non-AD Pathology Research Articles

FDG-PET Patterns Predict Amyloid Deposition and Clinical Profile in Corticobasal Syndrome.

Corticobasal syndrome (CBS) is an atypical parkinsonian syndrome related to multiple underlying pathologies. To investigate if individual brain [18 F]fluorodeoxyglucose-positron emission tomography (FDG-PET) patterns could distinguish CBS due to Alzheimer's disease (AD) from other pathologies based on [11 C]Pittsburgh Compound-B (PIB)-PET. Forty-five patients with probable CBS were prospectively evaluated regarding cognitive and movement disorders profile. They underwent FDG-PET and were distributed into groups: likely related to AD (CBS FDG-AD) or likely non-AD (CBS FDG-nonAD) pathology. Thirty patients underwent PIB-PET on a hybrid PET-magnetic resonance imaging equipment to assess their amyloid status. FDG and PIB-PET images were classified individually based on visual and semi-quantitative analysis, blinded to each other. Quantitative group analyses were also performed. CBS FDG-AD group demonstrated worse cognitive performances, mostly concerning attention, memory, visuospatial domains, and displayed more myoclonus and hallucinations. The non-AD metabolic group presented more often limb dystonia, ocular motor dysfunction, motor perseveration, and dysarthria. All patients classified as CBS FDG-AD tested positive at PIB-PET compared to 3 of 20 in the non-AD group. The individual FDG-PET classification demonstrated 76.92% of sensitivity, 100% of specificity and positive predictive value and 88.5% of balanced accuracy to detect positive PIB-PET scans. Individuals with positive and negative PIB-PET showed hypometabolism in posterior temporoparietal areas and in thalamus and brainstem, respectively, mainly contralateral to most affected side, disclosing possible metabolic signatures of CBS variants. FDG-PET was useful to predict AD and non-AD CBS variants depicting their specific degeneration patterns, different clinical features, and brain amyloid deposition. © 2020 International Parkinson and Movement Disorder Society.

Plasma p-tau181 accurately predicts Alzheimer\u2019s disease pathology at least 8\xa0years prior to post-mortem and improves the clinical characterisation of cognitive decline

The neuropathological confirmation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles (NFT) remains the gold standard for a definitive diagnosis of Alzheimer’s disease (AD). Nowadays, the in vivo diagnosis of AD is greatly aided by both cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers. Although highly accurate, their broad implementation is restricted by high cost, limited accessibility and invasiveness. We recently developed a high-performance, ultrasensitive immunoassay for the quantification of tau phosphorylated at threonine-181 (p-tau181) in plasma, which identifies AD pathophysiology with high accuracy. However, it remains unclear whether plasma p-tau181, measured years before the death, can predict the eventual neuropathological confirmation of AD, and successfully discriminates AD from non-AD dementia pathologies. We studied a unique cohort of 115 individuals with longitudinal blood collections with clinical evaluation at 8, 4 and 2 years prior to neuropathological assessment at death. The results demonstrate that plasma p-tau181 associates better with AD neuropathology and Braak staging than a clinical diagnosis 8 years before post-mortem. Moreover, while all patients had a diagnosis of AD dementia during life, plasma p-tau181 proved to discriminate AD from non-AD pathologies with high accuracy (AUC = 97.4%, 95% CI = 94.1–100%) even 8 years before death. Additionally, the longitudinal trajectory of plasma p-tau181 was assessed in all patients. We found that the main increases in plasma p-tau181 occurred between 8 and 4 years prior to death in patients with AD neuropathology and later plateauing. In contrast, non-AD pathologies and controls exhibited minor, albeit significant, increases in p-tau181 up until death. Overall, our study demonstrates that plasma p-tau181 is highly predictive and specific of AD neuropathology years before post-mortem examination. These data add further support for the use of plasma p-tau181 to aid clinical management in primary care and recruitment for clinical trials.

Does amnesia specifically predict Alzheimer’s pathology? A neuropathological study

Amnesia is a key component of Alzheimer’s disease (AD) and the most important feature of its clinical diagnosis but its specificity has recently been challenged. This study investigated the ability of amnesia to predict AD in a clinicopathological dementia series. Ninety-one patients to which free and cued verbal memory assessment was administered during early cognitive decline, were followed until autopsy. Patients’ histological diagnoses were classified as pure AD, mixed AD, and non-AD pathologies. Data-driven automated classification procedures explored the correspondence between memory performance and pathological diagnoses. Classifications revealed 3 clusters of performance reflecting different levels of amnesia. Little correspondence between these clusters and the presence of AD pathology was retrieved. A third of patients with pure/mixed AD pathology were non-amnesic at presentation and ≈45% of patients without AD pathology were amnesic. Data-driven prediction of AD pathology based on memory also had a poor accuracy. Free and cued memory assessments are fair tools to diagnose an amnesic syndrome but lack accuracy to predict AD pathology.

Cerebrospinal Fluid YKL-40 and Chitotriosidase Levels in Frontotemporal Dementia Vary by Clinical, Genetic and Pathological Subtype

Background: Chronic glial dysfunction may contribute to the pathogenesis of frontotemporal dementia (FTD). Cerebrospinal fluid (CSF) levels of glia-derived proteins YKL-40 and chitotriosidase are increased in Alzheimer’s disease (AD) but have not been explored in detail across the spectrum of FTD. Methods: We investigated whether CSF YKL-40 and chitotriosidase levels differed between FTD patients and controls, across different clinical and genetic subtypes of FTD, and between individuals with a clinical FTD syndrome due to AD versus non-AD (frontotemporal lobar degeneration, FTLD) pathology (based on CSF neurodegenerative biomarkers). Eighteen healthy controls and 64 people with FTD (behavioural variant FTD, n = 20; primary progressive aphasia [PPA], n = 44: nfvPPA, n = 16, svPPA, n = 11, lvPPA, n = 14, PPA-NOS, n = 3) were included. 10/64 had familial FTD, with mutations in GRN(n = 3), MAPT(n = 4), or C9orf72 (n = 3). 15/64 had neurodegenerative biomarkers consistent with AD pathology. Levels were measured by immunoassay and compared using multiple linear regressions. We also examined relationships of YKL-40 and chitotriosidase with CSF total tau (T-tau), phosphorylated tau 181 (P-tau) and β-amyloid 1–42 (Aβ42), with each other, and with age and disease du­ration. Results: CSF YKL-40 and chitotriosidase levels were higher in FTD, particularly lvPPA (both) and nfvPPA (YKL-40), compared with controls. GRN mutation carriers had higher levels of both proteins than controls and C9orf72 expansion carriers, and YKL-40 was higher in MAPT mutation carriers than controls. Individuals with underlying AD pathology had higher YKL-40 and chitotriosidase levels than both controls and those with likely FTLD pathology. CSF YKL-40 and chitotriosidase levels were variably associated with levels of T-tau, P-tau and Aβ42, and with each other, depending on clinical syndrome and underlying pathology. CSF YKL-40 but not chitotriosidase was associated with age, but not disease duration. Conclusion: CSF YKL-40 and chitotriosidase levels are increased in individuals with clinical FTD syndromes, particularly due to AD pathology. In a preliminary analysis of genetic groups, levels of both proteins are found to be highly elevated in FTD due to GRN mutations, while YKL-40 is increased in individuals with MAPT mutations. As glia-derived protein levels generally correlate with T-tau and P-tau levels, they may reflect the glial response to neurodegeneration in 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.

Diagnostic Accuracy of Amyloid versus FDG PET in Patients with Cognitive Impairment and Autopsy

Background: β-Amyloid and Flurodeoxyglucose (FDG) PET are clinically available diagnostic tools in the assessment of neurodegenerative disorders. We compared the diagnostic accuracy of [11C]Pittsburgh Compound B (PIB) and [18F]FDG PET in a large sample of patients with cognitive decline and neuropathology. Methods: 101 individuals underwent PIB and FDG during life and post-mortem neuropathological assessment. PET scans were visually interpreted by three raters blinded to clinical information. PIB scans were rated as positive or negative for cortical retention while FDG scans were read as showing an Alzheimer’s disease (AD) or non-AD metabolic pattern. AD neuropathological changes (ADNC) were measured at autopsy. Majority visual reads were compared to intermediate-high ADNC as the gold standard. Findings: 60 males and 41 females were included (average age: 67·2Y, mean MMSE: 21·9, mean PET-to-autopsy interval: 4·4Y). At autopsy, 32 patients showed pure AD pathology, 13 mixed AD and non-AD and 56 non-AD neuropathology. Compared to FDG, PIB showed higher sensitivity for detecting intermediate-high ADNC (96% [95% confidence interval: 89-100%] vs 80% [68-92%] for FDG, p=0·02) and higher negative predictive value (96% [91-100%] vs 84% [74-93%], p=0·01), but equivalent specificity (86% [76-95%] vs 84% [74-93%], p=0·80) and positive predictive value (84% [74-94%] vs 80% [68-92%], p=0·53). In patients with congruent PIB and FDG reads (77/101), combined sensitivity was 97% [92-100%] and specificity 98% [93-100%]. Nine of 24 patients with incongruent reads were found to have co-occurrence of AD and non-AD pathologies. Interpretation: PIB had higher sensitivity to detect intermediate-high ADNC compared to FDG, particularly at early clinical stages, with similar specificity. When both modalities are congruent, sensitivity and specificity approach 100%, while mixed pathology should be considered when PIB and FDG are incongruent. Funding Statement: National Institute of Health (R01-AG045611, P01-AG1972403, P50-AG023501, P30-AG010129, R01-AG032306, K24-AG053435, R01-AG038791, K08-AG052648, P30-AG010129, K23-AG045289), the Alzheimer’s Association (AARF-16-443577), Bluefield Project to Cure FTD, Tau Consortium. Declaration of Interests: Orit H Lesman-Segev – none, Renaud La Joie – none, Iryna Lobach - none, Howard J Rosen - Dr Rosen has received research support from Biogen Pharmaceuticals, has consulting agreements with Wave Neuroscience and Ionis Pharmaceuticals, and receives research support from NIH. Sang Won Seo - none, Mustafa Janabi - none, Suzanne L Baker - consult for Genentech, Lauren Edwards - none, Julie Pham - none, John Olichney - has received grant funding from Roche/Genentech, Adam Boxer - Dr. Boxer receives research support from NIH, the Tau Research Consortium, the Association for Frontotemporal Degeneration, Bluefield Project to Cure Frontotemporal Dementia, Corticobasal Degeneration Solutions, the Alzheimer’s Drug Discovery Foundation and the Alzheimer's Association. He has served as a consultant for Aeton, Abbvie, Alector, Amgen, Arkuda, Arvinas, Asceneuron, Ionis, Lundbeck, Novartis, Passage BIO, Sangamo, Samumed, Third Rock, Toyama and UCB, and received research support from Avid, Biogen, BMS, C2N, Cortice, Eli Lilly, Forum, Genentech, Janssen, Novartis, Pfizer, Roche and TauRx. Eric Huang - none, Marilu Gorno-Tempini – none, Ji-Hye L. Hwang - none, Charles DeCarli - none, Mackenzie Hepker - none, Salvatore Spina - none, Bruce L Miller – Dr. Miller receives grants in support of the Memory and Aging Center from the NIH/NIA, the Quest Diagnostics Dementia Pathway Collaboration, Cornell University and The Bluefield Project to Cure Frontotemporal Dementia. He serves as Medical Director for the John Douglas French Foundation; Scientific Director for the Tau Consortium; Director/Medical Advisory Board of the Larry L. Hillblom Foundation; and Past President of the International Society of Frontotemporal Dementia (ISFTD). Lea T Grinberg - Dr. Grinberg receives research support from Avid Radiopharmaceuticals, Eli Lilly. She has received consulting fees from Simon Foundation and Cura Sen Inc. She serves as associate editor for Frontiers in Aging Neurosciences, Frontiers in Dementia and Journal of Alzheimer Disease William W. Seeley - Dr. Seeley has received consulting fees from Biogen Idec, Third Rock Ventures, and Guidepoint Global Advisors. He serves on the editorial board of Acta Neuropathologica and Neuroimage Clinical. William J Jagust - Dr. Jagust has received honoraria as a consultant to Novartis, Genentech, and Curasen Gil D Rabinovici – Dr. Rabinovici receives research support from Avid Radiopharmaceuticals, Eli Lilly, GE Healthcare and Life Molecular Imaging. He has received honoraria as a consultant for Axon Neurosciences, Eisai and Merck, and speaking honoraria from GE Healthcare. Dr. Rabinovici serves as Associate Editor for JAMA Neurology. Ethics Approval Statement: Informed consent was obtained from all subjects or their surrogate decision makers, and the UCSF, UCD, University of California Berkeley (UCB) and/or Lawrence Berkeley National Laboratory (LBNL) Institutional Review Boards for human research approved the study.

Cognitive Resilience to Alzheimer's Disease Pathology in the Human Brain.

Past research has focused on risk factors for developing dementia, with increasing recognition of "resilient" people who live to old age with intact cognitive function despite pathological features of Alzheimer's disease (AD). To evaluate demographic factors, mid-life characteristics, and non-AD neuropathology findings that may be associated with cognitive resilience to AD pathology. We analyzed data from 276 autopsy cases with intermediate or high levels of AD pathology from the Adult Changes in Thought study. We defined cognitive resilience as having Cognitive Abilities Screening Instrument scores ≥86 within two years of death and no clinical dementia diagnosis; non-resilient people had dementia diagnoses from AD or other causes before death. We compared mid-life characteristics, demographics, and additional neuropathology findings between resilient and non-resilient people. We used multivariable logistic regression to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for being resilient compared to not being resilient adjusting for demographic and neuropathology factors. We classified 68 (25%) people as resilient and 208 (75%) as not resilient. A greater proportion of resilient people had a college degree (50%) compared with non-resilient (32%, p = 0.01). The odds of being resilient were significantly increased among people with a college education (OR = 2.01, 95% CI = 1.01-3.99) and significantly reduced among people with additional non-AD neuropathology findings such as hippocampal sclerosis (OR = 0.28, 95% CI = 0.09-0.89) and microinfarcts (OR = 0.34, 95% CI = 0.15-0.78). Increased education and absence of non-AD pathology may be independently associated with cognitive resilience, highlighting the importance of evaluating co-morbid factors in future research on mechanisms of cognitive resilience.

Clinical, neuropsychological and imaging characteristics of Alzheimer's disease patients presenting as corticobasal syndrome

BackgroundCorticobasal syndrome (CBS) can harbor diverse pathologies, such as corticobasal degeneration (CBD) and Alzheimer's disease (AD). CSF biochemical analysis in CBS patients can confidently distinguish between an AD (CBS-AD) and a non-AD (CBS-nAD) pathology. ObjectiveWe utilized classical CSF biomarkers to make a distinction between the two groups and examine their clinical, neuropsychological, neuropsychiatric and imaging differences. MethodsSeventeen patients with a CBS phenotype were included. Detailed clinical history, and neurological examination data were recorded. A thorough neuropsychological and neuropsychiatric test battery was performed, including Goldenberg apraxia test. Simple linear MRI measurements and planimetry data were utilized. CSF biomarkers for AD were ascertained. ResultsFive of seventeen CBS patients had a CSF AD profile. Patients with a CSF AD profile (CBS-AD; n = 5) were older and had a greater age at disease onset compared to CBS-nAD. CBS-AD patients had more frequently alien hand phenomena at examination and greater hippocampi surface asymmetry at MRI. CBS-nAD patients (n = 12) had lower superior colliculi width values. ConclusionClinical, neuropsychological and imaging data cannot confidently differentiate CBS-AD from CBS-nAD patients.

Parietal Involvement in the Semantic Variant of Primary Progressive Aphasia with Alzheimer's Disease Cerebrospinal Fluid Profile.

Semantic variant of primary progressive aphasia (svPPA) is typically associated with non-Alzheimer's disease (AD) pathology. However, some anatomopathological studies have found AD lesions in those patients. We compared brain perfusion SPECT of 18 svPPA patients with cerebrospinal fluid (CSF) biomarkers indicative of non-AD pathology (svPPA-nonAD) and three svPPA patients with CSF biomarkers indicative of underlying AD (svPPA-AD). All svPPA patients had severe left temporopolar hypoperfusion. SvPPA-nonAD had additional anterior cingulate and mediofrontal hypoperfusion, whereas svPPA-AD had greater left parietal and posterior cingulate involvement. Parietal damage in svPPA constitutes a biomarker for underlying Alzheimer pathology thus refining the classification of this PPA variant.

Cerebrospinal fluid soluble TREM2 levels in frontotemporal dementia differ by genetic and pathological subgroup

BackgroundReliable biomarkers of frontotemporal dementia (FTD) are currently lacking. FTD may be associated with chronic immune dysfunction, microglial activation and raised inflammatory markers, particularly in progranulin (GRN) mutation carriers. Levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2) are elevated in Alzheimer’s disease (AD), but they have not been fully explored in FTD.MethodsWe investigated whether cerebrospinal fluid (CSF) sTREM2 levels differ between FTD and controls, across different clinical and genetic subtypes of FTD, or between individuals with FTD due to AD versus non-AD pathology (based on CSF neurodegenerative biomarkers). We also assessed relationships between CSF sTREM2 and other CSF biomarkers (total tau [T-tau], tau phosphorylated at position threonine-181 [P-tau] and β-amyloid 1–42 [Aβ42]) and age and disease duration. Biomarker levels were measured using immunoassays in 17 healthy controls and 64 patients with FTD (behavioural variant FTD, n = 20; primary progressive aphasia, n = 44). Ten of 64 had familial FTD, with mutations in GRN (n = 3), MAPT (n = 4), or C9orf72 (n = 3). Fifteen of 64 had neurodegenerative biomarkers consistent with AD pathology (11 of whom had logopenic variant PPA). Levels were compared using multivariable linear regressions.ResultsCSF sTREM2 levels did not differ between FTD and controls or between clinical subgroups. However, GRN mutation carriers had higher levels than controls (mean ([SD] = 9.7 [2.9] vs. 6.8 [1.6] ng/ml; P = 0.028) and MAPT (3.9 [1.5] ng/ml; P = 0.003] or C9orf72 [4.6 [1.8] ng/ml; P = 0.006) mutation carriers. Individuals with AD-like CSF had higher sTREM2 levels than those with non-AD-like CSF (9.0 [3.6] vs. 6.9 [3.0] ng/ml; P = 0.029). CSF sTREM2 levels were associated with T-tau levels in control and FTD groups and also with P-tau in those with FTD and AD-like CSF. CSF sTREM2 levels were influenced by both age and disease duration in FTD.ConclusionsAlthough CSF sTREM2 levels are not raised in FTD overall or in a particular clinical subtype of FTD, levels are raised in familial FTD associated with GRN mutations and in FTD syndromes due to AD pathology. Because CSF sTREM2 levels correlate with a marker of neuronal injury (T-tau), sTREM2 should be explored as a biomarker of disease intensity in future longitudinal studies of FTD.

Utilizing semantic intrusions to identify amyloid positivity in mild cognitive impairment.

Semantic intrusion (SI) errors may highlight specific breakdowns in memory associated with preclinical Alzheimer disease (AD); however, there have been no investigations to determine whether SI errors occur with greater frequency in persons with amnestic mild cognitive impairment (aMCI) confirmed as amyloid positive (Amy+) vs those who have clinical symptoms of aMCI-AD with negative amyloid scans (suspected non-AD pathology [SNAP]) or persons who are diagnosed with other brain disorders affecting cognition. Eighty-eight participants with aMCI underwent brain amyloid PET and MRI scans and were classified as early AD (Amy+), SNAP (Amy-), or other neurological/psychiatric diagnosis (Amy-). We focused on SI on the Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L) targeting proactive semantic interference (PSI; old semantic learning interferes with new semantic learning), failure to recover from PSI after an additional learning trial (frPSI), and retroactive semantic interference (new semantic learning interferes with memory for old semantic learning). SIs on measures of PSI and frPSI distinguished between Amy+ AD and SNAP and other non-AD cases. PSI and frPSI intrusions evidenced moderately high associations with reduced volumes in the entorhinal cortex, superior temporal regions, and supramarginal gyrus. No such associations were observed in cases with SNAP. SIs on the LASSI-L related to PSI and frPSI uniquely differentiated Amy+ and Amy- participants with aMCI and likely reflect deficits with inhibition and source memory in preclinical AD not captured by traditional cognitive measures. This may represent a specific, noninvasive test successful at distinguishing cases with true AD from those with SNAP.

FV3. Decomposing amnestic mild cognitive impairment by means of FDG-PET: Distinct hypometabolic subtypes differ in relation to biomarkers of Alzheimer’s disease and clinical trajectories

Background Amnestic mild cognitive impairment (aMCI) is a clinical diagnosis with considerable etiologic heterogeneity. While the condition often represents prodromal Alzheimer’s disease (AD), patients may also progress to other dementia types, stay stable, or even reverse to normal cognition. Detection of glucose hypometabolism by means of FDG-PET is a very sensitive in vivo marker of neuronal dysfunction, and represents one of the best established methods for early detection of AD-typical neurodegeneration. We aimed to characterize the heterogeneity of hypometabolic patterns among individuals diagnosed with aMCI. Methods We applied Ward’s hierarchical clustering to voxel-wise FDG-PET data of 329 aMCI patients from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort to identify subgroups of distinct brain-wide metabolic patterns in this population. Identified subgroups were compared to 179 cognitively normal ADNI controls and characterized with respect to cognition, AV45-PET- and CSF-based biomarkers of amyloid and tau pathology, APOE genotype, as well as clinical progression over 2 years. Results Four aMCI subgroups with markedly differing metabolic profiles were identified ( Fig. 1 ): (i) an ‘AD-typical’ pattern of temporoparietal hypometabolism (N = 135, 41%), (ii) restricted ‘limbic’ hypometabolism (N = 56, 17%), (iii) a ‘posterior ventral’ hypometabolic pattern including the occipital lobe (N = 56, 17%), and (iv) ‘normal’ metabolism that did not differ from control values of cognitively normal individuals (N = 82, 25%). ‘AD-typical’ and ‘limbic’ subgroups exhibited biomarker characteristics consistent with AD, but differed in proportion of APOE4 carriers, tau levels, hippocampal atrophy, and cognitive trajectories. The ‘posterior ventral’ subgroup showed relatively mild amyloid uptake but no significant tau biomarker abnormalities, and aMCI patients with ‘normal’ metabolism did not show abnormal biomarkers nor cognitive decline. Conclusions ‘AD-typical’ and ‘limbic’ hypometabolism likely represent distinct endophenotypes of prodromal AD, whereas a posterior ventral pattern of cortical hypometabolism may reflect non-AD pathologies, atypical AD variants, or comorbid conditions. One out of four individuals with clinically diagnosed aMCI did not show notable hypometabolic brain dysfunction, biomarker abnormalities, or clinical trajectories indicative of neurodegenerative disease.

PET AMYLOID IMAGING WITH FLORBETAPIR AND COGNITION IN THE OLDEST-OLD: THE 90+ STUDY

PET Amyloid imaging has been shown to identify younger elderly individuals at higher risk of cognitive decline, but it is unknown if this relationship persists in the oldest-old, people aged 90 and over. Here we determine if amyloid burden measured by florbetapir-PET predicts cognitive decline in oldest-old participants. The study included 144 participants from The 90+ Study, a longitudinal investigation in people aged 90 and older. Participants underwent florbetapir-PET imaging within 6 months (average=56 days) of cognitive testing. Testing was repeated every 6 months and included the Modified Mini-Mental State exam, California Verbal Learning Test 10-minute delay, animal fluency, and Trails A and B. Test scores were z-transformed and averaged into a composite cognitive score. Amyloid load was measured in the precuneus/posterior cingulate region of interest using cerebral white matter mask as the reference and was dichotomized as Aβ− and Aβ+ (SUVR≥0.81). Cognitive scores for the Aβ− and Aβ+ groups were compared at baseline with linear regression. Rates of decline for the two groups were compared with mixed effects models. All regressions adjusted for baseline age and gender. At scanning time, participants were on average 94 years (range:90-102) and cognitive diagnosis as follows: 92 normal cognition, 44 cognitively impaired without dementia, and 8 with dementia. 63% of participants were women and 53% college graduates. One third of participants (34%) were classified as having Aβ+ scans. Median follow-up was 1.7 years (range:0.4-5 years). At baseline, people with Aβ+ scans had worse scores on cognitive tests than people with Aβ− scans (all p<0.05). Rate of decline, however, did not differ between groups for any of the tests or the composite score (Aβ+ -0.21 SD/year vs. Aβ− -0.17 SD/year, p=0.50) (Table). In individuals aged 90 and older, high amyloid burden on florbetapir-PET was associated with worse cognitive performance at baseline but not with a faster rate of cognitive decline over an average of 1.7 years. Possible explanations for this discrepancy include a short follow-up, decline in people with Aβ+ scans beginning at a younger age, or the frequent presence of non-AD pathologies at this age obscuring the relationship between amyloid and cognition.

Non-Alzheimer's contributions to dementia and cognitive resilience in The 90+ Study.

The diagnosis of Alzheimer's disease (AD) in the oldest-old is complicated by the increasing prevalence of age-related neurofibrillary tangles, plaques and non-AD pathologies such as cerebrovascular disease (CVD), hippocampal sclerosis (HS), aging-related tau astrogliopathy (ARTAG), as well as TDP-43 and Lewy pathology. The contribution of these non-AD pathologies to dementia and cognitive resilience is unclear. We assessed the level of AD neuropathologic change (ADNPC) and non-AD pathology in 185 participants enrolled in The 90+ Study with available cognitive assessments and brain tissue. Logistic regression models-adjusting for age, sex and education-determined the association between each pathology and dementia or between subgroups. 53% had dementia, primarily AD or mixed AD; 23% had cognitive impairment without dementia (CIND); 23% were not impaired. Both AD and non-AD pathology was prevalent. 100% had tangles, 81% had plaques, and both tangles and plaques associated with dementia. ARTAG distributed across limbic (70%), brainstem (39%) and cortical regions (24%). 49% had possible CVD and 26% had definite CVD, while HS was noted in 15%. Cortical ARTAG, CVD and HS were each associated with dementia, but limbic and brainstem ARTAGs were not. TDP-43 and Lewy pathologies were found in 36 and 17% and both associated with dementia. No pathology distinguished CIND and the not impaired. By NIA-AA criteria and dementia status, the cohort was subdivided into four groups: those with minimal ADNPC included the not dementia (ND) and Not AD dementia groups; and those with significant ADNPC included the Resilient without dementia and AD dementia groups. Compared to the ND group, the Not AD dementia group had more HS, cortical ARTAG, TDP-43, and Lewy pathology. Compared to the AD dementia group, the Resilient group had less CVD, no HS and less cortical ARTAG, TDP-43 and Lewy pathology. Our findings imply that reductions in non-AD pathologies including CVD contribute to cognitive resilience in the oldest-old.

Multiproteinopathy, neurodegeneration and old age: a case study

ABSTRACTA complex spectrum of mixed brain pathologies is common in older people. This clinical pathologic conference case study illustrates the challenges of formulating clinicopathologic correlations in late-onset neurodegenerative diseases featuring cognitive-behavioral syndromes with underlying multiple proteinopathy. Studies on the co-existence and interactions of Alzheimer’s disease (AD) with neurodegenerative non-AD pathologies in the aging brain are needed to understand the pathogenesis of neurodegeneration and to support the development of diagnostic biomarkers and therapies.

Atrophy, metabolism and cognition in the posterior cortical atrophy spectrum based on Alzheimer's disease cerebrospinal fluid biomarkers.

IntroductionIn vivo clinical, anatomical and metabolic differences between posterior cortical atrophy (PCA) patients presenting with different Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers profiles are still unknown.MethodsTwenty-seven PCA patients underwent CSF examination and were classified as 1) PCA with a typical CSF AD profile (PCA-tAD; abnormal amyloid and T-tau/P-tau biomarkers, n = 13); 2) PCA with an atypical AD CSF profile (PCA-aAD; abnormal amyloid biomarker only, n = 9); and 3) PCA not associated with AD (PCA-nonAD; normal biomarkers, n = 5). All patients underwent clinical and cognitive assessment, structural MRI, and a subset of them underwent brain 18F-FDG PET.ResultsAll patients' groups showed a common pattern of posterior GM atrophy and hypometabolism typical of PCA, as well as equivalent demographics and clinical/cognitive profiles. PCA-tAD patients showed a group-specific pattern of hypometabolism in the left fusiform gyrus and inferior temporal gyrus. PCA-aAD did not present a group-specific atrophy pattern. Finally, group-specific gray matter atrophy in the right dorsolateral prefrontal cortex, left caudate nucleus and right medial temporal regions and hypometabolism in the right supplementary motor area and paracentral lobule were observed in PCA-nonAD patients.ConclusionOur findings suggest that both PCA-tAD and PCA-aAD patients are on the AD continuum, in agreement with the recently suggested A/T/N model. Furthermore, in PCA, the underlying pathology has an impact at least on the anatomo-functional presentation. Brain damage observed in PCA-tAD and PCA-aAD was mostly consistent with the well-described presentation of the disease, although it was more widespread in PCA-tAD group, especially in the left temporal lobe. Additional fronto-temporal (especially dorsolateral prefrontal) damage seems to be a clue to underlying non-AD pathology in PCA, which warrants the need for longitudinal follow-ups to investigate frontal symptoms in these patients.

BRAIN VOLUME, CEREBRAL β-AMYLOID DEPOSITION, AND AGEING: A STUDY OF OVER 200 INDIVIDUALS BORN IN THE SAME WEEK IN 1946

Ageing is associated with cerebral atrophy and accumulation of cerebral β-amyloid. We examined the relationships between β-amyloid load and brain volume in a large cohort of individuals born in the same week in 1946. We analysed cross-sectional data from Insight 46; a sub-study of the MRC National Survey of Health and Development(NSHD) which includes individuals born in mainland Britain in one week in 1946. Participants had 18F-Florbetapir PET and volumetric T1-weighted MRI on the same 3T-PET/MR unit. β-amyloid load was quantified as a cortical standard uptake value ratios (SUVR) using a cerebellar reference region. The relationship between automated measurements of whole brain, ventricle, hippocampal and lobar volumes, age at time of scan and β-amyloid load was examined using regression models and voxel based morphometry, incorporating total intracranial volume and gender as co-variates. Data from 210 individuals without dementia or significant neurological/psychiatric illness were included. Mean age at scanning was 70.1±0.39 years (range 69.3–70.8). 38 individuals were β-amyloid positive: defined as SUVr=>1.078. Comparison of positive and negative groups revealed no difference in volumetric measurements. However, within β-amyloid-positive individuals, SUVR was negatively associated with total brain volume(p=0.034). There was also evidence of an interaction between β-amyloid status(positive/negative) and SUVR in terms of their effects on total brain volume(p=0.006) across the whole sample. Age at scanning was associated with increased ventricular volume (p=0.014) and with lower total brain(p<0.001), hippocampal(p=0.003), frontal lobe(p=0.023) and temporal lobe(p=0.042) volumes. Whole-brain voxel based morphometry analysis(FWE corrected, p<0.05) revealed age to be associated with volume loss in fronto-temporal regions, thalamus, and cingulate gyri. These preliminary data suggest that there is no significant difference in brain volume between β-amyloid positive and negative individuals aged ∼70 years, but there is some evidence for volume loss once a β-amyloid threshold level is reached. Unexpectedly, there was also a relationship between age and total brain volume independent of β-amyloid load over a very narrow age range. Whether this reflects recruitment bias, non-AD pathologies or ageing effects is unclear. These findings will be examined in a larger sample size utilizing life course and genetic data in the future.

Clinical marker for Alzheimer disease pathology in logopenic primary progressive aphasia.

To determine whether logopenic features of phonologic loop dysfunction reflect Alzheimer disease (AD) neuropathology in primary progressive aphasia (PPA). We performed a retrospective case-control study of 34 patients with PPA with available autopsy tissue. We compared baseline and longitudinal clinical features in patients with primary AD neuropathology to those with primary non-AD pathologies. We analyzed regional neuroanatomic disease burden in pathology-defined groups using postmortem neuropathologic data. A total of 19/34 patients had primary AD pathology and 15/34 had non-AD pathology (13 frontotemporal lobar degeneration, 2 Lewy body disease). A total of 16/19 (84%) patients with AD had a logopenic spectrum phenotype; 5 met published criteria for the logopenic variant (lvPPA), 8 had additional grammatical or semantic deficits (lvPPA+), and 3 had relatively preserved sentence repetition (lvPPA-). Sentence repetition was impaired in 68% of patients with PPA with AD pathology; forward digit span (DF) was impaired in 90%, substantially higher than in non-AD PPA (33%, p < 0.01). Lexical retrieval difficulty was common in all patients with PPA and did not discriminate between groups. Compared to non-AD, PPA with AD pathology had elevated microscopic neurodegenerative pathology in the superior/midtemporal gyrus, angular gyrus, and midfrontal cortex (p < 0.01). Low DF scores correlated with high microscopic pathologic burden in superior/midtemporal and angular gyri (p ≤ 0.03). Phonologic loop dysfunction is a central feature of AD-associated PPA and specifically correlates with temporoparietal neurodegeneration. Quantitative measures of phonologic loop function, combined with modified clinical lvPPA criteria, may help discriminate AD-associated PPA.

Outcomes after diagnosis of mild cognitive impairment in a large autopsy series.

To determine clinical and neuropathological outcomes following a clinical diagnosis of mild cognitive impairment (MCI). Data were drawn from a large autopsy series (N = 1,337) of individuals followed longitudinally from normal or MCI status to death, derived from 4 Alzheimer Disease (AD) Centers in the United States. Mean follow-up was 7.9 years. Of the 874 individuals ever diagnosed with MCI, final clinical diagnoses were varied: 39.2% died with an MCI diagnosis, 46.8% with a dementia diagnosis, and 13.9% with a diagnosis of intact cognition. The latter group had pathological features resembling those with a final clinical diagnosis of MCI. In terms of non-AD pathologies, both primary age-related tauopathy (p < 0.05) and brain arteriolosclerosis pathology (p < 0.001) were more severe in MCI than cognitively intact controls. Among the group that remained MCI until death, mixed AD neuropathologic changes (ADNC; ≥1 comorbid pathology) were more frequent than "pure" ADNC pathology (55% vs 22%); suspected non-Alzheimer pathology comprised the remaining 22% of cases. A majority (74%) of subjects who died with MCI were without "high"-level ADNC, Lewy body disease, or hippocampal sclerosis pathologies; this group was enriched in cerebrovascular pathologies. Subjects who died with dementia and were without severe neurodegenerative pathologies tended to have cerebrovascular pathology and carry the MCI diagnosis for a longer interval. MCI diagnosis usually was associated with comorbid neuropathologies; less than one-quarter of MCI cases showed "pure" AD at autopsy. Ann Neurol 2017;81:549-559.

Author response: Incident parkinsonism in older adults without Parkinson disease.

We thank Drs. Bohnen and Muller for their interest in our study on the high incidence of parkinsonism in community-dwelling older adults without PD.1 They note, and we agree, that many factors other than PD pathology contribute to parkinsonian signs in older persons.2,3 Further, Drs. Bohnen and Muller make an excellent point regarding the implications of our findings for aging persons with PD; namely, the factors that contribute to parkinsonism in persons without PD are also likely to contribute to parkinsonism in persons with PD. This may have implications for treatment response and progression of PD. The situation is similar to that of Alzheimer disease (AD). In older persons, mixed pathologies are the most common cause of AD dementia and the coexisting non-AD pathology contributes to both the detection of AD and a more rapid rate of progression.4,5 We agree that physicians need to consider coexisting conditions that make an ever-larger contribution to many diseases with age.