Reichard, Ross R.

AbstractBackgroundSummarizing the multiplicity and heterogeneity of cerebrovascular disease (CVD) features into a single measure has been difficult in both pathology and imaging studies. The objective of this work was to evaluate the association between neuroimaging surrogates of CVD and two available neuropathologic CVD scales in those with both antemortem imaging CVD measures and post‐mortem CVD evaluation. We used (1) Strozyk scale (Strozyk et. al. NBA 2010) which is based on presence and number of three macroscopic lesions (large infarctions, lacunar infarctions, and leukoencephalopathy) and (2) Kalaria scale (Deramecourt et. al. Neurology 2012) which summarizes detailed evaluation of vessel wall modifications (arteriolosclerosis, amyloid angiopathy), perivascular spaces, myelin loss, microinfarctions, and large infarctions.MethodWe identified n=51 individuals in Mayo Clinic Study of Aging (mean age of 83.8 years, 37% female) with MRI scans within 5 years of death. We computed CVD measures from DTI (fractional anisotropy of the genu of the corpus callosum [FAGCC] and fractional anisotropy of cingulum adjoining the hippocampus [FACGH]), FLAIR (white matter hyperintensities [WMH] and total number of infarctions), and T2* GRE (total number of microbleeds). We also computed our recently developed imaging CVD composite score which summarizes the variability in all individual CVD imaging measures described above. We computed the Strozyk and Kalaria scales on postmortem tissue. We used weighted linear regression models with adjustments for MRI scan time to death to evaluate the associations between the antemortem neuroimaging measures and pathology scales in those who had scans within 3 years of death (N=31) and 5 years of death (N=51) (tables 1 and 2).ResultOf all the neuroimaging measures, DTI measures were the best predictors of the Strozyk and Kalaria Scales (p<0.05). In sensitivity analyses of data in Table 1, FAGCC explained 44% and FACGH predicted only 5.5% variability in white matter sub‐component of the Strozyk scale. The CVD composite score was a poor surrogate of the composite pathological scales.ConclusionMicrostructural white matter injury measurement using DTI may be a good surrogate of pathological CVD scales and possibly captures diffuse (and early) changes to white matter and secondary neurodegeneration due to lesions.

AbstractBackgroundThe Neurodegenerative Research Group (NRG) at Mayo clinic has followed patients with degenerative speech and/or language disorders for over a decade. In this presentation I will present data from this cohort to inform a broader discussion about the importance of apraxia of speech (AOS) and its subtypes, heterogeneity within the agrammatic PPA variant, and perils of mixed phenotypes.MethodWe reviewed the NRG database to identify patients who initially presented with isolated (PPAOS), AOS in conjunction with agrammatic aphasia (AOS‐PAA), isolated agrammatic aphasia (PAA), and patients who had PAA or AOS overlapping with another degenerative diagnosis. Data from the following clinical instruments were abstracted: WAB AQ (aphasia severity), UPDRS III (parkinsonism), WAB Praxis (ideomotor apraxia), and the MoCA (cognitive ability). We assessed the effect of baseline diagnosis and AOS subtype on these outcomes over time using Bayesian linear mixed effects models. We qualitatively reviewed longitudinal diagnostic trajectories. Preliminary analyses were done on available autopsy data.ResultPAA was associated with greater aphasia at baseline and more rapid decline; PPAOS was associated with normal language at baseline and slow decline; and PAA‐AOS with intermediate baseline aphasia and decline. However, for those with AOS longitudinal decline differed based on AOS subtype: prosodic PPAOS was associated with the slowest decline and phonetic PAA‐AOS with the fastest. Some patients met criteria for non‐PPA disorders during follow up. However, compared to patients who met criteria for these disorders at enrollment, the speech/language‐first patients remained qualitatively distinct, and neither resembled the cases that were mixed at onset. Preliminary autopsy data suggests that AOS is predictive of tau and that the specific tauopathy may be related to the initial syndrome and AOS subtype.ConclusionThe differences between PAA, PAA‐AOS and PPAOS suggest that these disorders should not be lumped. In fact, the longitudinal trajectories are sufficiently different that doing so would add noise to observational and interventional studies. Instead, more detailed phenotyping, including AOS subtype, can aid prognostication and may improve prediction of the underlying pathology. Finally, caution should be exercised when considering PPAOS and PPA patients for other FTLD diagnostic categories.

AbstractBackgroundAdvancing age is an important risk factor for dementia and cancer. An inverse association between these conditions has been described, yet caution from potential biases/confounders is warranted. Dementia and cancer may represent a spectrum of opposing dysregulated degenerative (apoptosis) and growth (proliferative) pathways respectively (Driver, 2014). Risk or resiliency factors affecting these pathways may influence cognitive outcomes in the oldest‐old. We sought to investigate demographics, clinical characteristics, and the impact of medical comorbidity on possible risk‐resiliency factors for neurodegeneration in nondemented and demented oldest‐old who died and underwent autopsy.MethodMedical records of 161 decedents (female n=134) from the Mayo Clinic 95+ year‐old cohort (age range 95‐106 years‐old) were reviewed. Groups consisting of nondemented (n=72) and demented (n=89) decedents were stratified and compared according to demographics and clinical variables, including history of cancer. Autopsy and neuropathologic evaluation was also conducted.ResultAge at death, sex, race, and education showed no differences between nondemented and demented decedents. History of cancer was higher in nondemented (57%) compared to demented decedents (30%) (p=0.002). APOE ε4 allele presence did not differ amongst groups, while APOE ε2 allele was more common in the nondemented group (p=0.026). History of coronary artery disease was higher in the nondemented (p=0.033). No differences were observed in other vascular risk factors, alcohol use, or depression. Smoking history approached significance and was higher in nondemented compared to demented (p=0.068). MMSE scores were higher in the nondemented group (p<0.001). Neuropathology findings included a lower Braak tangle staging in nondemented (median=III) compared to demented (median=V) groups (p<0.001) and less frequent diffuse plaques observed in the nondemented (67%) compared with those demented (93%) (p<0.001).ConclusionDementia is less frequent among cancer survivors in the 95+ oldest‐old. Disease‐related mechanisms associated with malignancy and surviving it may be protective against neurodegeneration in the oldest old.

AbstractBackgroundNeocortical tau can be present in over half of patients with Lewy body disease at autopsy, and may influence the timing of when a diagnosis of Dementia with Lewy bodies (DLB) can be made. We examined whether the core features, onset age and latency of probable DLB diagnosis differ by pathological subgroups.MethodAll patients (n=176) met clinical criteria for probable DLB, underwent autopsy and were classified as transitional or diffuse Lewy body disease (TLBD, DLBD). The TLBD and DLBD groups were further subdivided based on the absence of neocortical tangles represented by a low (L) Braak NFT stage of 0‐III or by the presence of neocortical tangles represented by a high (H) Braak NFT stage of IV‐VI. Onset age and latency from cognitive symptom onset to probable DLB were compared for TLBD‐L (n=30), DLBD‐L (n=47), DLBD‐H (n=78) and TLBD‐H (n=21).ResultThe TLBD‐H group met criteria for DLB at an older age (median 76 years) compared to TLBD‐L, DLBD‐L or DLBD‐H groups (median age 70 years, p<0.001). The latency to probable DLB from cognitive onset was shortest for TLBD‐L and DLBD‐L (median < 1 year), which was shorter than DLBD‐H (median 2 years; p=0.016), each of which were shorter than TLBD‐H (median 7.3 years; p<0.001). RBD was more common in men (79% men vs. 40% women, p<0.001) and in patients without neocortical tangles (86% vs. 57%, p<0.001). Patients with RBD met criteria for probable DLB at a younger age than those without a history of RBD (median 69 years vs. 76 years, p<0.001). Men had a shorter latency to probable DLB than women (median 1.0 year vs. 2.8 years, p<0.01), but this was related to RBD status that was more common in men.ConclusionPresence of RBD in both sexes led to a younger onset age and shorter latency to diagnosis of probable DLB. Patients with more widespread tau relative to α‐synuclein pathology (TLBD‐H) were older when probable DLB was diagnosed compared to those with so‐called pure Lewy body disease (TLBD‐L, DLBD‐L) or those with diffuse α‐synuclein and tau pathology (DLBD‐H).

Abstract Aims Hippocampal findings are implicated in the pathogenesis of sudden unexplained death in childhood (SUDC), although some studies have identified similar findings in sudden explained death in childhood (SEDC) cases. We blindly reviewed hippocampal histology in SUDC and SEDC controls. Methods Hippocampal haematoxylin and eosin (H&E) slides ( n = 67; 36 SUDC, 31 controls) from clinical and forensic collaborators were evaluated by nine blinded reviewers: three board‐certified forensic pathologists, three neuropathologists and three dual‐certified neuropathologists/forensic pathologists. Results Among nine reviewers, about 50% of hippocampal sections were rated as abnormal (52.5% SUDC, 53.0% controls), with no difference by cause of death (COD) ( p = 0.16) or febrile seizure history ( p = 0.90). There was little agreement among nine reviewers on whether a slide was within normal range (Fleiss' κ = 0.014, p = 0.47). Within reviewer groups, there were no findings more frequent in SUDC compared with controls, with variability in pyramidal neuron and dentate gyrus findings. Across reviewer groups, there was concordance for bilamination and granule cell loss. Neither SUDC (51.2%) nor control (55.9%) slides were considered contributory to determining COD ( p = 0.41). Conclusions The lack of an association of hippocampal findings in SUDC and controls, as well as inconsistency of observations by multiple blinded reviewers, indicates discrepancy with previous studies and an inability to reliably identify hippocampal maldevelopment associated with sudden death (HMASD). These findings underscore a need for larger studies to standardise evaluation of hippocampal findings, identifying the range of normal variation and changes unrelated to SUDC or febrile seizures. Molecular studies may help identify novel immunohistological markers that inform on COD.

AbstractBackgroundWhile β‐amyloid and tau PET imaging are widely studied in cognitive aging and Alzheimer’s disease (AD), little is known about findings in aging multiple sclerosis (MS) patients. As aging is an essential factor in developing neurodegeneration in MS, β‐amyloid and tau biomarkers may be utilized to understand the influence of AD pathophysiology on cognitive aging in MS.MethodWe studied patients with MS (n=16) and controls (n=80) matched for age, sex and APOE ε4 status from the population‐based Mayo Clinic Study of Aging who underwent Pittsburgh compound‐B (PiB) PET imaging. Twelve of the 16 patients with MS and 60 matching controls also underwent flortaucipir (AV1451) tau PET. Cortical PiB and AV1451 standard uptake value ratios (SUVr) from previously determined AD signature regions and from the entire cortex were calculated for group comparisons and testing for associations with age.ResultAD signature PiB SUVr (p=0.044), total cortical PiB SUVr (p=0.048) and the frequency of abnormal PiB SUVrs (p=0.040) were lower in patients with MS than controls. Although AD signature and total cortical AV1451 SUVrs were not different between the groups, the frequency of abnormal AV1451 SUVrs was higher (p=0.041) in patients with MS than controls. The association of AD signature PiB SUVr with age was steeper in the controls compared to patients with MS (p=0.002). Similarly, the association of total cortical PiB SUVr with age was steeper in the controls compared to patients with MS (p=0.002). There was no difference in the association of AV1451 SUVr findings with age between the MS patients and controls (Figure 1). The AD signature PiB SUVr increased more with increasing AD signature AV1451 SUVr in controls than in patients with MS (p=0.03) (Figure 2).ConclusionIn patients with MS, cortical β‐amyloid deposition was lower than age‐matched controls, while cortical tau deposition was not different between the groups. This suggests that some aspect of MS pathobiology retards the accumulation of β‐amyloid, but not the accumulation of tau.

AbstractBackgroundWe report a group of individuals presenting with a progressive dementia syndrome characterized by predominant dysfunction in core executive functions and positive biomarkers for Alzheimer’s pathophysiology.MethodIn this retrospective review, we report on 55 participants with a clinically defined progressive dysexecutive syndrome with 18F‐fluorodeoxyglucose‐positron emission tomography (FDG) and AD biomarker positivity. A subset of these individuals enrolled in our ADRC were compared to other phenotypic variants of AD.ResultSixty‐two percent were female with a mean of 15.2 years of education. Mean age of symptom onset was 53.8 while mean age at diagnosis was 57.2 years. Multi‐domain cognitive impairment was evident in neuropsychological testing with executive dysfunction most consistently and severely affected. The frontal and/or parietal regions demonstrate clear hypometabolism on positron emission tomography in all cases. Genetic testing for autosomal dominant genes was negative in all 8 participants tested and at least one APOE ε4 allele was present in 14/26. EEG was abnormal in 14/17 cases. CSF and neuroimaging biomarkers (PIB‐PET and Tau‐PET) were consistent with Alzheimer’s disease pathophysiology, although CSF p‐tau was normal in 24% of cases. In two participants that came to autopsy, the hippocampus was relatively spared compared to frontal and parietal cortex. Participants presenting with a progressive dysexecutive syndrome and evidence of AD pathology are labeled dAD. Comparing FDG in dAD relative to other AD phenotypes revealed unique areas of relatively greater hypometabolism in parieto‐frontal cortex and relative sparing of medial temporal (vs typical AD), visual (vs PCA), and left temporal (vs lvPPA) (Figure 1). Controlling for age did not alter patterns of regional differences. This demonstrates regional variability related to clinical phenotype not accountable by variation in age, duration, stage, or severity (Figure 2).ConclusionA progressive dysexecutive syndrome should be recognized as a distinct clinical phenotype. This clinical presentation can be due to Alzheimer’s disease but is not specific for any single etiology (non‐AD cases of progressive dysexecutive syndrome will be discussed). Prominent impairment of executive task performance, young‐age of onset, normal CSF p‐tau, and relative preservation of the hippocampus were commonly encountered in this case series of dAD.

AbstractBackgroundDigital pathology and machine learning (ML) workflows have paradigm shifting potential especially in the field of Alzheimer’s disease and related disorders. However, many institutions/centers may not have access to these technologies. To provide benchmark data, a survey was developed and distributed to National Institutes of Health’s Alzheimer’s Disease Centers (ADCs) in the United States.MethodSurvey questions covered topics such as: infrastructure (i.e. type of digital slide scanners used), funding sources (i.e. how the scanner was funded), and data management/storage (i.e. size of digital files). After development, review, and approval by the ADC digital pathology working group, the survey was distributed via email to 35 past and current ADC directors and/or ADC neuropathology core leaders. Participation in the survey was completely voluntary and answers did not contain any personal data.ResultThe survey generated over a 90% response rate, and the majority of those who completed the survey were neuropathology core leaders; 81% stated their ADC had access to a digital slide scanner, most common brand being Aperio/Leica. One third of respondents stated there was a fee for service to utilize the scanner. For digital pathology and/or ML resources, 40% of respondents stated none are supported in any way by their ADC. To cover the purchase and operation of the scanner, 50% stated they had institutional support. Many were unsure of the approximate average scanned file size of digital images (37%) and total amount of storage space that files occupied (50%). Many (75%) were aware of other departments at their institution working with digital pathology and/or ML, but a similar percentage was unaware of multi‐university or industry partnerships.ConclusionThese results demonstrate many ADCs have access to a digital slide scanner and had institutional support to cover the purchase. However, further investigation is needed to understand hurdles and barriers for implementing both digital pathology and ML workflows aiding in standardized methods across ADCs.

Abstract We report a group of patients presenting with a progressive dementia syndrome characterized by predominant dysfunction in core executive functions, relatively young age of onset and positive biomarkers for Alzheimer’s pathophysiology. Atypical frontal, dysexecutive/behavioural variants and early-onset variants of Alzheimer’s disease have been previously reported, but no diagnostic criteria exist for a progressive dysexecutive syndrome. In this retrospective review, we report on 55 participants diagnosed with a clinically defined progressive dysexecutive syndrome with 18F-fluorodeoxyglucose-positron emission tomography and Alzheimer’s disease biomarkers available. Sixty-two per cent of participants were female with a mean of 15.2 years of education. The mean age of reported symptom onset was 53.8 years while the mean age at diagnosis was 57.2 years. Participants and informants commonly referred to initial cognitive symptoms as ‘memory problems’ but upon further inquiry described problems with core executive functions of working memory, cognitive flexibility and cognitive inhibitory control. Multi-domain cognitive impairment was evident in neuropsychological testing with executive dysfunction most consistently affected. The frontal and parietal regions which overlap with working memory networks consistently demonstrated hypometabolism on positron emission tomography. Genetic testing for autosomal dominant genes was negative in all eight participants tested and at least one APOE ε4 allele was present in 14/26 participants tested. EEG was abnormal in 14/17 cases with 13 described as diffuse slowing. Furthermore, CSF or neuroimaging biomarkers were consistent with Alzheimer’s disease pathophysiology, although CSF p-tau was normal in 24% of cases. Fifteen of the executive predominate participants enrolled in research neuroimaging protocols and were compared to amnestic (n = 110), visual (n = 18) and language (n = 7) predominate clinical phenotypes of Alzheimer’s disease. This revealed a consistent pattern of hypometabolism in parieto-frontal brain regions supporting executive functions with relative sparing of the medial temporal lobe (versus amnestic phenotype), occipital (versus visual phenotype) and left temporal (versus language phenotype). We propose that this progressive dysexecutive syndrome should be recognized as a distinct clinical phenotype disambiguated from behavioural presentations and not linked specifically to the frontal lobe or a particular anatomic substrate without further study. This clinical presentation can be due to Alzheimer’s disease but is likely not specific for any single aetiology. Diagnostic criteria are proposed to facilitate additional research into this understudied clinical presentation.

Abstract Sudden unexplained death in childhood (SUDC) affects children &gt;1-year-old whose cause of death remains unexplained following comprehensive case investigation and is often associated with hippocampal abnormalities. We prospectively performed systematic neuropathologic investigation in 20 SUDC cases, including (i) autopsy data and comprehensive ancillary testing, including molecular studies, (ii) ex vivo 3T MRI and extensive histologic brain samples, and (iii) blinded neuropathology review by 2 board-certified neuropathologists. There were 12 girls and 8 boys; median age at death was 33.3 months. Twelve had a history of febrile seizures, 85% died during apparent sleep and 80% in prone position. Molecular testing possibly explained 3 deaths and identified genetic mutations in TNNI3, RYR2, and multiple chromosomal aberrations. Hippocampal abnormalities most often affected the dentate gyrus (altered thickness, irregular configuration, and focal lack of granule cells), and had highest concordance between reviewers. Findings were identified with similar frequencies in cases with and without molecular findings. Number of seizures did not correlate with hippocampal findings. Hippocampal alterations were the most common finding on histological review but were also found in possibly explained deaths. The significance and specificity of hippocampal findings is unclear as they may result from seizures, contribute to seizure pathogenesis, or be an unrelated phenomenon.