To evaluate the incidence of mosaicism in de novo neurofibromatosis 2 (NF2).
Patients fulfilling NF2 criteria, but with no known affected family member from a previous generation (n = 1055), were ...tested for NF2 variants in lymphocyte DNA and where available tumor DNA. The proportion of individuals with a proven or presumed mosaic NF2 variant was assessed and allele frequencies of identified variants evaluated using next-generation sequencing.
The rate of proven/presumed mosaicism was 232/1055 (22.0%). However, nonmosaic heterozygous pathogenic variants were only identified in 387/1055 (36.7%). When variant detection rates in second generation nonmosaics were applied to de novo cases, we assessed the overall probable mosaicism rate to be 59.7%. This rate differed by age from 21.7% in those presenting with bilateral vestibular schwannoma <20 years to 80.7% in those aged ≥60 years. A mosaic variant was detected in all parents of affected children with a single-nucleotide pathogenic NF2 variant.
This study has identified a very high probable mosaicism rate in de novo NF2, probably making NF2 the condition with the highest expressed rate of mosaicism in de novo dominant disease that is nonlethal in heterozygote form. Risks to offspring are small and probably correlate with variant allele frequency detected in blood.
Aims There is increasing interest in the nature of the emotion recognition deficit in Huntington’s disease (HD) with conflicting reports of disproportionate impairments for some emotions in some ...modalities. This review aimed to clarify the pattern of emotion recognition deficits in HD. Methods A systematic review and narrative synthesis was conducted for studies investigating emotion recognition in Huntington’s disease. Embase, MEDLINE, PsychINFO and PubMed were searched from 1993 to 2010, and citation and reference list searches were also conducted. 1724 citations were identified. Results Sixteen studies met inclusion criteria. In manifest HD recognition of facial anger was found most consistently, although recognition of all negative emotions (facial and vocal) tended to be impaired. In premanifest HD impairments were inconsistent, but are seen in all facial expressions of negative emotion. Inconsistency may represent the variability inherent in HD although may also be due to between-study differences in methodology. Conclusions Current evidence supports the conclusion that recognition of all negative emotions tends to be impaired in HD, particularly in the facial domain. Future work should focus on using more ecologically-valid tests, and testing inter-modality differences.
Abstract
Background
While
APOE
‐ε4 carriers are at higher risk of Alzheimer’s disease (AD), there is evidence that
APOE
‐ε4 may have some beneficial effects across the life‐span, including on ...cognition. It is unclear how such effects may relate to subtle memory decline during the preclinical phase of AD. Two previous studies reported that
APOE
‐ε4 carriers recalled object locations more accurately than non‐carriers on the “What was where?” visual short‐term memory binding test (10.1016/j.cortex.2016.12.016; 10.1016/j.neurobiolaging.2018.09.017), but these studies did not account for preclinical AD pathology.
Method
The “What was where?” task (Figure 1) was administered to participants in Insight 46 – a sub‐study of the British 1946 birth cohort – who were all born during the same week (aged 69‐71 at assessment (Table 1)). Outcomes included object identification and a sensitive analogue measure of localisation error (the distance between the location reported by the participant and the true location). Two‐dimensional mixture models (10.31234/osf.io/q57fm) were used to isolate three sources of localisation error: imprecision, guessing, and misbinding (swapping an object’s location with that of a different object). β‐Amyloid status (positive / negative) was determined from
18
F‐Florbetapir‐PET. Multivariable regression models were used to investigate differential effects of
APOE
genotype (ε4‐carrier / non‐carrier) and β‐amyloid status on performance in 398 cognitively‐normal participants, adjusting for confounders including a prospectively‐collected measure of childhood cognitive ability.
Result
APOE
‐ε4 and β‐amyloid had opposing effects on object identification, with
APOE
‐ε4 predicting better recall and β‐amyloid‐positivity predicting poorer recall.
APOE
‐ε4 carriers also recalled object locations more precisely, but a subtle detrimental effect of β‐amyloid on localisation was seen only among non‐carriers (Table 2
,
Figure 2). Childhood cognitive ability also predicted performance over 60 years later (Table 2).
Conclusion
In this large population‐based sample of cognitively‐normal ∼70‐year‐olds, a positive association between
APOE
‐ε4 and short‐term visual memory was observed. For the localization measure, this appeared to be protective against a subtle deficit associated with β‐amyloid pathology. This is consistent with the antagonistic pleiotropy hypothesis – whereby a gene controls both beneficial and detrimental traits – and provides novel evidence that these effects persist into older age, even among individuals who may be in the preclinical stages of AD.
Background
While APOE‐ε4 carriers are at higher risk of Alzheimer’s disease (AD), there is evidence that APOE‐ε4 may have some beneficial effects across the life‐span, including on cognition. It is ...unclear how such effects may relate to subtle memory decline during the preclinical phase of AD. Two previous studies reported that APOE‐ε4 carriers recalled object locations more accurately than non‐carriers on the “What was where?” visual short‐term memory binding test (10.1016/j.cortex.2016.12.016; 10.1016/j.neurobiolaging.2018.09.017), but these studies did not account for preclinical AD pathology.
Method
The “What was where?” task (Figure 1) was administered to participants in Insight 46 – a sub‐study of the British 1946 birth cohort – who were all born during the same week (aged 69‐71 at assessment (Table 1)). Outcomes included object identification and a sensitive analogue measure of localisation error (the distance between the location reported by the participant and the true location). Two‐dimensional mixture models (10.31234/osf.io/q57fm) were used to isolate three sources of localisation error: imprecision, guessing, and misbinding (swapping an object’s location with that of a different object). β‐Amyloid status (positive / negative) was determined from 18F‐Florbetapir‐PET. Multivariable regression models were used to investigate differential effects of APOE genotype (ε4‐carrier / non‐carrier) and β‐amyloid status on performance in 398 cognitively‐normal participants, adjusting for confounders including a prospectively‐collected measure of childhood cognitive ability.
Result
APOE‐ε4 and β‐amyloid had opposing effects on object identification, with APOE‐ε4 predicting better recall and β‐amyloid‐positivity predicting poorer recall. APOE‐ε4 carriers also recalled object locations more precisely, but a subtle detrimental effect of β‐amyloid on localisation was seen only among non‐carriers (Table 2, Figure 2). Childhood cognitive ability also predicted performance over 60 years later (Table 2).
Conclusion
In this large population‐based sample of cognitively‐normal ∼70‐year‐olds, a positive association between APOE‐ε4 and short‐term visual memory was observed. For the localization measure, this appeared to be protective against a subtle deficit associated with β‐amyloid pathology. This is consistent with the antagonistic pleiotropy hypothesis – whereby a gene controls both beneficial and detrimental traits – and provides novel evidence that these effects persist into older age, even among individuals who may be in the preclinical stages of AD.
Abstract
Background
Age is the biggest risk factor for dementia, yet human brains do not age uniformly. The British 1946 birth cohort, the world’s longest continuously running birth cohort, provides ...a unique opportunity to assess these variations in biological ageing. So‐called ‘brain age’ is a biomarker of brain ageing, derived from machine‐learning analysis trained on a large sample of healthy brains (N=2001). Brain age has previously been related to cognitive ageing, physiological ageing and mortality risk (DOI: 10.1038/mp.2017.62), supporting the validity of this approach for assessing biological ageing.
Method
502 participants in the Insight 46 study, all born during one week in 1946, completed baseline cognitive and neuroimaging assessments at age 69‐71. 468 underwent combined
18
florbetapir PET‐MRI scans, from which amyloid status (positive/negative), whole brain volume (WBV), total intracranial volume (TIV) and hippocampal volumes (HV) were derived. The T1‐weighted sequence was passed through the Brain‐age algorithm (https://github.com/james‐cole/brainageR), deriving brain predicted‐age (BPA) and brain‐predicted age difference (brain‐PAD; BPA minus chronological age). Serum neurofilament light (NFL) concentration was measured via Simoa immunoassay. A Preclinical Alzheimer’s Cognitive Composite Score (PACC) was calculated as a mean of z‐scores of the Mini‐mental state exam (MMSE), logical memory delayed recall, digit symbol substitution score and the Face‐Name test. Life course metrics (childhood cognitive scores, education level and Framingham Risk scores) were obtained from previous cohort assessments. Multivariate regression models were used to investigate whether life course metrics predict BPA, as well as whether NFL levels, brain volumes, or cognitive scores correlated with BPA, adjusting for chronological age.
Result
There was a significant difference between the 229 females assessed (mean BPA 65.2 years) compared with the 239 males assessed (mean BPA 70.7). BPA was independently associated with serum NFL concentration (p = 0.071) and inversely with whole brain volume (p < 0.001). Life course factors did not predict brain age.
Conclusion
The results showed a significant association of BPA, a cross‐sectional imaging metric, with a biochemical marker of neuronal damage (NFL) and sex. BPA has utility as an imaging metric that can integrate multiple modalities contributing to biological age, with potential as a predictive biomarker of cognitive decline.
Background
Age is the biggest risk factor for dementia, yet human brains do not age uniformly. The British 1946 birth cohort, the world’s longest continuously running birth cohort, provides a unique ...opportunity to assess these variations in biological ageing. So‐called ‘brain age’ is a biomarker of brain ageing, derived from machine‐learning analysis trained on a large sample of healthy brains (N=2001). Brain age has previously been related to cognitive ageing, physiological ageing and mortality risk (DOI: 10.1038/mp.2017.62), supporting the validity of this approach for assessing biological ageing.
Method
502 participants in the Insight 46 study, all born during one week in 1946, completed baseline cognitive and neuroimaging assessments at age 69‐71. 468 underwent combined 18florbetapir PET‐MRI scans, from which amyloid status (positive/negative), whole brain volume (WBV), total intracranial volume (TIV) and hippocampal volumes (HV) were derived. The T1‐weighted sequence was passed through the Brain‐age algorithm (https://github.com/james‐cole/brainageR), deriving brain predicted‐age (BPA) and brain‐predicted age difference (brain‐PAD; BPA minus chronological age). Serum neurofilament light (NFL) concentration was measured via Simoa immunoassay. A Preclinical Alzheimer’s Cognitive Composite Score (PACC) was calculated as a mean of z‐scores of the Mini‐mental state exam (MMSE), logical memory delayed recall, digit symbol substitution score and the Face‐Name test. Life course metrics (childhood cognitive scores, education level and Framingham Risk scores) were obtained from previous cohort assessments. Multivariate regression models were used to investigate whether life course metrics predict BPA, as well as whether NFL levels, brain volumes, or cognitive scores correlated with BPA, adjusting for chronological age.
Result
There was a significant difference between the 229 females assessed (mean BPA 65.2 years) compared with the 239 males assessed (mean BPA 70.7). BPA was independently associated with serum NFL concentration (p = 0.071) and inversely with whole brain volume (p < 0.001). Life course factors did not predict brain age.
Conclusion
The results showed a significant association of BPA, a cross‐sectional imaging metric, with a biochemical marker of neuronal damage (NFL) and sex. BPA has utility as an imaging metric that can integrate multiple modalities contributing to biological age, with potential as a predictive biomarker of cognitive decline.
Background
Accelerated Forgetting (AF) is the phenomenon whereby material is retained normally over short intervals (minutes or hours) but forgotten abnormally rapidly over longer periods (days or ...weeks). AF has been observed in presymptomatic carriers of mutations causing familial Alzheimer’s disease (AD) (doi:10.1016/S1474‐4422(17)30434‐9). To our knowledge, no studies have investigated whether AF is sensitive to preclinical AD pathology in cognitively‐normal older adults.
Method
Participants in the Insight 46 study, a sub‐study of the British 1946 birth cohort, completed baseline cognitive and neuroimaging assessments at age 69‐71. For the follow‐up visits (∼29 months later), we complemented the clinic visit assessments of Complex Figure Drawing and the Face‐Name test (FNAME‐12) with a 7‐day delay version administered by telephone (Figure 1). AF scores were calculated as the percentage of material retained after 7 days, relative to retention after 30 minutes. Cerebral atrophy between baseline and follow‐up was quantified from T1‐weighted MRI using the Brain Boundary Shift Integral (BBSI). β‐amyloid status at baseline (positive / negative) was determined from 18F‐Florbetapir‐PET.
As follow‐up assessments are still underway, preliminary interim analyses have been conducted based on 195 cognitively‐normal individuals with complete neuroimaging data (see Table 1 for characteristics). Multivariable regression models were used to investigate the effects of β‐amyloid status and BBSI on AF, and to explore interactions between these two predictors, adjusting for potential confounders including prospectively‐collected measures of childhood cognitive ability and education.
Result
Despite no statistically‐significant differences after a 30‐minute delay, β‐amyloid‐positive participants retained a lower percentage of Complex Figure material over 7 days (71.8% vs. 80.7%, p=0.010) and a trend to a lower percentage of FNAME‐12 material (69.4% vs. 77.2%, p = 0.083) (Table 2, Figure 2). Higher education predicted better retention of the Complex Figure. Among β‐amyloid‐positive participants only, greater cerebral atrophy predicted poorer retention of the Complex Figure (Table 2, Figure 3).
Conclusion
These results provide novel evidence of AF in cognitively‐normal β‐amyloid‐positive 72‐year‐olds. AF may be a sensitive outcome measure for therapeutic trials in preclinical AD, as it may reveal subtle memory decline at an earlier stage than traditional assessments. The interaction between β‐amyloid pathology and cerebral atrophy merits longitudinal investigation.
Abstract
Background
Accelerated Forgetting (AF) is the phenomenon whereby material is retained normally over short intervals (minutes or hours) but forgotten abnormally rapidly over longer periods ...(days or weeks). AF has been observed in presymptomatic carriers of mutations causing familial Alzheimer’s disease (AD) (doi:10.1016/S1474‐4422(17)30434‐9). To our knowledge, no studies have investigated whether AF is sensitive to preclinical AD pathology in cognitively‐normal older adults.
Method
Participants in the Insight 46 study, a sub‐study of the British 1946 birth cohort, completed baseline cognitive and neuroimaging assessments at age 69‐71. For the follow‐up visits (∼29 months later), we complemented the clinic visit assessments of Complex Figure Drawing and the Face‐Name test (FNAME‐12) with a 7‐day delay version administered by telephone (Figure 1). AF scores were calculated as the percentage of material retained after 7 days, relative to retention after 30 minutes. Cerebral atrophy between baseline and follow‐up was quantified from T1‐weighted MRI using the Brain Boundary Shift Integral (BBSI). β‐amyloid status at baseline (positive / negative) was determined from
18
F‐Florbetapir‐PET.
As follow‐up assessments are still underway, preliminary interim analyses have been conducted based on 195 cognitively‐normal individuals with complete neuroimaging data (see Table 1 for characteristics). Multivariable regression models were used to investigate the effects of β‐amyloid status and BBSI on AF, and to explore interactions between these two predictors, adjusting for potential confounders including prospectively‐collected measures of childhood cognitive ability and education.
Result
Despite no statistically‐significant differences after a 30‐minute delay, β‐amyloid‐positive participants retained a lower percentage of Complex Figure material over 7 days (71.8% vs. 80.7%,
p
=0.010) and a trend to a lower percentage of FNAME‐12 material (69.4% vs. 77.2%,
p
= 0.083) (Table 2, Figure 2). Higher education predicted better retention of the Complex Figure. Among β‐amyloid‐positive participants only, greater cerebral atrophy predicted poorer retention of the Complex Figure (Table 2, Figure 3).
Conclusion
These results provide novel evidence of AF in cognitively‐normal β‐amyloid‐positive 72‐year‐olds. AF may be a sensitive outcome measure for therapeutic trials in preclinical AD, as it may reveal subtle memory decline at an earlier stage than traditional assessments. The interaction between β‐amyloid pathology and cerebral atrophy merits longitudinal investigation.
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