Dataset Information

Psychological Impact of Predictive Genetic Testing for Inherited Alzheimer Disease and Frontotemporal Dementia: The IT-DIAfN Protocol.

ABSTRACT:

Aim

Our aim was to evaluate the psychological impact of predictive genetic testing in individuals at-risk for inherited dementia who underwent a structured counseling and testing protocol.

Methods

Participants were healthy at-risk relatives from families with at least one affected patient, in whom a disease-associated genetic variant had been ascertained. A comprehensive psychological assessment (personality, anxiety and depression, quality of life, coping strategies, resilience and health-related beliefs) was administered at baseline, at 6 months and 12 months follow-up.

Results

Twenty-four participants from 13 families were included. Sixteen participants underwent blood sampling and genetic analysis; 6 resulted to be carriers of pathogenic variants (1 in PSEN1, 1 in PSEN2, 4 in GRN). Carriers showed higher score on the Resilience Scale for Adults (RSA) - social competence, and on Multidimensional Health Locus of Control - internal, than noncarriers (P=0.03 for both). Ten at-risk relatives who completed the follow-up showed improvement in RSA - planned future (P=0.01) with respect to baseline.

Discussion

Our case series showed that at-risk individuals undergoing predictive testing showed benefit on personal life and no detrimental impact on a broad range of psychological outcomes. Higher social skills and lower internal health locus of control in carriers may be an early psychological correlate of preclinical dementia.

SUBMITTER: Galluzzi S

PROVIDER: S-EPMC9132242 | biostudies-literature | 2022 Apr-Jun 01

REPOSITORIES: biostudies-literature

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Publications

Psychological Impact of Predictive Genetic Testing for Inherited Alzheimer Disease and Frontotemporal Dementia: The IT-DIAfN Protocol.

Galluzzi Samantha S Mega Anna A Di Fede Giuseppe G Muscio Cristina C Fascendini Sara S Benussi Luisa L Tagliavini Fabrizio F Frisoni Giovanni B GB Di Maria Emilio E

Alzheimer disease and associated disorders 20220316 2

<h4>Aim</h4>Our aim was to evaluate the psychological impact of predictive genetic testing in individuals at-risk for inherited dementia who underwent a structured counseling and testing protocol.<h4>Methods</h4>Participants were healthy at-risk relatives from families with at least one affected patient, in whom a disease-associated genetic variant had been ascertained. A comprehensive psychological assessment (personality, anxiety and depression, quality of life, coping strategies, resilience a ...[more]

PMID: 35293381

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Project description:ImportanceNeurodegenerative diseases can cause dysfunction of neural structures involved in judgment, executive function, emotional processing, sexual behavior, violence, and self-awareness. Such dysfunctions can lead to antisocial and criminal behavior that appears for the first time in the adult or middle-aged individual or even later in life.ObjectiveTo investigate the frequency and type of criminal behavior among patients with a diagnosed dementing disorder.Design, setting, and participantsWe conducted a retrospective medical record review of 2397 patients who were seen at the University of California, San Francisco, Memory and Aging Center between 1999 and 2012, including 545 patients with Alzheimer disease (AD), 171 patients with behavioral variant of frontotemporal dementia (bvFTD), 89 patients with semantic variant of primary progressive aphasia, and 30 patients with Huntington disease. Patient notes containing specific keywords denoting criminal behavior were reviewed. Data were stratified by criminal behavior type and diagnostic groups.Main outcomes and measuresFrequencies of criminal behavior and χ² statistics were calculated.ResultsOf the 2397 patients studied, 204 (8.5%) had a history of criminal behavior that emerged during their illness. Of the major diagnostic groups, 42 of 545 patients (7.7%) with AD, 64 of 171 patients (37.4%) with bvFTD, 24 of 89 patients (27.0%) with semantic variant of primary progressive aphasia, and 6 of 30 patients (20%) with Huntington disease exhibited criminal behavior. A total of 14% of patients with bvFTD were statistically significantly more likely to present with criminal behavior compared with 2% of patients with AD (P < .001) and 6.4% were statistically significantly more likely to exhibit violence compared with 2% of patients with AD (P = .003). Common manifestations of criminal behavior in the bvFTD group included theft, traffic violations, sexual advances, trespassing, and public urination in contrast with those in the AD group, who commonly committed traffic violations, often related to cognitive impairment.Conclusions and relevanceCriminal behavior is more common in patients with bvFTD and semantic variant of primary progressive aphasia than in those with AD and is more likely to be an early manifestation of the disorder. Judicial evaluations of criminality in the demented individual might require different criteria than the classic "insanity defense" used in the American legal system; these individuals should be treated differently by the law. The appearance of new-onset criminal behavior in an adult should elicit a search for frontal and anterior temporal brain disease and for dementing disorders.

Project description:Frontotemporal dementia (FTD) is a highly heritable group of neurodegenerative disorders, with around 30% of patients having a strong family history. The majority of that heritability is accounted for by autosomal dominant mutations in the chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), and microtubule-associated protein tau (MAPT) genes, with mutations more rarely seen in a number of other genes. This review will discuss the recent updates in the field of genetic FTD. Age at symptom onset in genetic FTD is variable with recently identified genetic modifiers including TMEM106B (in GRN carriers particularly) and a polymorphism at a locus containing two overlapping genes LOC101929163 and C6orf10 (in C9orf72 carriers). Behavioural variant FTD (bvFTD) is the most common diagnosis in each of the genetic groups, although in C9orf72 carriers amyotrophic lateral sclerosis either alone, or with bvFTD, is also common. An atypical neuropsychiatric presentation is also seen in C9orf72 carriers and family members of carriers are at greater risk of psychiatric disorders including schizophrenia and autistic spectrum disorders. Large natural history studies of presymptomatic genetic FTD are now underway both in Europe/Canada (GENFI-the Genetic FTD Initiative) and in the US (ARTFL/LEFFTDS study), collaborating together under the banner of the FTD Prevention Initiative (FPI). These studies are taking forward the validation of cognitive, imaging and fluid biomarkers that aim to robustly measure disease onset, staging and progression in genetic FTD. Grey matter changes on MRI and hypometabolism on FDG-PET are seen at least 10 years before symptom onset with white matter abnormalities seen earlier, but the pattern and exact timing of changes differ between different genetic groups. In contrast, tau PET has yet to show promise in genetic FTD. Three key fluid biomarkers have been identified so far that are likely to be helpful in clinical trials-CSF or blood neurofilament light chain levels (in all groups), CSF or blood progranulin levels (in GRN carriers) and CSF poly(GP) dipeptide repeat protein levels (in C9orf72 carriers). Increased knowledge about genetic FTD has led to more clinical presymptomatic genetic testing but this has not yet been mirrored in the development of either an accepted FTD-specific testing protocol or provision of appropriate psychological support mechanisms for those living through the at-risk phase. This will become even more relevant as disease-modifying therapy trials start in each of the genetic groups over the next few years.

Project description:Biomarkers that can predict disease progression in individuals with genetic frontotemporal dementia are urgently needed. We aimed to identify whether baseline MRI-based grey and white matter abnormalities are associated with different clinical progression profiles in presymptomatic mutation carriers in the GENetic Frontotemporal dementia Initiative. Three hundred eighty-seven mutation carriers were included (160 GRN, 160 C9orf72, 67 MAPT), together with 240 non-carrier cognitively normal controls. Cortical and subcortical grey matter volumes were generated using automated parcellation methods on volumetric 3T T1-weighted MRI scans, while white matter characteristics were estimated using diffusion tensor imaging. Mutation carriers were divided into two disease stages based on their global CDR®+NACC-FTLD score: presymptomatic (0 or 0.5) and fully symptomatic (1 or greater). The w-scores in each grey matter volumes and white matter diffusion measures were computed to quantify the degree of abnormality compared to controls for each presymptomatic carrier, adjusting for their age, sex, total intracranial volume, and scanner type. Presymptomatic carriers were classified as 'normal' or 'abnormal' based on whether their grey matter volume and white matter diffusion measure w-scores were above or below the cut point corresponding to the 10th percentile of the controls. We then compared the change in disease severity between baseline and one year later in both the 'normal' and 'abnormal' groups within each genetic subtype, as measured by the CDR®+NACC-FTLD sum-of-boxes score and revised Cambridge Behavioural Inventory total score. Overall, presymptomatic carriers with normal regional w-scores at baseline did not progress clinically as much as those with abnormal regional w-scores. Having abnormal grey or white matter measures at baseline was associated with a statistically significant increase in the CDR®+NACC-FTLD of up to 4 points in C9orf72 expansion carriers, and 5 points in the GRN group as well as a statistically significant increase in the revised Cambridge Behavioural Inventory of up to 11 points in MAPT, 10 points in GRN, and 8 points in C9orf72 mutation carriers. Baseline regional brain abnormalities on MRI in presymptomatic mutation carriers are associated with different profiles of clinical progression over time. These results may be helpful to inform stratification of participants in future trials.

Project description:PurposeThe clinical features of autoimmune retinopathy (AIR) can resemble and be difficult to differentiate from inherited retinal degenerations (IRDs). Misdiagnosis of an IRD as AIR causes unnecessary treatment with immunosuppressive agents. The purpose of this study is to calculate the predictive value of genetic testing for IRDs in patients with suspected AIR and provide clinical examples where genetic testing has been useful.MethodsWe identified patients seen at MEEI between April 2013 and January 2017 for whom the differentiation of AIR vs. IRDs was difficult based on clinical assessment alone. All patients had some atypical features for AIR, but tested positive for anti-retinal antibodies. Within this group, we identified six patients who had genetic testing for IRDs with the Genetic Eye Disease panel for retinal genes (GEDi-R). We calculated the positive predictive value (PPV) and negative predictive value (NPV) of genetic testing in a population with approximately equal numbers of IRD and AIR patients.ResultsSix patients had clinical features that made distinguishing between IRDs and AIR on a clinical basis difficult and were sent for genetic testing: four women and two men with a mean age of 59.5 years. In two of these six patients, genetic diagnoses were made based upon the identification of known pathogenic variants in the common IRD genes USH2A and RHO. Two patients had variants of unknown significance within genes associated with IRDs, and the other two had no relevant genetic findings. Given the 60% sensitivity and 3% false positive rate for GEDi-R testing and assuming a 50% pre-test probability of having an IRD, the PPV for GEDi-R for detecting IRD is 95.2% and the NPV is 70.8%.Conclusions and importanceIn patients for whom the differential diagnosis of AIR and IRDs is unclear based on clinical information, genetic testing can be a valuable tool when it identifies an IRD, sparing the patient unnecessary immunosuppressive treatment. However, the test has a low NPV so a negative genetic testing result does not confidently exclude IRD as the true diagnosis.

Project description:BackgroundFrontotemporal dementia is a highly heritable neurodegenerative disorder. In about a third of patients, the disease is caused by autosomal dominant genetic mutations usually in one of three genes: progranulin (GRN), microtubule-associated protein tau (MAPT), or chromosome 9 open reading frame 72 (C9orf72). Findings from studies of other genetic dementias have shown neuroimaging and cognitive changes before symptoms onset, and we aimed to identify whether such changes could be shown in frontotemporal dementia.MethodsWe recruited participants to this multicentre study who either were known carriers of a pathogenic mutation in GRN, MAPT, or C9orf72, or were at risk of carrying a mutation because a first-degree relative was a known symptomatic carrier. We calculated time to expected onset as the difference between age at assessment and mean age at onset within the family. Participants underwent a standardised clinical assessment and neuropsychological battery. We did MRI and generated cortical and subcortical volumes using a parcellation of the volumetric T1-weighted scan. We used linear mixed-effects models to examine whether the association of neuropsychology and imaging measures with time to expected onset of symptoms differed between mutation carriers and non-carriers.FindingsBetween Jan 30, 2012, and Sept 15, 2013, we recruited participants from 11 research sites in the UK, Italy, the Netherlands, Sweden, and Canada. We analysed data from 220 participants: 118 mutation carriers (40 symptomatic and 78 asymptomatic) and 102 non-carriers. For neuropsychology measures, we noted the earliest significant differences between mutation carriers and non-carriers 5 years before expected onset, when differences were significant for all measures except for tests of immediate recall and verbal fluency. We noted the largest Z score differences between carriers and non-carriers 5 years before expected onset in tests of naming (Boston Naming Test -0·7; SE 0·3) and executive function (Trail Making Test Part B, Digit Span backwards, and Digit Symbol Task, all -0·5, SE 0·2). For imaging measures, we noted differences earliest for the insula (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume was 0·80% in mutation carriers and 0·84% in non-carriers; difference -0·04, SE 0·02) followed by the temporal lobe (at 10 years before expected symptom onset, mean volume as a percentage of total intracranial volume 8·1% in mutation carriers and 8·3% in non-carriers; difference -0·2, SE 0·1).InterpretationStructural imaging and cognitive changes can be identified 5-10 years before expected onset of symptoms in asymptomatic adults at risk of genetic frontotemporal dementia. These findings could help to define biomarkers that can stage presymptomatic disease and track disease progression, which will be important for future therapeutic trials.FundingCentres of Excellence in Neurodegeneration.

Dataset Information

Psychological Impact of Predictive Genetic Testing for Inherited Alzheimer Disease and Frontotemporal Dementia: The IT-DIAfN Protocol.

Aim

Methods

Results

Discussion

Publications

Psychological Impact of Predictive Genetic Testing for Inherited Alzheimer Disease and Frontotemporal Dementia: The IT-DIAfN Protocol.

Similar Datasets

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