Data stewardship in FTLD research: Investigator and research participant views.

INTRODUCTION: Federal policies and guidelines have expanded the return of individual results to participants and expectations for data sharing between investigators and through repositories. Here, we report investigators' and study participants' views and experiences with data stewardship practices within frontotemporal lobal degeneration (FTLD) research, which reveal unique ethical challenges. METHODS: Semi-structured interviews with (1) investigators conducting FTLD research that includes genetic data collection and/or analysis and (2) participants enrolled in a single site longitudinal FTLD study. RESULTS: Analysis of the interviews identified three meta themes: perspectives on data sharing, experiences with enrollment and participation, and data management and security as mechanisms for participant protections. DISCUSSION: This study identified a set of preliminary gaps and needs regarding data stewardship within FTLD research. The results offer initial insights on ethical challenges to data stewardship aimed at informing future guidelines and policies.

Case report: TMEM106B haplotype alters penetrance of GRN mutation in frontotemporal dementia family.

Frontotemporal dementia (FTD) is the second-most common young-onset dementia. Variants in the TMEM106B gene have been proposed as modifiers of FTD disease risk, especially in progranulin (GRN) mutation carriers. A patient in their 50s presented to our clinic with behavioral variant FTD (bvFTD). Genetic testing revealed the disease-causing variant c.349 + 1G > C in GRN. Family testing revealed that the mutation was inherited from an asymptomatic parent in their 80s and that the sibling also carries the mutation. Genetic analyses showed that the asymptomatic parent and sibling carry two copies of the protective TMEM106B haplotype (defined as c.554C > G, p.Thr185Ser), whereas the patient is heterozygous. This case report illustrates that combining TMEM106B genotyping with GRN mutation screening may provide more appropriate genetic counseling on disease risk in GRN families. Both the parent and sibling were counseled to have a significantly reduced risk for symptomatic disease. Implementing TMEM106B genotyping may also promote the collection of biosamples for research studies to improve our understanding of the risk-and disease-modifying effect of this important modifier gene.

Temporal order of clinical and biomarker changes in familial frontotemporal dementia.

Unlike familial Alzheimer's disease, we have been unable to accurately predict symptom onset in presymptomatic familial frontotemporal dementia (f-FTD) mutation carriers, which is a major hurdle to designing disease prevention trials. We developed multimodal models for f-FTD disease progression and estimated clinical trial sample sizes in C9orf72, GRN and MAPT mutation carriers. Models included longitudinal clinical and neuropsychological scores, regional brain volumes and plasma neurofilament light chain (NfL) in 796 carriers and 412 noncarrier controls. We found that the temporal ordering of clinical and biomarker progression differed by genotype. In prevention-trial simulations using model-based patient selection, atrophy and NfL were the best endpoints, whereas clinical measures were potential endpoints in early symptomatic trials. f-FTD prevention trials are feasible but will likely require global recruitment efforts. These disease progression models will facilitate the planning of f-FTD clinical trials, including the selection of optimal endpoints and enrollment criteria to maximize power to detect treatment effects.

The Advisory Group on Risk Evidence Education for Dementia: Multidisciplinary and Open to All.

The brain changes of Alzheimer's disease and other degenerative dementias begin long before cognitive dysfunction develops, and in people with subtle cognitive complaints, clinicians often struggle to predict who will develop dementia. The public increasingly sees benefits to accessing dementia risk evidence (DRE) such as biomarkers, predictive algorithms, and genetic information, particularly as this information moves from research to demonstrated usefulness in guiding diagnosis and clinical management. For example, the knowledge that one has high levels of amyloid in the brain may lead one to seek amyloid reducing medications, plan for disability, or engage in health promoting behaviors to fight cognitive decline. Researchers often hesitate to share DRE data, either because they are insufficiently validated or reliable for use in individuals, or there are concerns about assuring responsible use and ensuring adequate understanding of potential problems when one's biomarker status is known. Concerns include warning people receiving DRE about situations in which they might be compelled to disclose their risk status potentially leading to discrimination or stigma. The Advisory Group on Risk Evidence Education for Dementia (AGREEDementia) welcomes all concerned with how best to share and use DRE. Supporting understanding in clinicians, stakeholders, and people with or at risk for dementia and clearly delineating risks, benefits, and gaps in knowledge is vital. This brief overview describes elements that made this group effective as a model for other health conditions where there is interest in unfettered collaboration to discuss diagnostic uncertainty and the appropriate use and communication of health-related risk information.

Genetic counseling for prion disease: Updates and best practices.

Prion disease is a rare, fatal, and often rapidly progressive neurodegenerative disease. Ten to fifteen percent of cases are caused by autosomal dominant gain-of-function variants in the prion protein gene, PRNP. Rarity and phenotypic variability complicate diagnosis, often obscuring family history and leaving families unprepared for the genetic implications of an index case. Several recent developments inspire this update in best practices for prion disease genetic counseling. A new prion-detection assay has transformed symptomatic diagnosis. Meanwhile, penetrance, age of onset, and duration of illness have been systematically characterized across PRNP variants in a global cohort. Clinically, the traditional genotype-phenotype correlation has weakened over time, and the term genetic prion disease may now better serve providers than the historical subtypes Creutzfeldt-Jakob disease, fatal familial insomnia, and Gerstmann-Sträussler-Scheinker disease. Finally, in the age of genetically targeted therapies, clinical trials for prion disease are being envisaged, and healthy at-risk individuals may be best positioned to benefit. Such individuals need to be able to access clinical services for genetic counseling and testing. Thus, this update on the genetics of prion disease and best practices for genetic counseling for this disease aims to provide the information needed to expand genetic counseling services.

Proposed research criteria for prodromal behavioural variant frontotemporal dementia.

At present, no research criteria exist for the diagnosis of prodromal behavioural variant frontotemporal dementia (bvFTD), though early detection is of high research importance. Thus, we sought to develop and validate a proposed set of research criteria for prodromal bvFTD, termed 'mild behavioural and/or cognitive impairment in bvFTD' (MBCI-FTD). Participants included 72 participants deemed to have prodromal bvFTD; this comprised 55 carriers of a pathogenic mutation known to cause frontotemporal lobar degeneration, and 17 individuals with autopsy-confirmed frontotemporal lobar degeneration. All had mild behavioural and/or cognitive changes, as judged by an evaluating clinician. Based on extensive clinical workup, the prodromal bvFTD group was divided into a Development Group (n = 22) and a Validation Group (n = 50). The Development Group was selected to be the subset of the prodromal bvFTD group for whom we had the strongest longitudinal evidence of conversion to bvFTD, and was used to develop the MBCI-FTD criteria. The Validation Group was the remainder of the prodromal bvFTD group and was used as a separate sample on which to validate the criteria. Familial non-carriers were included as healthy controls (n = 165). The frequencies of behavioural and neuropsychiatric features, neuropsychological deficits, and social cognitive dysfunction in the prodromal bvFTD Development Group and healthy controls were assessed. Based on sensitivity and specificity analyses, seven core features were identified: apathy without moderate-severe dysphoria, behavioural disinhibition, irritability/agitation, reduced empathy/sympathy, repetitive behaviours (simple and/or complex), joviality/gregariousness, and appetite changes/hyperorality. Supportive features include a neuropsychological profile of impaired executive function or naming with intact orientation and visuospatial skills, reduced insight for cognitive or behavioural changes, and poor social cognition. Three core features or two core features plus one supportive feature are required for the diagnosis of possible MBCI-FTD; probable MBCI-FTD requires imaging or biomarker evidence, or a pathogenic genetic mutation. The proposed MBCI-FTD criteria correctly classified 95% of the prodromal bvFTD Development Group, and 74% of the prodromal bvFTD Validation Group, with a false positive rate of <10% in healthy controls. Finally, the MBCI-FTD criteria were tested on a cohort of individuals with prodromal Alzheimer's disease, and the false positive rate of diagnosis was 11-16%. Future research will need to refine the sensitivity and specificity of these criteria, and incorporate emerging biomarker evidence.

The contribution of behavioral features to caregiver burden in FTLD spectrum disorders.

INTRODUCTION: Caregivers of patients with frontotemporal lobar degeneration (FTLD) spectrum disorders experience tremendous burden, which has been associated with the neuropsychiatric and behavioral features of the disorders. METHODS: In a sample of 558 participants with FTLD spectrum disorders, we performed multiple-variable regressions to identify the behavioral features that were most strongly associated with caregiver burden, as measured by the Zarit Burden Interview, at each stage of disease. RESULTS: Apathy and disinhibition, as rated by both clinicians and caregivers, as well as clinician-rated psychosis, showed the strongest associations with caregiver burden, a pattern that was consistent when participants were separated cross-sectionally by disease stage. In addition, behavioral features appeared to contribute most to caregiver burden in patients with early dementia. DISCUSSION: Caregivers should be provided with early education on the management of the behavioral features of FTLD spectrum disorders. Interventions targeting apathy, disinhibition, and psychosis may be most useful to reduce caregiver burden.

Age of Onset of Huntington's Disease in Carriers of Reduced Penetrance Alleles.

BACKGROUND: Age of manifest Huntington's disease (HD) onset correlates with number of CAG repeats in the huntingtin gene. Little is known about onset with 36 to 39 repeats, the "reduced penetrance" (RP) range. OBJECTIVES: We provide allele-specific estimates of HD penetrance (diagnostic confidence level of 4) for RP allele carriers. METHODS: We analyzed 431 pre-manifest RP allele carriers from Enroll-HD, the largest prospective observational HD study. Cumulative penetrance (CP) was estimated from Kaplan-Meier curves. RESULTS: No one with 36 repeats (n = 25) phenoconverted. CP for 38 repeats (n = 120) was 32% (95% confidence interval [CI] 0%-55%) and 51% (CI, 10%-73%) by ages 70 and 75, respectively, and 68% (CI, 46%-81%) and 81% (CI, 58%-92%) by ages 70 and 75 for 39 repeats (n = 253). CP was not estimable at those ages for 37 repeats (n = 33). CONCLUSIONS: Differences by RP-range repeat length did not reach significance with a 3-year median follow-up duration among censored individuals. © 2021 International Parkinson and Movement Disorder Society.

Recognition memory and divergent cognitive profiles in prodromal genetic frontotemporal dementia.

Although executive dysfunction is the characteristic cognitive marker of behavioral variant frontotemporal dementia (bvFTD), episodic memory deficits are relatively common, and may be present even during the prodromal disease phase. In a cohort of mutation carriers with mild behavioral and/or cognitive symptoms consistent with prodromal bvFTD, we aimed to investigate patterns of performance on an abbreviated list learning task, with a particular focus on recognition memory. We further aimed to characterize the cognitive prodromes associated with the three major genetic causes of frontotemporal dementia, as emerging evidence suggests there may be subtle differences in cognitive profiles among carriers of different genetic mutations. Participants included 57 carriers of a pathogenic mutation in microtubule-associated protein tau (MAPT, N = 23), or progranulin (GRN, N = 15), or a or a hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72, N = 19), with mild cognitive and/or behavioral symptoms consistent with prodromal bvFTD. Familial non-carriers were included as controls (N = 143). All participants completed a comprehensive neuropsychological examination, including an abbreviated list learning test assessing episodic memory recall and recognition. MAPT mutation carriers performed worse than non-carriers in terms of list recall, and had difficulty discriminating targets from distractors on the recognition memory task, primarily due to the endorsement of distractors as targets. MAPT mutation carriers also showed nonverbal episodic memory and semantic memory dysfunction (object naming). GRN mutation carriers were variable in performance and overall the most dysexecutive. Slowed psychomotor speed was evident in C9orf72 repeat expansion carriers. Identifying the earliest cognitive indicators of bvFTD is of critical clinical and research importance. List learning may be a sensitive cognitive marker for incipient dementia in MAPT and potentially a subset of GRN carriers. Our results highlight that distinct cognitive profiles may be evident in carriers of the three disease-causing genes during the prodromal disease stage.

Predictive testing for neurodegenerative diseases in the age of next-generation sequencing.

The availability and cost of next-generation sequencing (NSG) now allow testing large numbers of genes simultaneously. However, the gold standard for predictive testing has been to test only for a known family mutation or confirmed family disease. The goal of this study was to investigate the psychological impact of predictive testing for autosomal dominant neurodegenerative diseases without a known family mutation using next-generation sequencing panels compared to single-gene testing of a known family mutation. Fourteen individuals from families with a known mutation and 10 individuals with unknown family mutations participated. Participants completed questionnaires on demographics, genetic knowledge, and psychological measures of anxiety, depression, perceived personal control, rumination, and intolerance to uncertainty at baseline and 1 and 6 months after receiving results. Decision regret was measured 1 and 6 months after receiving results. Participants completed a modified Huntington disease genetic testing protocol with genetic counseling and neurological and psychological evaluation. Genetic testing of either the known family mutation or an NGS panel of neurodegenerative disease genes was performed. Semi-structured interviews were performed at 6 months post-results about their experience. Two-sample t tests were performed on data collected at each time point to identify significant between-group differences in demographic variables, baseline psychological scores, and baseline genetic knowledge scores. Within-group change over time was assessed by a mixed-effects model. Results of this study indicate that NGS panels for predictive testing for neurodegenerative disease are safe and beneficial to participants when performed within a modified HD protocol. Though significant differences in psychological outcomes were found, these differences may have been driven by genetic results and baseline psychological differences between individuals within the groups. Participants did not regret their decision to test and were largely pleased with the testing protocol.

Frontal Pole Hypometabolism Linked to Reduced Prosocial Sexual Behaviors in Frontotemporal Dementia and Corticobasal Syndrome.

BACKGROUND: Changes in sexual behaviors in frontotemporal dementia (FTD) are common and multifaceted, but not well characterized. OBJECTIVE: To characterize changes in sexual behaviors and intimacy in FTD compared to corticobasal syndrome (CBS) and normal controls (NC), and to evaluate the neuroanatomical associations of these changes. METHODS: Spouses of 30 FTD patients, 20 CBS patients, and 35 NC completed the Sexual Symptoms in Neurological Illness and Injury Questionnaire (SNIQ), which captures changes in sexual interest, inappropriate sexual behaviors, and prosocial sexual behaviors. 25 patients with FTD and 14 patients with CBS also received 18-flouorodeoxyglucose positron-emission topography (18FDG-PET) scans to determine the metabolic changes associated with these symptoms. RESULTS: FTD patients showed a greater increase in inappropriate sexual behaviors than CBS patients [p = 0.009] and NC [p < 0.001] and a greater decrease in prosocial sexual behaviors than CBS patients [p = 0.026] and NC [p < 0.001]. Groups did not differ in change in sexual interest. Among both patient groups, the most common change was decreased prosocial sexual behaviors p < 0.01. Hypometabolism in Brodmann's Area 10 (BA10), within the right frontal pole, correlated with decreased prosocial sexual behaviors [p(FWE-corr) <0.05, k = 44]. No anatomical associations were found with other sexual changes. CONCLUSION: Decreased prosocial sexual behavior was associated with hypometabolism in BA 10, an area tied to social knowledge and theory of mind, supporting the idea that changes reflect social-cognitive deficits due to frontal dysfunction.

Quality of life and caregiver burden in familial frontotemporal lobar degeneration: Analyses of symptomatic and asymptomatic individuals within the LEFFTDS cohort.

OBJECTIVE: The Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects evaluates familial frontotemporal lobar degeneration (FTLD) kindreds with MAPT, GRN, or C9orf72 mutations. Objectives were to examine whether health-related quality of life (HRQoL) correlates with clinical symptoms and caregiver burden, and whether self-rated and informant-rated HRQoL would correlate with each other. METHODS: Individuals were classified using the Clinical Dementia Rating (CDR® ) Scale plus National Alzheimer's Coordinating Center (NACC) FTLD. HRQoL was measured with DEMQOL and DEMQOL-proxy; caregiver burden with the Zarit Burden Interview (ZBI). For analysis, Pearson correlations and weighted kappa statistics were calculated. RESULTS: The cohort of 312 individuals included symptomatic and asymptomatic individuals. CDR® plus NACC FTLD was negatively correlated with DEMQOL (r = -0.20, P = .001), as were ZBI and DEMQOL (r = -0.22, P = .0009). There was fair agreement between subject and informant DEMQOL (κ = 0.36, P <.0001). CONCLUSION: Lower HRQoL was associated with higher cognitive/behavior impairment and higher caregiver burden. These findings demonstrate the negative impact of FTLD on individuals and caregivers.

Structural Brain Changes in Pre-Clinical FTD MAPT Mutation Carriers.

BACKGROUND: Frontotemporal dementia (FTD) is the second most common cause of early-onset neurodegenerative dementia. Several studies have focused on early imaging changes in FTD patients, but once subjects meet full criteria for FTD diagnosis, structural changes are generally widespread. OBJECTIVE: This study aims to determine the earliest structural brain changes in asymptomatic MAPT MUTATION carriers. METHODS: This is a cross-sectional multicenter study comparing global and regional brain volume and white matter integrity in a group of MAPT mutation preclinical carriers and controls. Participants belong to multiple generations of six families with five MAPT mutations. All participants underwent a medical examination, neuropsychological tests, genetic analysis, and a magnetic resonance scan (3T, scout, T1-weighted image followed by EPI (BOLD), MPRAGE, DTI, FLAIR, and ASL sequences). RESULTS: Volumes of five cortical and subcortical areas were strongly correlated with mutation status: temporal lobe (left amygdala, left temporal pole), cingulate cortex (left rostral anterior cingulate gyrus, right posterior cingulate), and the lingual gyrus in the occipital lobe. We did not find significant differences in whole brain volume, white matter hyperintensities volume, and white matter integrity using DTI analysis. CONCLUSION: Temporal lobe, cingulate cortex and the lingual gyrus seem to be early targets of the disease and may serve as biomarkers for FTD prior to overt symptom onset.

Genetic screening of a large series of North American sporadic and familial frontotemporal dementia cases.

INTRODUCTION: The Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) consortia are two closely connected studies, involving multiple North American centers that evaluate both sporadic and familial frontotemporal dementia (FTD) participants and study longitudinal changes. METHODS: We screened the major dementia-associated genes in 302 sporadic and 390 familial (symptomatic or at-risk) participants enrolled in these studies. RESULTS: Among the sporadic patients, 16 (5.3%) carried chromosome 9 open reading frame 72 (C9orf72), microtubule-associated protein tau (MAPT), and progranulin (GRN) pathogenic variants, whereas in the familial series we identified 207 carriers from 146 families. Of interest, one patient was found to carry a homozygous C9orf72 expansion, while another carried both a C9orf72 expansion and a GRN pathogenic variant. We also identified likely pathogenic variants in the TAR DNA binding protein (TARDBP), presenilin 1 (PSEN1), and valosin containing protein (VCP) genes, and a subset of variants of unknown significance in other rare FTD genes. DISCUSSION: Our study reports the genetic characterization of a large FTD series and supports an unbiased sequencing screen, irrespective of clinical presentation or family history.

Utility of the global CDR® plus NACC FTLD rating and development of scoring rules: Data from the ARTFL/LEFFTDS Consortium.

INTRODUCTION: We created global rating scoring rules for the CDR® plus NACC FTLD to detect and track early frontotemporal lobar degeneration (FTLD) and to conduct clinical trials in FTLD. METHODS: The CDR plus NACC FTLD rating was applied to 970 sporadic and familial participants from the baseline visit of Advancing Research and Treatment in Frontotemporal Lobar Degeneration (ARTFL)/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS). Each of the eight domains of the CDR plus NACC FTLD was equally weighed in determining the global score. An interrater reliability study was completed for 40 participants. RESULTS: The CDR plus NACC FTLD showed very good interrater reliability. It was especially useful in detecting clinical features of mild non-fluent/agrammatic variant primary progressive aphasia participants. DISCUSSION: The global CDR plus NACC FTLD score could be an attractive outcome measure for clinical trials in symptomatic FTLD, and may be useful in natural history studies and clinical trials in FTLD spectrum disorders.

Awareness of genetic risk in the Dominantly Inherited Alzheimer Network (DIAN).

INTRODUCTION: Although some members of families with autosomal dominant Alzheimer's disease mutations learn their mutation status, most do not. How knowledge of mutation status affects clinical disease progression is unknown. This study quantifies the influence of mutation awareness on clinical symptoms, cognition, and biomarkers. METHODS: Mutation carriers and non-carriers from the Dominantly Inherited Alzheimer Network (DIAN) were stratified based on knowledge of mutation status. Rates of change on standard clinical, cognitive, and neuroimaging outcomes were examined. RESULTS: Mutation knowledge had no associations with cognitive decline, clinical progression, amyloid deposition, hippocampal volume, or depression in either carriers or non-carriers. Carriers who learned their status mid-study had slightly higher levels of depression and lower cognitive scores. DISCUSSION: Knowledge of mutation status does not affect rates of change on any measured outcome. Learning of status mid-study may confer short-term changes in cognitive functioning, or changes in cognition may influence the determination of mutation status.

Assessment of executive function declines in presymptomatic and mildly symptomatic familial frontotemporal dementia: NIH-EXAMINER as a potential clinical trial endpoint.

INTRODUCTION: Identifying clinical measures that track disease in the earliest stages of frontotemporal lobar degeneration (FTLD) is important for clinical trials. Familial FTLD provides a unique paradigm to study early FTLD. Executive dysfunction is a clinically relevant hallmark of FTLD and may be a marker of disease progression. METHODS: Ninety-three mutation carriers with no symptoms or minimal/questionable symptoms (MAPT, n = 31; GRN, n = 28; C9orf72, n = 34; Clinical Dementia Rating scale plus NACC FTLD Module < 1) and 78 noncarriers enrolled through Advancing Research and Treatment in Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects studies completed the Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (NIH-EXAMINER) and the UDS neuropsychological battery. Linear mixed-effects models were used to identify group differences in cognition at baseline and longitudinally. We examined associations between cognition, clinical functioning, and magnetic resonance imaging volumes. RESULTS: NIH-EXAMINER scores detected baseline and differences in slopes between carriers and noncarriers, even in carriers with a baseline Clinical Dementia Rating scale plus NACC FTLD Module = 0. NIH-EXAMINER declines were associated with worsening clinical symptoms and brain volume loss. DISCUSSION: The NIH-EXAMINER is sensitive to cognitive changes in presymptomatic familial FTLD and is a promising surrogate endpoint.

Predictive Genetic Counseling for Neurodegenerative Diseases: Past, Present, and Future.

Predictive genetic counseling for neurodegenerative diseases commenced with Huntington's disease (HD). Because the psychological issues and outcomes have been best studied in HD, the HD genetic counseling and testing protocol is still accepted as the gold standard for genetic counseling for these diseases. Yet, advances in genomic technology have produced an abundance of new information about the genetics of diseases such as Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, and Parkinson's disease. The resulting expansion of genetic tests together with the availability of direct-to-consumer testing and clinical trials for treatment of these diseases present new ethical and practical issues requiring modifications to the protocol for HD counseling and new demands on both physicians and genetic counselors. This work reviews the history of genetic counseling for neurodegenerative diseases, its current practice, and the future direction of genetic counseling for these conditions.

Clinical and volumetric changes with increasing functional impairment in familial frontotemporal lobar degeneration.

INTRODUCTION: The Advancing Research and Treatment in Frontotemporal Lobar Degeneration and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects longitudinal studies were designed to describe the natural history of familial-frontotemporal lobar degeneration due to autosomal dominant mutations. METHODS: We examined cognitive performance, behavioral ratings, and brain volumes from the first time point in 320 MAPT, GRN, and C9orf72 family members, including 102 non-mutation carriers, 103 asymptomatic carriers, 43 mildly/questionably symptomatic carriers, and 72 carriers with dementia. RESULTS: Asymptomatic carriers showed similar scores on all clinical measures compared with noncarriers but reduced frontal and temporal volumes. Those with mild/questionable impairment showed decreased verbal recall, fluency, and Trail Making Test performance and impaired mood and self-monitoring. Dementia was associated with impairment in all measures. All MAPT carriers with dementia showed temporal atrophy, but otherwise, there was no single cognitive test or brain region that was abnormal in all subjects. DISCUSSION: Imaging changes appear to precede clinical changes in familial-frontotemporal lobar degeneration, but specific early clinical and imaging changes vary across individuals.