Brad Dickerson

Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer's disease in the presenilin 1 E280A kindred: a case-control study

BACKGROUND We have previously characterised functional brain abnormalities in young adults at genetic risk for late-onset Alzheimers disease. To gain further knowledge on the preclinical phase of Alzheimers disease, we sought to characterise structural and functional MRI, CSF, and plasma biomarkers in a cohort of young adults carrying a high-penetrance autosomal dominant mutation that causes early-onset Alzheimers disease. METHODS Between January and August, 2010, 18-26-year-old presenilin 1 (PSEN1) E280A mutation carriers and non-carriers from the Colombian Alzheimers Prevention Initiative Registry in Medellín Antioquia, Colombia, had structural MRI, functional MRI during associative memory encoding and novel viewing and control tasks, and cognitive assessments. Consenting participants also had lumbar punctures and venepunctures. Outcome measures were task-dependent hippocampal or parahippocampal activations and precuneus or posterior cingulate deactivations, regional grey matter reductions, CSF Aβ(1-42), total tau and phospho-tau(181) concentrations, and plasma Aβ(1-42) concentrations and Aβ(1-42):Aβ(1-40) ratios. Structural and functional MRI data were compared using automated brain mapping algorithms and search regions related to Alzheimers disease. Cognitive and fluid biomarkers were compared using Mann-Whitney tests. FINDINGS 44 participants were included: 20 PSEN1 E280A mutation carriers and 24 non-carriers. The carrier and non-carrier groups did not differ significantly in their dementia ratings, neuropsychological test scores, or proportion of apolipoprotein E (APOE) ɛ4 carriers. Compared with non-carriers, carriers had greater right hippocampal and parahippocampal activation (p=0·001 and p<0·014, respectively, after correction for multiple comparisons), less precuneus and posterior cingulate deactivation (all p<0·010 after correction), and less grey matter in several parietal regions (all p<0·002 uncorrected and corrected p=0·009 in the right parietal search region). In the 20 participants (ten PSEN1 E280A mutation carriers and ten non-carriers) who had lumbar punctures and venepunctures, mutation carriers had higher CSF Aβ(1-42) concentrations (p=0·008) and plasma Aβ(1-42) concentrations (p=0·01) than non-carriers. INTERPRETATION Young adults at genetic risk for autosomal dominant Alzheimers disease have functional and structural MRI findings and CSF and plasma biomarker findings consistent with Aβ(1-42) overproduction. Although the extent to which the underlying brain changes are either neurodegenerative or developmental remain to be determined, this study shows the earliest known biomarker changes in cognitively normal people at genetic risk for autosomal dominant Alzheimers disease. FUNDING Banner Alzheimers Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Boston University Department of Psychology, Colciencias, National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the State of Arizona.

Hippocampal Hyperactivation Associated with Cortical Thinning in Alzheimer's Disease Signature Regions in Non-Demented Elderly Adults

Alzheimers disease (AD) is associated with functional and structural alterations in a distributed network of brain regions supporting memory and other cognitive domains. Functional abnormalities are present in mild cognitive impairment (MCI) with evidence of early hyperactivity in medial temporal lobe regions, followed by failure of hippocampal activation as dementia develops. Atrophy in a consistent set of cortical regions, the “cortical signature of AD,” has been reported at the stage of dementia, MCI, and even in clinically normal (CN) older individuals predicted to develop AD. Despite multiple lines of evidence for each of these findings, the relationship between this structural marker of AD-related neurodegeneration and this functional marker of the integrity of the episodic memory system has not yet been elucidated. We investigated this relationship in 34 nondemented older humans (CN, N = 18; MCI, N = 16). Consistent with previous studies, we found evidence of hippocampal hyperactivation in MCI compared with CN. Additionally, within this MCI group, increased hippocampal activation correlated with cortical thinning in AD-signature regions. Even within the CN group, increased hippocampal activity was negatively correlated with cortical thinning in a subset of regions, including the superior parietal lobule (r = −0.66; p < 0.01). These findings, across a continuum of nondemented and mildly impaired older adults, support the hypothesis that paradoxically increased hippocampal activity may be an early indicator of AD-related neurodegeneration in a distributed network.

NEUROIMAGING BIOMARKERS IN THE FRONTOTEMPORAL LOBAR DEGENERATION SPECTRUM

SUVR in the medial temporal lobe. Left. Voxelwise ANCOVA analyses of Flortaucipir, comparing 41 ε4 carriers (32 ε3/ε4 + 9 ε4/ε4) to 35 ε4 non-carriers (34 ε3/ε3 + 1 ε2/ε3); two patients carrying ε2/ε4 were not included in this analysis. No significant cluster was found in the ε4 carriers < ε4 non-carriers contrast, even at the uncorrected p<0.001 threshold. Right. Confirmation of the voxelwise finding based on the average Flortaucipir SUVR extracted from the medial temporal lobe in native space using FreeSurfer (combining hippocampus, amygdala, and entorhinal cortex). Bars indicate median and quartiles within each group and the effect size is given as Cohen’s d (with 95% confidence interval) Table 2 Associations between global cortical PET SUVR and clinical/demographic characteristics

Hormonal Cycles, Brain Network Connectivity, and Windows of Vulnerability to Affective Disorder

The rate of affective disorder is substantially higher in women than in men, and considerable evidence points to the actions of ovarian hormones in mediating this disparity. In this Opinion, we discuss the hypothesis that cyclic changes in ovarian hormone levels produce cyclic alterations in connectivity between the intrinsic networks of the brain. These alterations produce specific temporal windows within the menstrual cycle when internetwork connectivity is increased, associated with increased stress reactivity and better memory for unpleasant, arousing events, leading to increased negative mood and susceptibility to affective disorder. Our windows of vulnerability model offers insights for both treatment of affective disorder and research on sex differences in the brain.

DIFFERENCES BETWEEN SPORADIC AND FAMILIAL BEHAVIORAL VARIANT FTD IN ADVANCING RESEARCH AND TREATMENT FOR FTLD (ARTFL) CLINICAL RESEARCH CONSORTIUM

psychiatric disorders with similar clinical presentations. Methods: We conducted a multi-center naturalistic follow-up study. We included subjects aged 45-75 years presenting with a frontal lobe syndrome, consisting of apathy, disinhibition, and/or compulsive behavior. All participants underwent extensive neuropsychiatric phenotyping, MRI of the brain, [18F]FDG-PET, and CSF biomarker analysis. Genetic analysis was performed when appropriate and in the majority of patients C9orf72 status was investigated. Results:We included 137 subjects. After 2 years of follow-up, data were available of 105 patients. The diagnostic distribution was bvFTD (34 (32%); 30 probable, 4 definite); psychiatric disorders (43 (41%)), and other neurological disorders (28 (27%)). All subjects with a diagnosis of possible bvFTD at baseline (n1⁄45) received a psychiatric diagnosis at follow-up. Depression was the most prevalent psychiatric disorder. Contributing clinical features were stereotyped behavior and disinhibition in favor of bvFTD; and a history of psychiatric disorder, male gender, depressed mood and nervousness in favor of a psychiatric disorder. The Ekman Faces Test successfully discriminated bvFTD from both other groups. MRI had a sensitivity of 70% and specificity of 93% for bvFTD. [18F]FDG-PET, which was performed when MRI was normal or inconclusive, had a sensitivity of 90%, but a specificity of only 68% for bvFTD. The relatively high rate of false-positive bvFTD diagnoses at baseline was partly attributable to false-positive [18F]FDG-PET scans. Combined CSF neurofilament light chain, YKL40, and P-tau/tau ratio had a high diagnostic accuracy to discriminate bvFTD from psychiatric disorders (AUC 0.94). Genetic mutation carriers more often had atypical additional investigations.Conclusions:Our study shows that an abnormal [18F] FDG-PET should be interpreted with caution in the differential diagnosis of the late-onset frontal lobe syndrome, whereas additional CSF biomarkers might be helpful in case of doubt during the diagnostic process. Our findings stress the need for an adapted diagnostic paradigm for bvFTD.

DETAILS OF THE NEW ALZHEIMER’S ASSOCIATION BEST CLINICAL PRACTICE GUIDELINES FOR THE EVALUATION OF NEURODEGENERATIVE COGNITIVE BEHAVIORAL SYNDROMES, ALZHEIMER’S DISEASE AND DEMENTIAS IN THE UNITED STATES

mostly been studied in relation to Alzheimer’s Disease(AD). As loss of functional independence is a feature of all dementia diagnoses, we investigated if WMHs predict activities of daily living (ADL) in a cohort of dementia patients with AD or Dementia with Lewy Bodies (DLB), and if this association is influenced by specific dementia-diagnosis.Methods:In the Sunnybrook Dementia Study, we examined if WMHs are associated with ADLs crosssectionally in 277 dementia patients with varying degrees of cerebral small vessel disease (AD1⁄4227, DLB1⁄450), and longitudinally in 164 patients (AD1⁄4136, DLB1⁄428), in which ADL were reassessed afterw1.5 years. All patients underwent standardized volumetric MRI, and ADL and neuropsychiatric assessment. Total WMH volumes were quantified by semiautomatic segmentation using Lesion Explorer. Basic and instrumental ADL (BADL and IADL) were assessed by Disability Assessment for Dementia scale. Multiple linear regression models adjusted for age, sex, global cognition (Mini-Mental-State Examination-MMSE), and neuropsychiatric symptoms (Neuropsychiatric-Inventory), were used to test if WMH volume predicts ADL in a cohort of AD and DLB patients combined. Longitudinal analyses were adjusted additionally for baseline ADL score and time between two ADL assessments. After testing an interaction between WMHs and diagnosis, we subsequently tested the association of WMH and ADL in models stratified for diagnosis. Results: Of the 277 patients (Mean age 70.8610.0 years), 52 % (n1⁄4145) were women. Compared to DLB, AD patients were older (P1⁄4<0.001), had lower MMSE (P1⁄40.02) and neuropsychiatric symptoms(P1⁄4<0.001), and higher WMH-volume at baseline (AD1⁄46.668.8cc;DLB1⁄43.264.1cc; P1⁄40.01). In the combined sample, patients with higher WMH volume were more likely to perform worse on BADL (Interaction-pvalue WMHs and diagnosis1⁄40.001) but not on IADL. In models stratified for diagnosis, higher WMH volume was associated with worse performance on BADL(Difference:-4.8,95%CI:-8.3,-1.4, p-value:0.007). and IADL(Difference:-4.7,95%CI:-9.7,0.3, p-value:0.06) in DLB patients only. In longitudinal analyses also, patients with higher WMH volume declined significantly on BADLs (decline(b)-7.3,95%CI:-13.8,-0.7,p-value:0.03) and IADLs (decline(b)-6.5,95%CI:-13.4,0.5,p-value:0.06) in the DLB group only. No associations were observed in AD patients. Conclusions:Despite the lower burden of WMHs, WMHs more strongly predicted ADLs in DLB than in AD patients. WMHs possibly interact with DLB pathology differently than with AD pathology consequently influencing functionality.

VERBAL FLUENCY IN ATYPICAL PHENOTYPES OF ALZHEIMER’S DISEASE

lineal model with age as covariate) for the three groups in MMSE1⁄4 MiniMental State Examination; CAMCOG-R1⁄4 Cambridge Cognitive AssessmentRevised; TMT-A1⁄4 Trail Making TestForm A seconds; TMT-B1⁄4 Trail Making TestFormB seconds; BNT1⁄4Boston Naming Test total score; CVLT-SDFR1⁄4 Short Delay Free Recall from California Verbal Learning Test; CVLT-SDCR1⁄4 Short Delay Cued Recall from California Verbal Learning Test; CVLT-LDFR1⁄4 Long Delay Free Recall from California Verbal Learning Test; CVLTLDCR1⁄4LongDelay Cued Recall fromCalifornia Verbal Learning Test; CVLT-Recognition. Poster Presentations: Sunday, July 22, 2018 P537

ANTI-CORRELATED NETWORKS SHOW PARADOXICAL INCREASED CORTICAL THICKNESS IN ALZHEIMER’S DISEASE

controls following thresholding of automated search results for parameters with a posterior probability of 95% of being non-zero. Connections for controls are depicted in Figure 2. Patients showed decreased self-inhibition, denoted by a positive value , in the posterior cingulate cortex (PCC), left and right hippocampal formation (LHF, RHF), and left and right lateral parietal cortex (LLPC, RLPC) compared to controls. Additionally, decreased connectivity was noted from LLPC to the medial prefrontal cortex and increased connectivity was noted from RLPC to PCC. Conclusions:Effective connectivity differed between AD/MCI and control within the DMN. Decreased self-inhibition would increase time to return to baseline, potentially influencing behavioral outcomes.

HARMONIZING TOGETHER: SPEECH AND MUSIC THERAPY AND SUPPORT FOR PATIENTS AND PARTNERS WITH PPA

The Frontotemporal Disorders Unit at Massachusetts General Hospital, Boston, Massachusetts, USA, facilitated an eight-week interdisciplinary therapeutic support group targeted at early stage PPA patients and their care partners. Group goals included providing patients and their care partners with functional communication strategies, decreasing patient isolation, support for caregiver resilience and music therapy to promote utilization of language, social engagement and emotional connections between patients and care partners.

QUANTITATIVE SCORING OF [18F] FLORTAUCIPIR PET SCANS IN TYPICAL AND ATYPICAL PHENOTYPES OF ALZHEIMER’S DISEASE

Figure 2. Voxel-wise mean tau z-score maps relative to young healthy controls are represented for A) amyloid negative CDR 0 older participants, B) amyloid positive CDR 0 participants, and C) amyloid positive CDR > 0 subjects. Results were mapped onto the cortical surface. Z-score of 1.96 represents a statistically significant (p<0.05) difference from controls. Voxel-wise frequency of abnormality maps relative to young healthy controls are represented for D) amyloid negative CDR 0 older participants, E) amyloid positive CDR 0 participants, and F) amyloid positive CDR > 0 subjects. Frequency of abnormality represents the voxel-wise percentage of participants who are abnormal relative to young healthy controls. Sara J. Makaretz, Jessica A. Collins, Kristin K. Sweeney, Samantha Krivensky, Scott M. McGinnis, Aaron P. Schultz, Keith A. Johnson, Brad C. Dickerson, Massachusetts General Hospital, Charlestown, MA, USA; Harvard Medical School, Boston, MA, USA; Brigham and Women’s Hospital, Boston, MA, USA. Contact e-mail: SMAKARETZ@mgh.harvard.edu