Limbic-predominant Alzheimer's Disease Research Articles

Imaging markers of cerebral amyloid angiopathy and hypertensive arteriopathy differentiate Alzheimer disease subtypes synergistically

BackgroundBoth cerebral amyloid angiopathy (CAA) and hypertensive arteriopathy (HA) are related to cognitive impairment and dementia. This study aimed to clarify CAA- and HA-related small vessel disease (SVD) imaging marker associations with cognitive dysfunction and Alzheimer disease (AD) subtypes.MethodsA sample of 137 subjects with clinically diagnosed late-onset AD identified from the dementia registry of a single center from January 2017 to October 2021 were enrolled. Semi-quantitative imaging changes (visual rating scale grading) suggestive of SVD were analyzed singularly and compositely, and their correlations with cognitive domains and AD subtypes were examined.ResultsPatients with typical and limbic-predominant AD subtypes had worse cognitive performance and higher dementia severity than minimal-atrophy subtype patients. Deep white matter hyperintensity (WMH) presence correlated inversely with short-term memory (STM) performance. The three composite SVD scores correlated with different cognitive domains and had distinct associations with AD subtypes. After adjusting for relevant demographic factors, multivariate logistic regression (using minimal-atrophy subtype as the reference condition) revealed the following: associations of the typical subtype with periventricular WMH [odds ratio (OR) 2.62; 95% confidence interval (CI), 1.23–5.57, p = 0.012], global SVD score (OR 1.67; 95%CI, 1.11–2.52, p = 0.009), and HA-SVD score (OR 1.93; 95%CI, 1.10–3.52, p = 0.034); associations of limbic-predominant subtype with HA-SVD score (OR 2.57; 95%CI, 1.23–5.37, p = 0.012) and most global and domain-specific cognitive scores; and an association of hippocampal-sparing subtype with HA-SVD score (OR 3.30; 95%CI, 1.58–6.85, p = 0.001).ConclusionComposite SVD imaging markers reflect overall CAA and/or HA severity and may have differential associations with cognitive domains and AD subtypes. Our finding supports the possibility that the clinical AD subtypes may reflect differing burdens of underlying CAA and HA microangiopathologies.

Neuropathologic Features of Antemortem Atrophy-Based Subtypes of Alzheimer Disease.

Background and ObjectivesTo investigate whether antemortem MRI-based atrophy subtypes of Alzheimer disease (AD) differ in neuropathologic features and comorbid non-AD pathologies at postmortem.MethodsFrom the Alzheimer's Disease Neuroimaging Initiative cohort, we included individuals with antemortem MRI evaluating brain atrophy within 2 years before death, antemortem diagnosis of AD dementia/mild cognitive impairment, and postmortem-confirmed AD neuropathologic change. Antemortem atrophy subtypes were modeled as continuous phenomena based on a recent conceptual framework: typicality (spanning limbic-predominant AD to hippocampal-sparing AD) and severity (spanning typical AD to minimal atrophy AD). Postmortem neuropathologic evaluation included AD hallmarks, β-amyloid, and tau as well as non-AD pathologies, alpha-synuclein and TAR DNA-binding protein 43 (TDP-43). We also investigated the overall concomitance across these pathologies. Partial correlations assessed the associations between antemortem atrophy subtypes and postmortem neuropathologic outcomes.ResultsIn 31 individuals (26 AD dementia/5 mild cognitive impairment, mean age = 80 years, 26% females), antemortem typicality was significantly negatively associated with neuropathologic features, including β-amyloid (rho = −0.39 overall), tau (rho = −0.38 regionally), alpha-synuclein (rho = −0.39 regionally), TDP-43 (rho = −0.49 overall), and concomitance of pathologies (rho = −0.59 regionally). Limbic-predominant AD was associated with higher Thal phase, neuritic plaque density, and presence of TDP-43 compared with hippocampal-sparing AD. Regionally, limbic-predominant AD showed a higher presence of tau and alpha-synuclein pathologies in medial temporal structures, a higher presence of TDP-43, and concomitance of pathologies subcortically/cortically compared with hippocampal-sparing AD. Antemortem severity was significantly negatively associated with concomitance of pathologies (rho = −0.43 regionally), such that typical AD showed higher concomitance of pathologies than minimal atrophy AD.DiscussionWe provide a direct antemortem-to-postmortem validation, highlighting the importance of understanding atrophy-based heterogeneity in AD relative to AD and non-AD pathologies. We suggest that (1) typicality and severity in atrophy reflect differential aspects of susceptibility of the brain to AD and non-AD pathologies; and (2) limbic-predominant AD and typical AD subtypes share similar biological pathways, making them more vulnerable to AD and non-AD pathologies compared with hippocampal-sparing AD, which may follow a different biological pathway. Our findings provide a deeper understanding of associations of atrophy subtypes in AD with different pathologies, enhancing the prevailing knowledge of biological heterogeneity in AD and could contribute toward tracking disease progression and designing clinical trials in the future.

Distinct conformers of amyloid beta accumulate in the neocortex of patients with rapidly progressive Alzheimer's disease

Amyloid beta (Aβ) deposition in the neocortex is a major hallmark of Alzheimer's disease (AD), but the extent of deposition does not readily explain phenotypic diversity and rate of disease progression. The prion strain–like model of disease heterogeneity suggests the existence of different conformers of Aβ. We explored this paradigm using conformation-dependent immunoassay (CDI) for Aβ and conformation-sensitive luminescent conjugated oligothiophenes (LCOs) in AD cases with variable progression rates. Mapping the Aβ conformations in the frontal, occipital, and temporal regions in 20 AD patients with CDI revealed extensive interindividual and anatomical diversity in the structural organization of Aβ with the most significant differences in the temporal cortex of rapidly progressive AD. The fluorescence emission spectra collected in situ from Aβ plaques in the same regions demonstrated considerable diversity of spectral characteristics of two LCOs—quatroformylthiophene acetic acid and heptaformylthiophene acetic acid. Heptaformylthiophene acetic acid detected a wider range of Aβ deposits, and both LCOs revealed distinct spectral attributes of diffuse and cored plaques in the temporal cortex of rapidly and slowly progressive AD and less frequent and discernible differences in the frontal and occipital cortex. These and CDI findings indicate a major conformational diversity of Aβ accumulating in the neocortex, with the most notable differences in temporal cortex of cases with shorter disease duration, and implicate distinct Aβ conformers (strains) in the rapid progression of AD.

Editors' Note: Biological Subtypes of Alzheimer Disease: A Systematic Review and Meta-analysis

In the article, “Biological Subtypes of Alzheimer Disease: A Systematic Review and Meta-analysis,” Dr. Ferreira et al. performed a systematic review and meta-analysis on Alzheimer disease (AD) subtype studies based on postmortem and neuroimaging data until July 2019. They identified 4 main subtypes of AD—typical, limbic-predominant, hippocampal-sparing (these 3 being based on the distribution of tau-related pathology and regional atrophy), and minimal atrophy AD. They concluded that 2 core dimensions of the heterogeneity were seen in AD—typicality and severity with further influence driven by a combination of protective factors, risk factors, and concomitant non-AD brain pathologies. In response, Dr. Uleman et al. identify 2 main points for expanding the work of this study—examining the details of the AD criteria used in the individual studies because this too would introduce heterogeneity and could potentially influence the review's conclusions and a reliance on 2 simple linear axes (severity and typicality), which do not capture the complex physiologic pathways of interaction that underlie additional aspects of resilience and resistance in AD. They suggest that drawing on insights about elucidating mechanisms of resilience and resistance to cognitive decline in concussion may be helpful in this regard. Responding to these comments, the authors counter that details on the AD criteria used in the studies included in their review are available in the supplementary material and briefly summarize the trends observed in these criteria. They note that inter-study variability in subtyping methods, rather than AD diagnostic criteria, were a major source of heterogeneity. They clarify that they cannot specify whether the severity and typicality axes are linear and postulate that most of the factors in their model have complex relationships to each other. The authors note the need to empirically test and expand their conceptual model to better understand heterogeneity in AD. This exchange provides a glimpse into the complexities of AD subtyping and the various interconnected factors that are at play. In the article, “Biological Subtypes of Alzheimer Disease: A Systematic Review and Meta-analysis,” Dr. Ferreira et al. performed a systematic review and meta-analysis on Alzheimer disease (AD) subtype studies based on postmortem and neuroimaging data until July 2019. They identified 4 main subtypes of AD—typical, limbic-predominant, hippocampal-sparing (these 3 being based on the distribution of tau-related pathology and regional atrophy), and minimal atrophy AD. They concluded that 2 core dimensions of the heterogeneity were seen in AD—typicality and severity with further influence driven by a combination of protective factors, risk factors, and concomitant non-AD brain pathologies. In response, Dr. Uleman et al. identify 2 main points for expanding the work of this study—examining the details of the AD criteria used in the individual studies because this too would introduce heterogeneity and could potentially influence the review's conclusions and a reliance on 2 simple linear axes (severity and typicality), which do not capture the complex physiologic pathways of interaction that underlie additional aspects of resilience and resistance in AD. They suggest that drawing on insights about elucidating mechanisms of resilience and resistance to cognitive decline in concussion may be helpful in this regard. Responding to these comments, the authors counter that details on the AD criteria used in the studies included in their review are available in the supplementary material and briefly summarize the trends observed in these criteria. They note that inter-study variability in subtyping methods, rather than AD diagnostic criteria, were a major source of heterogeneity. They clarify that they cannot specify whether the severity and typicality axes are linear and postulate that most of the factors in their model have complex relationships to each other. The authors note the need to empirically test and expand their conceptual model to better understand heterogeneity in AD. This exchange provides a glimpse into the complexities of AD subtyping and the various interconnected factors that are at play.

Predictive value of visually rated tau PET imaging for amyloid status, atrophy, and syndromic diagnosis across a spectrum of neurodegenerative phenotypes

AbstractBackgroundWe aimed to investigate the utility of qualitative visual rating of 18F‐flortaucipir tau PET to predict amyloid status, neurodegeneration and syndromic diagnosis across a range of phenotypes associated with underlying Alzheimer disease (AD) and non‐AD neuropathologies.MethodFTP PET, PiB PET, and high resolution T1 MRI scans were rated independently by visual inspection by two raters blinded to clinical diagnosis in n=118 subjects, a subset of whom had clinical diagnoses of amnesic MCI/dementia (n=26), posterior cortical atrophy (n=12), logopenic primary progressive aphasia (n=8), nonfluent PPA (n=7), semantic PPA (n=5), corticobasal syndrome (n=7), behavioral variant frontotemporal dementia (n=2), progressive supranuclear palsy (n=2), dementia with Lewy bodies (n=6), Parkinson disease (n=11), or control (n=20). Scans were classified based on level of uptake [no elevation, questionable or mild elevation, substantial elevation] and distribution of uptake [suggestive of typical AD, limbic predominant AD, hippocampal sparing AD, FTLD, or indeterminate]. PiB PET and MRI scans were rated with respect to level and distribution of uptake/atrophy.Result41/42 subjects with FTP scans classified with substantially elevated signal had PiB scans classified with elevated amyloid, versus 7/11 subjects with FTP classified as having questionable/mild elevation in a distribution suggesting AD, 1/30 with questionable/mild elevation in a distribution suggesting FTLD, 0/9 with questionable/mild elevation in an indeterminate distribution, and 1/26 classified with no elevation in FTP signal. Similarly, 41/42 subjects with FTP classified as having substantially elevated signal had MRI scans classified as having atrophy suggesting neurodegeneration, versus 44/50 subjects with FTP classified as having questionable/mild elevation and 14/26 with no elevation in signal. FTP scans were read to be suggestive of AD‐typ in 21/26 subjects with an amnesic syndrome, suggestive of AD‐hs in 16/20 subjects with lvPPA or PCA, and suggestive of FLTD in 14/23 subjects with bvFTD, nvPPA, svPPA, CBS, or PSP.ConclusionVisually rated tau PET imaging reliably predicts amyloid status and atrophy suggesting neurodegeneration in subjects with substantially elevated signal reflecting neocortical tau. Distribution helps both to determine likelihood of underlying AD neuropathology in cases with questionable/mild signal elevation, and in some cases to predict syndromic diagnosis within the spectrums of AD and FTLD.

Biological subtypes of Alzheimer disease: A systematic review and meta-analysis.

ObjectiveTo test the hypothesis that distinct subtypes of Alzheimer disease (AD) exist and underlie the heterogeneity within AD, we conducted a systematic review and meta-analysis on AD subtype studies based on postmortem and neuroimaging data.MethodsEMBASE, PubMed, and Web of Science databases were consulted until July 2019.ResultsNeuropathology and neuroimaging studies have consistently identified 3 subtypes of AD based on the distribution of tau-related pathology and regional brain atrophy: typical, limbic-predominant, and hippocampal-sparing AD. A fourth subtype, minimal atrophy AD, has been identified in several neuroimaging studies. Typical AD displays tau-related pathology and atrophy both in hippocampus and association cortex and has a pooled frequency of 55%. Limbic-predominant, hippocampal-sparing, and minimal atrophy AD had a pooled frequency of 21%, 17%, and 15%, respectively. Between-subtype differences were found in age at onset, age at assessment, sex distribution, years of education, global cognitive status, disease duration, APOE ε4 genotype, and CSF biomarker levels.ConclusionWe identified 2 core dimensions of heterogeneity: typicality and severity. We propose that these 2 dimensions determine individuals' belonging to one of the AD subtypes based on the combination of protective factors, risk factors, and concomitant non-AD brain pathologies. This model is envisioned to aid with framing hypotheses, study design, interpretation of results, and understanding mechanisms in future subtype studies. Our model can be used along the A/T/N classification scheme for AD biomarkers. Unraveling the heterogeneity within AD is critical for implementing precision medicine approaches and for ultimately developing successful disease-modifying drugs for AD.

Selective Vulnerability of the Nucleus Basalis of Meynert Among Neuropathologic Subtypes of Alzheimer Disease

Corticolimbic patterns of neurofibrillary tangle (NFT) accumulation define neuropathologic subtypes of Alzheimer disease (AD), which underlie the clinical heterogeneity observed antemortem. The cholinergic system, which is the target of acetylcholinesterase inhibitor therapy, is selectively vulnerable in AD. To investigate the major source of cholinergic innervation, the nucleus basalis of Meynert (nbM), in order to determine whether there is differential involvement of NFT accumulation or neuronal loss among AD subtypes. In this cross-sectional study, retrospective abstraction of clinical records and quantitative assessment of NFTs and neuron counts in the nbM was completed in January 2019 at the Mayo Clinic using the Florida Autopsied Multi-Ethnic (FLAME) cohort, which had been accessioned from 1991 until 2015. The FLAME cohort is derived from the deeded autopsy program funded throughout the State of Florida's memory disorder clinic referral services. Of the 2809 consecutively accessioned FLAME cohort, 1464 were identified as neuropathologically diagnosed AD cases and nondemented normal controls available for clinicopathologic assessment. Quantification of NFTs and neuronal density in the anterior nbM was performed blinded to neuropathologic groupings. Demographic and clinical characteristics, including cognitive decline measured using the Mini-Mental State Examination score (range, 0-30), were evaluated. The anterior nbM was investigated quantitatively for neuronal loss and NFT accumulation. In total, 1361 AD subtypes and 103 nondemented controls were assessed. The median (interquartile range) age at death was 72 (66-80) years in hippocampal sparing (HpSp) AD, 81 (76-86) years in typical AD, and 86 (82-90) years in limbic predominant AD. The median (interquartile range) count per 0.125 mm2 of thioflavin S-positive NFTs was highest in the nbM of HpSp AD (14 [9-20]; n = 163), lower in typical AD (10 [5-16]; n = 937), and lowest in limbic predominant AD (8 [5-11], n = 163) (P < .001). The median (interquartile range) neuronal density per millimeters squared was lowest in HpSp AD cases (22 [17-28]; n = 148), higher in typical AD (25 [19-30]; n = 727), and highest in limbic predominant AD (26 [19-32]; n = 127) (P = .002). Multivariable regression modeling of clinical and demographic variables was performed to assess overlap in NFT accumulation and neuronal density differences among AD subtypes. Higher NFT accumulation in the nbM was associated with younger age at onset for HpSp AD (β, -1.5; 95% CI, -2.9 to -0.15; P = .03) and typical AD (β, -3.2; 95% CI, -3.9 to -2.4; P < .001). In addition, higher NFT accumulation in the nbM of typical AD cases was associated with female sex (β, 2.5; 95% CI, 1.4-3.5; P < .001), apolipoprotein E ε4 allele (β, 1.3; 95% CI, 0.15-2.5; P = .03), and lower Mini-Mental State Examination scores (β, -1.8; 95% CI, -3.2 to -0.31; P = .02). Demographic and clinical progression variables were not associated with NFT accumulation in the nbM of limbic predominant AD cases. These data provide supportive evidence that NFT accumulation in the nbM may underlie more widespread and severe cholinergic deficits in young-onset AD, in particular in patients with HpSp AD. Moreover, these findings underscore the importance of considering age at onset, sex, and apolipoprotein E genotype when assessing outcomes in AD.

Tau Subtypes of Alzheimer's Disease Determined in vivo Using Flortaucipir PET Imaging.

At autopsy, individuals with Alzheimer's disease (AD) exhibit heterogeneity in the distribution of neurofibrillary tangles in neocortical and hippocampal regions. Subtypes of AD, defined using an algorithm based on the relative number of tangle counts in these regions, have been proposed-hippocampal sparing (relative sparing of the hippocampus but high cortical load), limbic predominant (high hippocampal load but lower load in association cortices), and typical (balanced neurofibrillary tangles counts in the hippocampus and association cortices) AD-and shown to be associated with distinct antemortem clinical phenotypes. The ability to distinguish these AD subtypes from the more typical tau signature in vivo could have important implications for clinical research. Flortaucipir positron emission tomography (PET) images acquired from 45 amyloid-positive participants, defined clinically as mild cognitive impairment or AD, aged 50-92 years, 56% female, and estimated to be Braak V-VI based on their PET pattern of tau pathology, were studied. By translating the neuropathologic algorithm to flortaucipir PET scans, patterns of tau pathology consistent with autopsy findings, and with a similar prevalence, were identified in vivo. 6/45 (13%) participants were identified as hippocampal sparing and 6/45 (13%) as limbic predominant AD subtypes. Hippocampal sparing participants were significantly younger than those assigned to the other two subtypes. Worse performance on delayed recall was associated with increased hippocampal tau signal, and worse performance on the trail making test B-A was associated with lower values of the hippocampus to cortex ratio. Prospective studies can further validate the flortaucipir SUVR cut-points and the phenotype of the corresponding AD subtypes.

TDP-43 and Alzheimer's Disease Pathologic Subtype in Non-Amnestic Alzheimer's Disease Dementia.

TDP-43 has been shown to be strongly associated with memory loss, smaller hippocampal volumes, and faster rates of hippocampal atrophy in Alzheimer's disease (AD) patients with an amnestic presentation. Whether TDP-43 has any clinical or anatomical associations in AD patients with non-amnestic phenotype is unknown. To determine whether TDP-43 plays a significant role in the clinic-anatomic features of non-amnestic AD. All cases with pathologically confirmed intermediate-high probability AD from 1996-2012 were identified and retrospectively sub-classified into amnestic versus non-amnestic dementia at the time of presentation. Neurofibrillary tangle counts were performed in those with a non-amnestic presentation using thioflavin-S microscopy in the hippocampus and three neocortical regions, and all cases were subtyped into hippocampal-sparing, limbic-predominant, and typical AD pathology. TDP-43 immunoreactivity was used to assess for the presence of TDP-43. Statistical analyses helped determine whether pathologic subtype or TDP-43 was more strongly associated with clinico-imaging features. Out of 172 pathologically confirmed AD cases, 36 (19%) were classified as non-amnestic. Twenty-five of these 36 (69%) had typical pathology, 0 limbic-predominant pathology, and 11 (31%) hippocampal-sparing pathology. Eleven (44%) of the 25 cases with typical pathology were TDP-43+. Of the 11 cases with hippocampal-sparing pathology, 4 (36%) were TDP-43+. There were no differences in demographic, clinical, or neuroimaging features in those with TDP-43 versus those without except for older age at onset (p = 0.02) and age at death (p = 0.02) in those with TDP-43. AD pathological subtype accounted for slightly more of the variances in the neocortex than TDP-43. In non-amnestic AD, we find little evidence that clinical or anatomical features of the disease are related to TDP-43.

The contribution of small vessel disease to subtypes of Alzheimer's disease: a study on cerebrospinal fluid and imaging biomarkers.

We investigated whether subtypes of Alzheimer's disease (AD), that is, typical, limbic-predominant, hippocampal-sparing, and minimal atrophy AD, had a specific signature of small vessel disease and neurodegeneration. Four hundred twenty-three clinically diagnosed AD patients were included (161 typical, 121 limbic-predominant, 70 hippocampal-sparing, 71 minimal atrophy). One hundred fifty-six fulfilled a biomarkers-based AD diagnosis. White matter hyperintensities and cerebral microbleeds (CMB) had the highest prevalence in limbic-predominant AD, and the lowest prevalence in minimal atrophy AD. CMB existed evenly in lobar and deep brain areas in limbic-predominant, typical, and hippocampal-sparing AD. In minimal atrophy AD, CMB were mainly located in brain lobar areas. Perivascular spaces in the centrum semiovale were more prevalent in typical AD. Small vessel disease contributed to the prediction of Mini-Mental State Examination. Minimal atrophy AD showed highly pathological levels of cerebrospinal fluid Aß1-42, total tau, and phosphorylated tau, in the absence of overt brain atrophy. Cerebral amyloid angiopathy seems to have a stronger contribution to hippocampal-sparing and minimal atrophy AD, whereas hypertensive arteriopathy may have a stronger contribution to typical and limbic-predominant AD.

Neuropathologically defined subtypes of Alzheimer's disease differ significantly from neurofibrillary tangle-predominant dementia.

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.

Neuroimaging correlates of pathologically defined subtypes of Alzheimer's disease: a case-control study

Three 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. We 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). Of 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). Patterns 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. US National Institutes of Health (National Institute on Aging).

O4‐04‐01: Differentiating clinicopathologic and genetic aspects of hippocampal sclerosis in Alzheimer's disease from limbic predominant Alzheimer's disease and “pure” hippocampal sclerosis

O4‐04‐01: Differentiating clinicopathologic and genetic aspects of hippocampal sclerosis in Alzheimer's disease from limbic predominant Alzheimer's disease and “pure” hippocampal sclerosis

IC‐O2‐04: High resolution 7T MR imaging of cerebral small vessel disease

Autopsy studies report vascular pathology in the majority of patients with dementia, also in those with a clinical diagnosis of Alzheimer's disease (AD). Vascular co-morbidity in AD is potentially preventable, but we need more sensitive tools to study its etiology and to evaluate the effects of treatment. In this respect, microvascular lesions, in particular microinfarcts and microbleeds are of interest, because they appear to be very common, but may escape detection on regular clinical brain MRI. Ultra high field strength MRI scanners may offer a breakthrough in the detection of microvascular lesions, due to their high spatial resolution and high sensitivity to susceptibility effects. Our group studies small vessel disease on 7T MRI, focusing on microvascular lesions (i.e. microbleeds and microinfarcts), as novel imaging markers of the vascular burden in ageing-related cognitive decline and AD. Our projects involve different study populations, including 1) patients who had an ischaemic stroke, 2) patients with early AD or MCI, 3) patients with type 2 diabetes (a vascular risk factor predisposing to AD) and 4) healthy older controls. Patients (n>200 in total) underwent both a 3T and a 7T MRI scan. The 7T scan (T1-, T2-, and T2*-weighted and FLAIR images) is used for the detection of microvascular lesions and high resolution non-contrast enhanced time-of-flight MR angiography. The 3T scan (3DT1-, T2-, and T2*-weighted, IR, FLAIR, and PD images; DTI; two-dimensional flow-encoded phase-contrast images through the carotid and basilar arteries) is used for automated analyses of brain, cerebrospinal fluid and WMH volumes, DTI analyses of white matter integrity, and assessment of cerebral perfusion. In my presentation I will provide an overview of our 7T MRI studies in these different patient populations. The presentation will address MR angiography, intracranial vascular wall imaging and high resolution measurements of focal atrophy. A particular focus will be on microbleeds and minute cortical infarcts. Patterns of grey matter loss in hippocampal sparing (HpSp), limbic predominant (LP) and typical AD compared to controls (FDR P <0.005)

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

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) ɛ4 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.