patients with typical AD and non-amnesic initial presentation had a significantly higher ratio of hippocampal to cortical volumes (median 0·045 [IQR 0·035-0·056]) than did those with an amnesic presentation (0·041 [0·031-0·057]; p=0·001).InterpretationPatterns of atrophy on MRI differ across the pathological subtypes of AD. MRI regional volumetric analysis can reliably track the distribution of neurofibrillary tangle pathology and can predict pathological subtype of AD at autopsy.FundingUS National Institutes of Health (National Institute on Aging).

Project description:Background: The National Institute on Aging-Alzheimer's Association (NIA-AA) has proposed a biological definition of Alzheimer's disease (AD): individuals with both abnormal amyloid and tau biomarkers (A+T+) would be defined as AD. It remains unclear why different cognitive status is present in subjects with biological AD. Resting-state functional magnetic resonance imaging (rsfMRI) has provided an opportunity to reveal the brain activity patterns in a biologically-defined AD cohort. Accordingly, we aimed to investigate distinct brain activity patterns in subjects with existed AD pathology but in the different cognitive stages. Method: We selected individuals with AD pathology (A+T+) and healthy controls (HC, A-T-) based on the cerebrospinal fluid (CSF) biomarkers. According to the cognitive stage, we divided the A+T+ cohort into three groups: (1) preclinical AD; (2) prodromal AD; and (3) AD with dementia (d-AD). We compared spontaneous brain activity measured by a fractional amplitude of low-frequency fluctuation (fALFF) approach among four groups. Results: The analysis of covariance (ANCOVA) results showed significant differences in fALFF in the posterior cingulate cortex/precuneus (PCC/PCu). Further, compared to HC, we found increased fALFF values in the right inferior frontal gyrus (IFG) in the preclinical AD stage, whereas prodromal AD patients showed reduced fALFF in the bilateral precuneus, right middle frontal gyrus (MFG), right precentral gyrus, and postcentral gyrus. Within the d-AD group, both hyperactivity (right fusiform gyrus, right parahippocampal gyrus (PHG)/hippocampus, and inferior temporal gyrus) and hypoactivity (bilateral precuneus, left posterior cingulate cortex, left cuneus and superior occipital gyrus) were detected. Conclusion: We found the distinct brain activity patterns in different cognitive stages among the subjects defined as AD biologically. Our findings may be helpful in understanding mechanisms leading to cognitive changes in the AD pathophysiological process.

Project description:IntroductionAlzheimer's disease (AD) and Lewy body disease (LBD) are the two most common neurodegenerative dementias and can occur in combination (AD+LBD). Due to overlapping biomarkers and symptoms, clinical differentiation of these subtypes could be difficult. However, it is unclear how the magnitude of diagnostic uncertainty varies across dementia spectra and demographic variables. We aimed to compare clinical diagnosis and post-mortem autopsy-confirmed pathological results to assess the clinical subtype diagnosis quality across these factors.MethodsWe studied data of 1,920 participants recorded by the National Alzheimer's Coordinating Center from 2005 to 2019. Selection criteria included autopsy-based neuropathological assessments for AD and LBD, and the initial visit with Clinical Dementia Rating (CDR) stage of normal, mild cognitive impairment, or mild dementia. Longitudinally, we analyzed the first visit at each subsequent CDR stage. This analysis included positive predictive values, specificity, sensitivity and false negative rates of clinical diagnosis, as well as disparities by sex, race, age, and education. If autopsy-confirmed AD and/or LBD was missed in the clinic, the alternative clinical diagnosis was analyzed.FindingsIn our findings, clinical diagnosis of AD+LBD had poor sensitivities. Over 61% of participants with autopsy-confirmed AD+LBD were diagnosed clinically as AD. Clinical diagnosis of AD had a low sensitivity at the early dementia stage and low specificities at all stages. Among participants diagnosed as AD in the clinic, over 32% had concurrent LBD neuropathology at autopsy. Among participants diagnosed as LBD, 32% to 54% revealed concurrent autopsy-confirmed AD pathology. When three subtypes were missed by clinicians, "No cognitive impairment" and "primary progressive aphasia or behavioral variant frontotemporal dementia" were the leading primary etiologic clinical diagnoses. With increasing dementia stages, the clinical diagnosis accuracy of black participants became significantly worse than other races, and diagnosis quality significantly improved for males but not females.DiscussionThese findings demonstrate that clinical diagnosis of AD, LBD, and AD+LBD are inaccurate and suffer from significant disparities on race and sex. They provide important implications for clinical management, anticipatory guidance, trial enrollment and applicability of potential therapies for AD, and promote research into better biomarker-based assessment of LBD pathology.

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Neuropathologically defined subtypes of Alzheimer's disease with distinct clinical characteristics: a retrospective study.

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Neuropathologically defined subtypes of Alzheimer's disease with distinct clinical characteristics: a retrospective study.

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