Early-onset Mild Cognitive Impairment Research Articles

P173: Structural Changes in the Hippocampal Subfields in Early-Onset Mild Cognitive Impairment

Objective:The aim of this study was to examine the structural change in the hippocampal subfields in early-onset (EO) mild cognitive impairment (MCI) patients associated with the APOE ε4 carrier state.Methods:This study had 50 subjects aged 55-63 years, all of whom were diagnosed with amnestic MCI at baseline via the Korean version of the Consortium to Establish a Registry for Alzheimer’s Disease Assessment Packet (CERAD-K). The EO-MCI patients were divided into the MCI continued (MCIcont) and Alzheimer’s disease (AD) converted (ADconv) groups 2 years later. The volumes of hippocampal subfields were measured for all the subjects. The calculations were based on the change of the volumes between the 2-year-interval brain Magnetic resonance image (MRI) scans between MCIcont and ADconv groups according to the Apolipoprotein ε4 (APOE ε4) carrier state.Results:There was a significant correlation between APOE ε4 allele and structural changes in several hippocampal subfields. The volume reduction in cornus ammonis 1 (CA1) field and subiculum, especially in the APOE ε4 carriers. The significance was more prominent in ADconv group.Conclusion:These results suggest that the possession of APOE ε4 allele may lead to significantly greater predilection for the structural changes in hippocampal subfields, showing significant changes, especially in the ADconv patients compared with MCIcont patients.

Proteomic analysis reveal early differences in plasma exosomes of Aβ(+) vs Aβ(‐) patients with early‐onset mild cognitive impairment: from BIOFACE to BIOPEXAL study

AbstractBackgroundin the clinical course of Alzheimer’s disease (AD) development, the dementia phase is commonly preceded by a prodromal AD phase, which is mainly characterized by reaching the highest levels of Aβ and p‐tau‐mediated neuronal injury and a mild cognitive impairment (MCI) clinical status. Because of that, most AD cases are diagnosed when neuronal damage is already established and irreversible. Therefore, a differential diagnosis of MCI causes in these prodromal stages is one of the greatest challenges for clinicians. Blood biomarkers are emerging as desirable tools for pre‐screening purposes, but the current results are still being analyzed and much more data is needed to be implemented in clinical practice. Because of that, plasma exosomes (pEXOs) are gaining popularity as a new source of biomarkers for the early stages of AD developmentMethodto identify an exosome proteomics signature linked to prodromal AD, we performed a cross‐sectional study on two groups of patients with early‐onset MCI (EOMCI) (Aβ +/‐) in which 184 biomarkers were measured in pEXOs, cerebrospinal fluid (CSF), and plasma samples using multiplex PEA technology of Olink© proteomics.Resultthe obtained results showed that proteins measured in pEXOs from EOMCI patients with established amyloidosis correlated with CSF p‐tau181 levels, brain ventricle volume changes, white matter hyperintensities, and MMSE scores. In addition, the correlations of pEXOs proteins with different parameters were able to discriminate between EOMCI Aβ(+) and Aβ(‐) patients, whereas the CSF or plasma proteome did not.Conclusionour findings suggest that pEXOs could be able to provide information regarding the initial amyloidotic changes of AD. At this early stage, our results may indicate that pEXOs biomarker profile is associated with the AD‐specific neurodegeneration process governed by p‐tau and Aβ. Circulating exosomes may acquire a pathological protein signature of AD before raw plasma, becoming potential biomarkers for identifying subjects at the earliest stages of AD development. However, additional research is required to comprehend the molecular pathways underlying these findings and validate the obtained results in an independent cohort.

Plasma extracellular vesicles reveal early molecular differences in amyloid positive patients with early-onset mild cognitive impairment

In the clinical course of Alzheimer’s disease (AD) development, the dementia phase is commonly preceded by a prodromal AD phase, which is mainly characterized by reaching the highest levels of Aβ and p-tau-mediated neuronal injury and a mild cognitive impairment (MCI) clinical status. Because of that, most AD cases are diagnosed when neuronal damage is already established and irreversible. Therefore, a differential diagnosis of MCI causes in these prodromal stages is one of the greatest challenges for clinicians. Blood biomarkers are emerging as desirable tools for pre-screening purposes, but the current results are still being analyzed and much more data is needed to be implemented in clinical practice. Because of that, plasma extracellular vesicles (pEVs) are gaining popularity as a new source of biomarkers for the early stages of AD development. To identify an exosome proteomics signature linked to prodromal AD, we performed a cross-sectional study in a cohort of early-onset MCI (EOMCI) patients in which 184 biomarkers were measured in pEVs, cerebrospinal fluid (CSF), and plasma samples using multiplex PEA technology of Olink© proteomics. The obtained results showed that proteins measured in pEVs from EOMCI patients with established amyloidosis correlated with CSF p-tau181 levels, brain ventricle volume changes, brain hyperintensities, and MMSE scores. In addition, the correlations of pEVs proteins with different parameters distinguished between EOMCI Aβ( +) and Aβ(-) patients, whereas the CSF or plasma proteome did not. In conclusion, our findings suggest that pEVs may be able to provide information regarding the initial amyloidotic changes of AD. Circulating exosomes may acquire a pathological protein signature of AD before raw plasma, becoming potential biomarkers for identifying subjects at the earliest stages of AD development.Graphical

Automatized FACEmemory\xae scoring is related to Alzheimer\u2019s disease phenotype and biomarkers in early-onset mild cognitive impairment: the BIOFACE cohort

BackgroundFACEmemory® is the first computerized, self-administered verbal episodic memory test with voice recognition. It can be conducted under minimal supervision and contains an automatic scoring system to avoid administrator errors. Moreover, it is suitable for discriminating between cognitively healthy and amnestic mild cognitive impairment (MCI) individuals, and it is associated with Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers. This study aimed to determine whether FACEmemory scoring is related to performance on classical memory tests and to AD biomarkers of brain magnetic resonance imaging (MRI) and CSF in patients with early-onset MCI (EOMCI).MethodsNinety-four patients with EOMCI from the BIOFACE study completed FACEmemory, classical memory tests (the Spanish version of the Word Free and Cued Selective Reminding Test -FCSRT-, the Word List from the Wechsler Memory Scale, third edition, and the Spanish version of the Rey–Osterrieth Complex Figure Test), and a brain MRI. Eighty-two individuals also underwent a lumbar puncture.ResultsFACEmemory scoring was moderately correlated with FCSRT scoring. With regard to neuroimaging MRI results, worse execution on FACEmemory was associated with lower cortical volume in the right prefrontal and inferior parietal areas, along with the left temporal and associative occipital areas. Moreover, the total FACEmemory score correlated with CSF AD biomarkers (Aβ1-42/Aβ1-40 ratio, p181-tau, and Aβ1-42/p181-tau ratio). When performance on FACEmemory was compared among the ATN classification groups, significant differences between the AD group and normal and SNAP groups were found.ConclusionsFACEmemory is a promising tool for detecting memory deficits sensitive to early-onset AD, but it also allows the detection of memory-impaired cases due to other etiologies. Our findings suggest that FACEmemory scoring can detect the AD endophenotype and that it is also associated with AD-related changes in MRI and CSF in patients with EOMCI. The computerized FACEmemory tool might be an opportunity to facilitate early detection of MCI in younger people than 65, who have a growing interest in new technologies.

Predictive Factors for Conversion to Dementia in Individuals with Early-Onset Mild Cognitive Impairment

Introduction: There is little research on factors predicting conversion to dementia in early-onset mild cognitive impairment (eoMCI), a transitional stage between healthy ageing and dementia in individuals below the age of 65. We aimed to examine whether sociodemographic and clinical factors at initial presentation predicted dementia progression in a cohort of eoMCI patients attending a memory service, at a university teaching hospital in the UK. Methods: This is a retrospective case note study of individuals diagnosed with eoMCI between 2000 and 2013 at the Younger Person’s Memory Service (YPMS) in Leicestershire, England. Data collected at assessment included social factors, demographic characteristics, and medical and psychiatric history, as well as standardized cognitive assessment scores. Variables were analysed using χ² or independent sample t tests to identify associations. A Cox regression survival analysis was done to identify predictive factors for dementia conversion. An ROC analysis for total CAMCOG was used to investigate sensitivity and specificity for dementia converters versus non-converters. Results: Out of 531 subjects who attended YPMS, 65 patients were given a diagnosis of eoMCI (47.7% female; mean age 56.4 ± 7.54 years). Of these, 21 (32.3%) converted to dementia during their course within the service. Comparison between subgroups revealed a significant association between dementia conversion and higher years of education and lower MMSE and CAMCOG (total and subscale) scores at baseline. Smoking history, alcohol use, or medical history such as diabetes or heart disease were not associated with conversion. Cox regression survival analysis showed higher education in years and lower total CAMCOG scores were significant predictors for conversion. Lower scores on the recent memory, remote memory, learning memory, and executive function subscales of the CAMCOG were also significant predictors for conversion. ROC curve analysis for total CAMCOG demonstrated that the best detection of dementia converters can be achieved with a cutoff score of 90.5/107 (sensitivity of 76.2% and specificity of 68.2%). Area under the curve was 0.808 (95% CI: 0.697–0.920). Conclusion: More years in education and lower cognitive scores on CAMCOG at initial assessment are associated with progression to dementia from eoMCI. Further research is required to explore these predictive factors more.

BIOFACE: A prospective study of risk factors, cognition and biomarkers in a cohort of individuals with early‐onset mild cognitive impairment at Fundació ACE

AbstractBackgroundThe diagnosis of mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) is based on either cerebrospinal fluid (CSF) or neuroimaging biomarkers (Albert et al, 2011). Currently, several non‐invasive and cheaper blood‐based biomarkers are being investigated, including neuronal‐derived plasma exosomes (NPEs) (Winston et al, 2016). The role of neuroinflammation, oxidative stress and early vascular changes, prior to the onset of amyloidosis, has been described in the pathogenesis of AD (Iturria‐Medina et al, 2016) and vascular‐related proteins can be traced in plasma and NPEs using proteomics. However, these changes have not been studied in early onset MCI (EOMCI), that is, when symptoms begin under the age of 65 (Rossor et al, 2010).ObjectiveTo describe the rationale, study design and baseline characteristics of the BIOFACE cohort, a two‐year prospective observational study on EOMCI conducted at Fundació ACE in Barcelona, Spain. The study goal is to characterize different clinical, neuropsychological and biomarker phenotypes and to investigate CSF and plasma proteomics as well as the role of NPEs as early biomarkers of AD.MethodParticipants underwent neurological and neuropsychological batteries and multimodal biomarkers including brain MRI, APOE genotyping, plasma and NPEs, saliva, CSF, non‐invasive arterial peripheral testing, anthropometrics and neuro‐ophthalmological examinations. In the final visit, participants will undergo brain MRI, lumbar puncture and blood extraction for NPEs.ResultNinety‐seven patients with EOMCI were recruited. Most participants were women (59.8%). Mean age at symptom onset was 57 years; mean MMSE score was 28 with a mean of 12.13 years of education. First degree and presenile family history of dementia was present in 60.8% and 15.5%, respectively. Depressive and anxiety disorders, along with vascular risk factors, were the most frequent comorbidities. Syndromic diagnoses were established: possible amnestic MCI (n=32), possible non‐amnestic MCI (n=33), probable amnestic MCI (n=16) and probable non amnestic MCI (n=16). CSF biomarkers (ATN classification): A+ (n=15), A‐T/N+ (n=13), A‐T‐N‐ (n=57).ConclusionBIOFACE is a two‐year observational study of cognition and biomarkers that will shed light on the physiopathology and the potential utility of plasma proteomics and NPEs as non‐invasive early diagnostic and prognostic biomarkers in individuals with early onset MCI.

Fluid intelligence and its neural correlates in early onset mild cognitive impairment

AbstractBackgroundFluid intelligence refers to the ability of abstract reasoning, problem‐solving and other mental activities considered to be independent from learned knowledges and experience. It has been demonstrated that fluid intelligence is compromised in Mild Cognitive Impairment (MCI), but it also declines with ageing. We tested if fluid intelligence is also affected when MCI occurs before 65 years of age (i.e., in early‐onset MCI) and studied its specific functional and structural brain correlates independently from the effect of ageing.MethodEighty‐five subjects with early‐onset MCI (cognitive symptoms onset < 65 years) underwent extended neuropsychological assessment including Raven’s Coloured Progressive Matrices (RCPM), a culture‐free non‐verbal relational reasoning task that is considered a proxy of fluid intelligence. They also underwent multimodal Magnetic Resonance Imaging (MRI) protocol on a 3T scanner including high‐resolution T1 and sequences acquired at rest for functional MRI (fMRI). Performance at RCPM was related to regional grey matter volume using Voxel Based Morphometry (VBM) and to functional connectivity of resting‐state networks (RSNs) known to be related to cognition using independent component analysis.ResultsThe median RCPM score was 27 (range 8‐36, with 36 being the maximum obtainable score). Among all 85 patients, only 11.8% (N=10) performed below the age and education‐corrected cut‐off. These patients also had significantly lower scores in almost all the remaining neuropsychological tests, suggesting that they were in a more severe stage of MCI (i.e., close to conversion). VBM results showed that, across all patients, decreased performance on RCPM was associated with focal atrophy in right fronto‐temporal and bilateral parietal areas (Figure 1). FMRI acquired at rest showed that better performance on RCPM was associated with lower functional connectivity in areas of the anterior DMN and with higher functional connectivity in areas of the left fronto‐parietal RSN (also indicated as the working memory RSN).ConclusionIn patients with early‐onset MCI fluid intelligence is relatively preserved, associated with lower atrophy in right fronto‐temporal and bilateral parietal regions, and with decreased functional connectivity in the anterior DMN and increased in the left fronto‐parietal network.

BIOFACE: A Prospective Study of Risk Factors, Cognition, and Biomarkers in a Cohort of Individuals with Early-Onset Mild Cognitive Impairment. Study Rationale and Research Protocols.

Background:Mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) diagnosis is based on cerebrospinal fluid (CSF) or neuroimaging biomarkers. Currently, non-invasive and inexpensive blood-based biomarkers are being investigated, such as neuronal-derived plasma exosomes (NPEs). Neuroinflammation and early vascular changes have been described in AD pathogenesis and can be traced in plasma and NPEs. However, they have not been studied in early onset MCI (EOMCI).Objective:To describe the rationale, design, and baseline characteristics of the participants from the BIOFACE cohort, a two-year observational study on EOMCI conducted at Fundació ACE. The study goal is to characterize the different phenotypes from a clinical, neuropsychological, and biomarker point of view and to investigate the CSF and plasma proteomics as well as the role of NPEs as early biomarkers of AD.Methods:Participants underwent extended neurological and neuropsychological batteries, multimodal biomarkers including brain MRI, blood, saliva, CSF, anthropometric, and neuro-ophthalmological examinations.Results:Ninety-seven patients with EOMCI were recruited. 59.8%were women. Mean age at symptom onset was 57 years; mean MMSE was 28. First degree and presenile family history of dementia was present in 60.8%and 15.5%, respectively. Depressive and anxiety disorders along with vascular risk factors were the most frequent comorbidities. 29%of participants were APOE ɛ4 carriers, and 67%showed a CSF normal ATN profile.Conclusion:BIOFACE is a two-year study of clinical, cognition, and biomarkers that will shed light on the physiopathology and the potential utility of plasma and NPEs as non-invasive early diagnostic and prognostic biomarkers in people younger than 65 years.

Latent Class and Transition Analysis of Alzheimer's Disease Data

This study uses independent latent class analysis (LCA) and latent transition analysis (LTA) to explore accurate diagnosis and disease status change of a big Alzheimer's disease Neuroimaging Initiative (ADNI) data of 2,132 individuals over a 3-year period. The data includes clinical and neural measures of controls (CN), individuals with subjective memory complains (SMC), early-onset mild cognitive impairment (EMCI), late-onset mild cognitive impairment (LMCI), and Alzheimer's disease (AD). LCA at each time point yielded 3 classes: Class 1 is mostly composed of individuals from CN, SMC, and EMCI groups; Class 2 represents individuals from LMCI and AD groups with improved scores on memory, clinical, and neural measures; in contrast, Class 3 represents LMCI and from AD individuals with deteriorated scores on memory, clinical, and neural measures. However, 63 individuals from Class 1 were diagnosed as AD patients. This could be misdiagnosis, as their conditional probability of belonging to Class 1 (0.65) was higher than that of Class 2 (0.27) and Class 3 (0.08). LTA results showed that individuals had a higher probability of staying in the same class over time with probability >0.90 for Class 1 and 3 and probability >0.85 for Class 2. Individuals from Class 2, however, transitioned to Class 1 from time 2 to time 3 with a probability of 0.10. Other transition probabilities were not significant. Lastly, further analysis showed that individuals in Class 2 who moved to Class 1 have different memory, clinical, and neural measures to other individuals in the same class. We acknowledge that the proposed framework is sophisticated and time-consuming. However, given the severe neurodegenerative nature of AD, we argue that clinicians should prioritize an accurate diagnosis. Our findings show that LCA can provide a more accurate prediction for classifying and identifying the progression of AD compared to traditional clinical cut-off measures on neuropsychological assessments.

Type 2 Diabetes Mellitus May Exacerbate Gray Matter Atrophy in Patients With Early-Onset Mild Cognitive Impairment.

BackgroundThe precise physiopathological association between the courses of neurodegeneration and cognitive decline in type 2 diabetes mellitus (T2DM) remains unclear. This study sought to comprehensively investigate the distribution characteristics of gray matter atrophy in middle-aged T2DM patients with newly diagnosed mild cognitive impairment (MCI).MethodsFour groups, including 28 patients with early-onset MCI, 28 patients with T2DM, 28 T2DM patients with early-onset MCI (T2DM-MCI), and 28 age-, sex-, and education-matched healthy controls underwent three-dimensional high-resolution structural magnetic resonance imaging. Cortical and subcortical gray matter volumes were calculated, and a structural covariance method was used to evaluate the morphological relationships within the default mode network (DMN).ResultsOverlapped and unique cortical/subcortical gray matter atrophy was found in patients with MCI, T2DM and T2DM-MCI in our study, and patients with T2DM-MCI showed lower volumes in several areas than patients with MCI or T2DM. Volume loss in subcortical areas (including the thalamus, putamen, and hippocampus), but not in cortical areas, was related to cognitive impairment in patients with MCI and T2DM-MCI. No associations between biochemical measurements and volumetric reductions were found. Furthermore, patients with MCI and those with T2DM-MCI showed disrupted structural connectivity within the DMN.ConclusionThese findings provide further evidence that T2DM may exacerbate atrophy of specific gray matter regions, which may be primarily associated with MCI. Impairments in gray matter volume related to T2DM or MCI are independent of cardiovascular risk factors, and subcortical atrophy may play a more pivotal role in cognitive impairment than cortical alterations in patients with MCI and T2DM-MCI. The enhanced structural connectivity within the DMN in patients with T2DM-MCI may suggest a compensatory mechanism for the chronic neurodegeneration.

The Loss in Expectation of Life due to Early-Onset Mild Cognitive Impairment and Early-Onset Dementia in Norway

Introduction: Whether patients with early-onset dementia have poorer or improved survival compared with those with a late onset largely depends on the survival measure. Survival estimates for early-onset mild cognitive impairment (MCI) diagnosis are particularly scarce. We aimed to estimate life expectancy (LE) in patients with early-onset dementia or early MCI, and loss in expectation of life (LEL) for these groups. Comparisons were made with the general Norwegian population and a subgroup of patients with late-onset dementia. Methods: Early onset was defined as receiving a diagnosis of MCI or dementia before age 65 years. LE and LEL were predicted using flexible parametric survival models. Our study population was comprised of newly diagnosed (incident) cases (n = 4,906), aged 50–90 years at the time of diagnosis (672 were diagnosed before age 65 years, of which 291 were diagnosed with dementia), in the Norwegian register of persons assessed for cognitive symptoms (NorCog) between 2009 and 2017, and patients were followed up for mortality or censorship until January 2018. Results: Among the early-onset patients, 8 and 23% died during follow-up, in the MCI and dementia groups, respectively. Both early-onset MCI and especially early-onset dementia were associated with lower LE than in the general Norwegian population; LE for 60-year-old women in 2016 was 26 years in the general population, 20 years in MCI patients, and 7 years in dementia patients. The corresponding LE at 80 years was 10, 6, and 5 years. Thus, LEL were particularly pronounced for patients with early dementia. The diagnosis-specific LE pattern in men was similar to that in women. Discussion: Early-onset MCI was associated with substantial life years lost (5–6 years), but the loss was particularly pronounced for those with early-onset dementia, reducing the expected life length by 2 decades.

Smell identification function in early-onset Alzheimer's disease and mild cognitive impairment.

Little is known about olfactory identification (OI) function in early-onset Alzheimer's disease (EOAD) and early-onset mild cognitive impairment (eoMCI) with age of onset <65 years. We aimed to study OI in EOAD compared with eoMCI and age-matched healthy controls (HC). Nineteen EOAD subjects with mild to moderate dementia, 17 with eoMCI, and 21 HC recruited as a convenience sample from memory services were assessed for cognition, behavioral symptoms, and activities for daily living. The OI was tested using the University of Pennsylvania smell identification test (UPSIT). EOAD participants performed worse compared with eoMCI and HC on cognitive tests and OI (p < 0.001). Although eoMCI had poorer cognitive scores compared to HC, they were similar in their OI function. OI correlated with attention (r = 0.494, p = 0.031), executive functions (r = 0.508, p = 0.026), and praxis (r = 0.455, p = 0.05) within the EOAD group. OI impairment was significantly associated with the diagnosis of EOAD versus eoMCI, but not with eoMCI when compared with HC. OI could potentially be useful in differentiating EOAD from eoMCI. Studies with late-life MCI patients showing OI impairment relative to HC may be attributed to a different disease process. Independent replication in a larger sample is needed to validate these findings.

Changes in the Hippocampal Volume and Shape in Early-Onset Mild Cognitive Impairment

Objective The aim of this study was to examine the change in the hippocampal volume and shape in early-onset mild cognitive impairment (EO-MCI) associated with the APOE ε4 carrier state. Methods This study had 50 subjects aged 55–63 years, all of whom were diagnosed with MCI at baseline via the Korean version of the Consortium to Establish a Registry for Alzheimer’s Disease Assessment Packet. The EO-MCI patients were divided into the MCI continued (MCIcont) and Alzheimer’s disease (AD) converted (ADconv) groups 2 years later. The hippocampal volume and shape were measured for all the subjects. The local shape analysis (LSA) was used to conduct based on the 2-year-interval magnetic resonance imaging scans. Results There was a significant correlation between APOE ε4 allele and hippocampal volume atrophy. Over two years, the volume reduction in the left hippocampus was found to be faster than that in the right hippocampus, especially in the APOE ε4 carriers. LSA showed that the 2 subfields were significantly affected in the left hippocampus. Conclusion These results suggest that the possession of APOE ε4 allele may lead to greater predilection for left hippocampal atrophy in EO-MCI, and some specific subfields of the hippocampus may be more prominently involved.

Early-onset mild cognitive impairment in Parkinson\u2019s disease: Altered corticopetal cholinergic network

Degeneration of the substantia innominata (SI) is significantly correlated with cognitive performance in Parkinson’s disease (PD). We examined functional and structural patterns of SI degeneration in drug-naïve PD patients according to the duration of parkinsonism before mild cognitive impairment (MCI) diagnosis. Twenty PD patients with a shorter duration (PD-MCI-SD, <1 year), 18 patients with a longer duration (PD-MCI-LD, ≥1 year), and 29 patients with intact cognition (PD-IC) were included. Seed-based resting-state functional connectivity (rsFC) analysis using bilateral SI seed and region-of-interest-based volumetric analysis were performed. Compared to PD-IC, the collapsed PD-MCI group showed altered rsFC in the right frontal and bilateral parietal areas. PD-MCI-SD showed rsFC alteration in broader frontal and parietal areas compared to the other groups. Decreased rsFC in the right frontal area was also significantly correlated with shorter disease duration. No significant SI volume change was found between the groups. Altered rsFC between the SI and the frontal and parietal areas might be relevant to cognitive dysfunction in PD. Decreased rsFC between the SI and frontal area might be associated with early-onset MCI, suggesting that cholinergic deficits in the frontal brain areas might play an important role in the acceleration of cognitive decline in PD.

Prognosis of Early-Onset vs. Late-Onset Mild Cognitive Impairment: Comparison of Conversion Rates and Its Predictors.

Background: Despite having the same histopathological characteristics, early-onset and late-onset Alzheimer’s disease (AD) patients show some distinct clinical and neuropsychological profiles. Early Onset Mild Cognitive Impairment (EOMCI) is a less characterized group. The aim of this study is to characterize MCI probably due to AD in terms of the clinical, genetic, Cerebrospinal fluid (CSF) biomarkers profile and conversion rate of EOMCI, compared to the late-onset form (LOMCI). Methods: 159 MCI patients were divided in two groups: 52 EOMCI (onset < 65 years) and 107 LOMCI (onset ≥ 65 years). We investigated differences in neuropsychological scores, clinical variables, ApoE genotype, CSF biomarkers (Aβ42, t-Tau and p-Tau) in both groups. Conversion was ascertained during follow-up. Results: EOMCI showed a longer duration of symptoms prior to the first evaluation (EOMCI = 4.57 vs. LOMCI = 3.31, p = 0.008) and scored higher on the subjective memory complaints scale (9.91 vs. 7.85, p = 0.008), but performed better in brief cognitive tests (27.81 vs. 26.51, p < 0.001 in Mini-Mental State Examination; 19.84 vs. 18.67, p = 0.005 in Montreal Cognitive Assessment) than LOMCI. ApoE genotype distribution and CSF biomarker profile were similar in both groups, as was the conversion risk. Lower Aβ42 (Hazard ratio (HR): 0.998, 95% Confidence Interval (CI) = [0.996–1.000], p = 0.042), higher t-Tau levels (HR: 1.003, 95%CI = [1.000–1.005], p = 0.039) and higher scores in the Alzheimer Disease Assessment Scale-Cognitive (HR: 1.186, 95%CI = [1.083–1.299], p = 0.002) increased the risk of conversion. Discussion: Despite differences in memory performance and memory complaints, EOMCI and LOMCI seem to represent indistinct biological groups that do not have a higher risk of conversion to AD or differ in risk factors for conversion.

Abstract P116: Physical Fitness in Early Adulthood: A Modifiable Risk Factor for Neurological and Psychiatric Diseases

Low cardiovascular fitness in mid- and late life represents a risk factor for several neurological diseases. However, the respective effect of aerobic cardiovascular and muscle fitness in early adulthood is largely unknown. Therefore, we analyzed these in young men with regard to long-term risk serious depression, bipolar disorders, stroke and dementia. We performed population-based longitudinal cohort studies of Swedish male conscripts registered in 1968-2005 for mandatory military service (approx. 1,800,000 subjects), representing about 95 % of all Swedish males at age 18 during this time period. Data on cardiovascular fitness (determined by the cycle ergometric test), muscle strength (isometric contraction) and cognitive performance (IQ tests) were subdivided into low, medium, high fitness groups. Over a 40-year follow-up, risk of serious depression, bipolar disorder, stroke and dementia were calculated with Cox proportional hazards models controlling for potential confounders. To identify cases, we used the International Classification of Diseases (ICD) 8-10 in the Hospital Discharge Register and the Cause of Death Register. Depression. Adjusted hazard ratios (HRs) with confidence interval (CI) show significant relationships between fitness and severe depression for low compared to high fitness: HR (CI) 1.80 (1.64-1.99) for cardiovascular fitness and 1.43 (1.32-1.55) for muscle strength. Bipolar disorders exhibited a lower, yet significant association with cardiovascular fitness and muscle strength (adjusted hazard ratios (HRs) with confidence interval (CI): 1.35 (1.12-1.63) and 1.22 (1.05-1.42), respectively. Stroke. Adjusted HRs show inverse relationships between fitness and stroke for low compared to high fitness HR (CI) 1.70 (1.50-1.93) for cardiovascular fitness and 1.39 (1.27-1.53) for muscle strength. All three stroke types (subarachnoidal hemorrhage, intracerebral hemorrhage and ischemic stroke displayed similar associations. There were stronger associations for fatal stroke. Dementia. Low compared to high cardiovascular fitness was significantly associated with an increased risk for diagnosis of dementia before age 60: HR (CI) 2.49 (1.87-3.32). Mild cognitive impairment (MCI) showed an even greater association: HR (CI) 3.57 (2.23-5.74). The combination of low cardiovascular fitness and poor cognitive performance in early adulthood was associated with a &gt;8-fold increase in the risk of early-onset MCI and a &gt;7-fold increased risk of early-onset dementia. In summary, this study sheds light on physical fitness as an early-life risk factor for psychiatric and neurological conditions, and underlines the potential for lifestyle modification to reduce the risk of late-life CNS impairments.

Structural Brain Changes in Early-Onset Alzheimer's Disease Subjects Using the LONI Pipeline Environment.

This study investigates 36 subjects aged 55-65 from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database to expand our knowledge of early-onset (EO) Alzheimer's Disease (EO-AD) using neuroimaging biomarkers. Nine of the subjects had EO-AD, and 27 had EO mild cognitive impairment (EO-MCI). The structural ADNI data were parcellated using BrainParser, and the 15 most discriminating neuroimaging markers between the two cohorts were extracted using the Global Shape Analysis (GSA) Pipeline workflow. Then the Local Shape Analysis (LSA) Pipeline workflow was used to conduct local (per-vertex) post-hoc statistical analyses of the shape differences based on the participants' diagnoses (EO-MCI+EO-AD). Tensor-based Morphometry (TBM) and multivariate regression models were used to identify the significance of the structural brain differences based on the participants' diagnoses. The significant between-group regional differences using GSA were found in 15 neuroimaging markers. The results of the LSA analysis workflow were based on the subject diagnosis, age, years of education, apolipoprotein E (ε4), Mini-Mental State Examination, visiting times, and logical memory as regressors. All the variables had significant effects on the regional shape measures. Some of these effects survived the false discovery rate (FDR) correction. Similarly, the TBM analysis showed significant effects on the Jacobian displacement vector fields, but these effects were reduced after FDR correction. These results may explain some of the differences between EO-AD and EO-MCI, and some of the characteristics of the EO cognitive impairment subjects.

Cardiovascular and cognitive fitness at age 18 and risk of early-onset dementia

Patients with early-onset dementia are a significantly under-recognized subgroup of patients with an increasing prevalence. Epidemiological studies are limited and studies of modifiable risk factors, such as physical fitness, are lacking. We aimed to investigate the associations between cardiovascular fitness individually and in combination with cognitive performance at age 18 and risk of early-onset dementia and mild cognitive impairment later in life. We performed a population-based cohort study of over 1.1 million Swedish, 18-year-old, male conscripts, who underwent conscription exams between 1968 and 2005. These males were then followed for up to 42 years. Objective data on cardiovascular fitness and cognitive performance were collected during conscription exams and were subsequently linked with hospital registries to calculate later risk of early-onset dementia and mild cognitive impairment using Cox proportional hazards models controlling for several confounders. The scores from the exams were divided into tertiles (low, medium, high) for the analyses. The mean follow-up time for the analyses was 25.7 years (standard deviation: 9.3) and the median was 27 years. In total, 30 195 315 person-years of follow-up were included in the study. In fully adjusted models, both low cardiovascular fitness and cognitive performance (compared to high) at age 18 were associated with increased risk for future early-onset dementia (cardiovascular fitness, n = 662 events: hazard ratio 2.49, 95%, confidence interval 1.87-3.32; cognitive performance, n = 657 events: hazard ratio 4.11, 95%, confidence interval 3.19-5.29) and mild cognitive impairment (cardiovascular fitness, n = 213 events: hazard ratio 3.57, 95%, confidence interval 2.23-5.74; cognitive performance, n = 212 events: hazard ratio 3.23, 95%, confidence interval 2.12-4.95). Poor performance on both cardiovascular fitness and cognitive tests was associated with a >7-fold (hazard ratio 7.34, 95%, confidence interval 5.08-10.58) and a >8-fold (hazard ratio 8.44, 95%, confidence interval 4.64-15.37) increased risk of early-onset dementia and early-onset mild cognitive impairment, respectively. In conclusion, lower cardiovascular fitness and cognitive performance in early adulthood were associated with an increased risk of early-onset dementia and mild cognitive impairment later in life, and the greatest risks were observed for individuals with a combination of low cardiovascular fitness and low cognitive performance.

Evaluation of memory impairment in aging adult survivors of childhood acute lymphoblastic leukemia treated with cranial radiotherapy.

Cranial radiotherapy (CRT) is a known risk factor for neurocognitive impairment in survivors of childhood cancer and may increase risk for mild cognitive impairment and dementia in adulthood. We performed a cross-sectional evaluation of survivors of childhood acute lymphoblastic leukemia (ALL) treated with 18 Gy (n = 127) or 24 Gy (n = 138) CRT. Impairment (age-adjusted score >1 standard deviation below expected mean, two-sided exact binomial test) on the Wechsler Memory Scale IV (WMS-IV) was measured. A subset of survivors (n = 85) completed structural and functional neuroimaging. Survivors who received 24 Gy, but not 18 Gy, CRT had impairment in immediate (impairment rate = 33.8%, 95% confidence interval [CI] = 25.9% to 42.4%; P < .001) and delayed memory (impairment rate = 30.2%, 95% CI = 22.6% to 38.6%; P < .001). The mean score for long-term narrative memory among survivors who received 24 Gy CRT was equivalent to that for individuals older than 69 years. Impaired immediate memory was associated with smaller right (P = .02) and left (P = .008) temporal lobe volumes, and impaired delayed memory was associated with thinner parietal and frontal cortices. Lower hippocampal volumes and increased functional magnetic resonance imaging activation were observed with memory impairment. Reduced cognitive status (Brief Cognitive Status Exam from the WMS-IV) was identified after 24 Gy (18.5%, 95% CI = 12.4% to 26.1%; P < .001), but not 18 Gy (8.7%, 95% CI = 4.4% to 15.0%; P = .11), CRT, suggesting a dose-response effect. Employment rates were equivalent (63.8% for 24 Gy CRT and 63.0% for 18 Gy CRT). Adult survivors who received 24 Gy CRT had reduced cognitive status and memory, with reduced integrity in neuroanatomical regions essential in memory formation, consistent with early onset mild cognitive impairment.

The Perinatal Adverse events and Special Trends in Cognitive Trajectory (PLASTICITY) - pre-protocol for a prospective longitudinal follow-up cohort study

Prospective follow-up studies on long term effects of pre- and perinatal adverse conditions in adulthood are rare. We will continue to follow the prospective cohort of initially 1196 subjects with predefined at-delivery risk factors out of 22,359 consecutive deliveries during 1971-74 at a single maternity hospital. The risk cohort and 93 controls have been followed up with a comprehensive clinical program at 5, 9, and 16 years of age and by questionnaire at the age of 30 years. Major medical events known to affect the development and growth of the brain, or cognitive functions and personality have been documented. Here we present a pre-protocol for the project, which we will call PLASTICITY, whose aim is to follow consenting subjects and controls into mid-adulthood and beyond, and to explore how the neonatal risk factors modulate neurodevelopmental and neurodegenerative processes such as learning disabilities, ADHD, aging, early onset mild cognitive impairment and even dementia. Our first focus is on the neurological and cognitive outcomes at age 40 years, using detailed neurological, neuropsychological, neuroimaging, genetic, blood chemistry and registry based methods. Results will be expected to offer information on the risk of neurological, psychiatric, metabolic and other medical consequences as well as the need for health and social services at the brink of middle age, when new degenerative phenomena are known to emerge. The evaluation at age 40 years will serve as a baseline for later aging studies. We welcome all comments and suggestions, which we will apply in finalizing details and inviting collaboration.