The APOE4 effect: structural brain differences in Alzheimer's disease according to the age at symptom onset.

BACKGROUND AND PURPOSE: How the APOE genotype can differentially affect cortical and subcortical memory structures in biomarker-confirmed early-onset (EOAD) and late-onset (LOAD) Alzheimer's disease (AD) was assessed. METHOD: Eighty-seven cerebrospinal fluid (CSF) biomarker-confirmed AD patients were classified according to their APOE genotype and age at onset. 28 were EOAD APOE4 carriers (+EOAD), 21 EOAD APOE4 non-carriers (-EOAD), 23 LOAD APOE4 carriers (+LOAD) and 15 LOAD APOE4 non-carriers (-LOAD). Grey matter (GM) volume differences were analyzed using voxel-based morphometry in Papez circuit regions. Multiple regression analyses were performed to determine the relation between GM volume loss and cognition. RESULTS: Significantly more mammillary body atrophy in +EOAD compared to -EOAD is reported. The medial temporal and posterior cingulate cortex showed less GM in +LOAD compared to -LOAD. Medial temporal GM volume loss was also found in +EOAD compared to -LOAD. With an exception for +EOAD, medial temporal GM was strongly associated with episodic memory in the three groups, whilst posterior cingulate cortex GM volume was more related with visuospatial abilities. Visuospatial abilities and episodic memory were also associated with the anterior thalamic nucleus in -LOAD. CONCLUSIONS: Our results show that the APOE genotype has a significant effect on GM integrity as a function of age of disease onset. Specifically, whilst LOAD APOE4 genotype is mostly associated with increased medial temporal and parietal atrophy compared to -LOAD, for EOAD APOE4 might have a more specific effect on subcortical (mammillary body) structures. The findings suggest that APOE genotype needs to be taken into account when classifying patients by age at onset.

Early-onset Alzheimer's disease shows a distinct neuropsychological profile and more aggressive trajectories of cognitive decline than late-onset.

OBJECTIVES: Early- and late-onset Alzheimer's disease (EOAD and LOAD) share the same neuropathological traits but show distinct cognitive features. We aimed to explore baseline and longitudinal outcomes of global and domain-specific cognitive function in a well characterized cohort of patients with a biomarker-based diagnosis. METHODS: In this retrospective cohort study, 195 participants were included and classified according to their age, clinical status, and CSF AD biomarker profile: 89 EOAD, 37 LOAD, 46 young healthy controls (age ≤ 65 years), and 23 old healthy controls (>65 years). All subjects underwent clinical and neuropsychological assessment, neuroimaging, APOE genotyping and lumbar puncture. RESULTS: We found distinct neuropsychological profiles between EOAD and LOAD at the time of diagnosis. Both groups showed similar performances on memory and language domains, but the EOAD patients displayed worsened deficits in visual perception, praxis, and executive tasks (p < 0.05). Longitudinally, cognitive decline in EOAD was more pronounced than LOAD in the global outcomes at the expense of these non-amnestic domains. We found that years of education significantly influenced the decline in most of the neuropsychological tests. Besides, the APOE ε4 status showed a significant effect on the decline of memory-related tasks within the EOAD cohort (p < 0.05). INTERPRETATION: Age of onset is a main factor shaping the cognitive trajectories in AD patients, with younger age driving to a steeper decline of the non-memory domains. Years of education are related to a transversal decline in all cognitive domains and APOE ε4 status to a specific decline in memory performance in EOAD.

Sex differences in early-onset Alzheimer's disease.

BACKGROUND AND PURPOSE: Sex is believed to drive heterogeneity in Alzheimer's disease (AD), although evidence in early-onset AD (EOAD; <65 years) is scarce. METHODS: We included 62 EOAD patients and 44 healthy controls (HCs) with core AD cerebrospinal fluid (CSF) biomarkers, neurofilament light chain levels, neuropsychological assessment, and 3-T magnetic resonance imaging. We measured cortical thickness (CTh) and hippocampal subfield volumes (HpS) using FreeSurfer. Adjusted linear models were used to analyze sex-differences and the relationship between atrophy and cognition. RESULTS: Compared to same-sex HCs, female EOAD subjects showed greater cognitive impairment and broader atrophy burden than male EOAD subjects. In a direct female-EOAD versus male-EOAD comparison, there were slight differences in temporal CTh, with no differences in cognition or HpS. CSF tau levels were higher in female EOAD than in male EOAD subjects. Greater atrophy was associated with worse cognition in female EOAD subjects. CONCLUSIONS: At diagnosis, there are sex differences in the pattern of cognitive impairment, atrophy burden, and CSF tau in EOAD, suggesting there is an influence of sex on pathology spreading and susceptibility to the disease in EOAD.

Baseline MRI atrophy predicts 2-year cognitive outcomes in early-onset Alzheimer's disease.

BACKGROUND: MRI atrophy predicts cognitive status in AD. However, this relationship has not been investigated in early-onset AD (EOAD, < 65 years) patients with a biomarker-based diagnosis. METHODS: Forty eight EOAD (MMSE ≥ 15; A + T + N +) and forty two age-matched healthy controls (HC; A - T - N -) from a prospective cohort underwent full neuropsychological assessment, 3T-MRI scan and lumbar puncture at baseline. Participants repeated the cognitive assessment annually. We used linear mixed models to investigate whether baseline cortical thickness (CTh) or subcortical volume predicts two-year cognitive outcomes in the EOAD group. RESULTS: In EOAD, hemispheric CTh and ventricular volume at baseline were associated with global cognition, language and attentional/executive functioning 2 years later (p < 0.0028). Regional CTh was related to most cognitive outcomes (p < 0.0028), except verbal/visual memory subtests. Amygdalar volume was associated with letter fluency test (p < 0.0028). Hippocampal volume did not show significant associations. CONCLUSION: Baseline hemispheric/regional CTh, ventricular and amygdalar volume, but not the hippocampus, predict two-year cognitive outcomes in EOAD.

Longitudinal brain atrophy and CSF biomarkers in early-onset Alzheimer's disease.

There is evidence of longitudinal atrophy in posterior brain areas in early-onset Alzheimer's disease (EOAD; aged < 65 years), but no studies have been conducted in an EOAD cohort with fluid biomarkers characterization. We used 3T-MRI and Freesurfer 6.0 to investigate cortical and subcortical gray matter loss at two years in 12 EOAD patients (A + T + N + ) compared to 19 controls (A-T-N-) from the Hospital Clínic Barcelona cohort. We explored group differences in atrophy patterns and we correlated atrophy and baseline CSF-biomarkers levels in EOAD. We replicated the correlation analyses in 14 EOAD (A + T + N + ) and 55 late-onset AD (LOAD; aged ≥ 75 years; A + T + N + ) participants from the Alzheimer's disease Neuroimaging Initiative. We found that EOAD longitudinal atrophy spread with a posterior-to-anterior gradient and beyond hippocampus/amygdala. In EOAD, higher initial CSF NfL levels correlated with higher ventricular volumes at baseline. On the other hand, higher initial CSF Aß42 levels (within pathological range) predicted higher rates of cortical loss in EOAD. In EOAD and LOAD subjects, higher CSF t-tau values at baseline predicted higher rates of subcortical atrophy. CSF p-tau did not show any significant correlation. In conclusion, posterior cortices, hippocampus and amygdala capture EOAD atrophy from early stages. CSF Aß42 might predict cortical thinning and t-tau/NfL subcortical atrophy.

Errorless Learning Therapy in Semantic Variant of Primary Progressive Aphasia.

BACKGROUND: The semantic variant of primary progressive aphasia (svPPA) is characterized by a progressive loss of semantic knowledge impairing the ability to name and to recognize the meaning of words. OBJECTIVE: We aimed to evaluate the immediate and short-term effect of errorless learning speech therapy on the naming and recognition of commonly used words in patients with svPPA. METHODS: Eight participants diagnosed with svPPA received 16 sessions of intensive errorless learning speech therapy. Naming and word comprehension tasks were evaluated at baseline, immediately postintervention, and at follow-up after 1, 3, and 6 months. These evaluations were performed using two item sets (a trained list and an untrained list). RESULTS: In the naming tasks, patients showed a significant improvement in trained items immediately after the intervention, but that improvement decayed progressively when therapy ended. No improvements were found either in trained comprehension or in untrained tasks. CONCLUSION: Errorless learning therapy could improve naming ability in patients with svPPA. This effect may be due to the relative preservation of episodic memory, but the benefit is not maintained over time, presumably because there is no consolidation.

Screening of dementia genes by whole-exome sequencing in Spanish patients with early-onset dementia: likely pathogenic, uncertain significance and risk variants.

Early-onset Alzheimer's disease (EOAD) and frontotemporal dementia (FTD) have a high proportion of genetically determined cases. Next-generation sequencing technologies have triggered the discovery of new mutations and genetic variants in dementia-causal genes. We performed whole-exome sequencing and selective analysis of known genes causative of EOAD and FTD in a well-characterized Spanish cohort of 103 patients (60 EOAD, 43 FTD) to find genetic variants associated to patients' phenotype. In EOAD patients, a new likely pathogenic variant in PSEN1 gene (p.G378R) was found. In FTD patients, 2 likely pathogenic variants were found, one in MAPT gene (p.P397S) and one in VCP gene (p.R159H). In our series, 2% of early-onset dementia without criteria for clinical genetic testing according to current guidelines presented a likely pathogenic mutation. We have also detected 13 additional variants of uncertain significance in causal genes, as well as rare variants in risk genes for dementia (ABCA7, SORL1, SQSTM1, and TREM2). Next-generation technologies in neurodegenerative diseases constitute a powerful tool that significantly contributes to patients' diagnosis.

Contribution of CSF biomarkers to early-onset Alzheimer's disease and frontotemporal dementia neuroimaging signatures.

Prior studies have described distinct patterns of brain gray matter and white matter alterations in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD), as well as differences in their cerebrospinal fluid (CSF) biomarkers profiles. We aim to investigate the relationship between early-onset AD (EOAD) and FTLD structural alterations and CSF biomarker levels. We included 138 subjects (64 EOAD, 26 FTLD, and 48 controls), all of them with a 3T MRI brain scan and CSF biomarkers available (the 42 amino acid-long form of the amyloid-beta protein [Aß42], total-tau protein [T-tau], neurofilament light chain [NfL], neurogranin [Ng], and 14-3-3 levels). We used FreeSurfer and FSL to obtain cortical thickness (CTh) and fraction anisotropy (FA) maps. We studied group differences in CTh and FA and described the "AD signature" and "FTLD signature." We tested multiple regression models to find which CSF-biomarkers better explained each disease neuroimaging signature. CTh and FA maps corresponding to the AD and FTLD signatures were in accordance with previous literature. Multiple regression analyses showed that the biomarkers that better explained CTh values within the AD signature were Aß and 14-3-3; whereas NfL and 14-3-3 levels explained CTh values within the FTLD signature. Similarly, NfL levels explained FA values in the FTLD signature. Ng levels were not predictive in any of the models. Biochemical markers contribute differently to structural (CTh and FA) changes typical of AD and FTLD.

Diagnostic Accuracy of MRI Visual Rating Scales in the Diagnosis of Early Onset Cognitive Impairment.

BACKGROUND: The diagnosis of incipient symptomatic stages of early-onset dementia is challenging. The magnetic resonance imaging (MRI) is an easy-access biomarker. OBJECTIVE: We aim to determine the distribution and diagnostic performance of the existing atrophy visual rating scales on MRI in initial stages of the most frequent neurodegenerative early onset dementias. METHODS: We evaluated the visual atrophy scales usefulness in two hundred subjects: seventy sporadic early onset Alzheimer's disease (AD) patients (48 amnestic and 22 non-amnestic), 14 patients with autosomal-dominant AD (ADAD), 25 sporadic frontotemporal dementia patients [11 with behavioral variant (bvFTD), nine with semantic variant of primary progressive aphasia (svPPA), and 5 with non-fluent primary progressive aphasia (nfvPPA)], 7 with genetically determined FTD (genetic FTD), 25 mild cognitive impairment due to non-degenerative disorders, and 59 healthy controls. All had MMSE≥18, 3T-brain MRI, and biomarker-supported diagnosis. Two raters evaluated six frontal, temporal, and parietal scales. Inter-rater reliability and diagnostic performance in terms of area under the receiver-operator curves and balanced accuracy were analyzed. RESULTS: Best scales to discriminate AD from controls were the anterior cingulate scale for amnestic and the posterior atrophy scale for sporadic non-amnestic AD and ADAD. The anterior temporal scale was the best for sporadic bvFTD and svPPA and the anterior cingulate scale was for nfvPPA. All scales performed well for the genetic FTD. However, no scale demonstrated good performance at discriminating AD from FTD or non-degenerative disorders. CONCLUSIONS: The clinicians should interpret with caution atrophy scale assessment in subjects with early-onset cognitive impairment given that none of the evaluated scales met the requirements for being a diagnostic biomarker.

Hippocampal atrophy has limited usefulness as a diagnostic biomarker on the early onset Alzheimer's disease patients: A comparison between visual and quantitative assessment.

NIA-AA diagnostic criteria include volumetric or visual rating measures of hippocampal atrophy (HA) as a diagnostic biomarker of Alzheimer's disease (AD). We aimed to determine its utility as a diagnostic biomarker for early onset Alzheimer's disease (EOAD) by assessing Medial Temporal Atrophy (MTA) and hippocampal volume (HV) determination. MTA score and HV quantified by FreeSurfer were assessed in 140 (aged ≤65) subjects with biomarker supported diagnosis: 38 amnesic (A-EOAD), 20 non-amnesic (NA-EOAD), 30 late onset AD (LOAD), 20 fronto-temporal dementia (FTD) and 32 healthy controls (HC). The results showed that the proportion of MTA ≥ 1.5 was higher on LOAD and FTD than EOAD and HC but none of the MTA thresholds (≥1, ≥1.5 and ≥ 2) showed acceptable diagnostic accuracy. LOAD had lower HV than the other groups. A-EOAD HV was lower than NA-EOAD and HC but equal to FTD. The 6258 mm3 cut-off showed good diagnostic accuracy between A-EOAD and HC. Both tools showed a moderate inverse correlation. In conclusion, MTA has a limited diagnostic utility as an EOAD biomarker as it does not discriminate AD from FTD or HC in initial symptomatic stages. HV may discriminate A-EOAD from HC but not from FTD.

Donepezil treatment stabilizes functional connectivity during resting state and brain activity during memory encoding in Alzheimer's disease.

Previous studies with functional magnetic resonance imaging (fMRI) demonstrated a differential brain activity and connectivity after treatment with donepezil in Alzheimer's disease (AD) when compared to healthy elders. Importantly however, there are no available studies where the placebo or control group included comparable AD patients relative to the treated groups. Fifteen patients recently diagnosed of AD were randomized to treatment (n = 8) or to control group (n = 7); the former receiving daily treatment of donepezil during 3 months. At baseline and follow-up, both groups underwent resting-state as well as task-fMRI examinations, this latter assessing encoding of visual scenes. The treated group showed higher connectivity in areas of the default mode network, namely the right parahippocampal gyrus at follow-up resting-fMRI as compared to the control group. On the other hand, for the task-fMRI, the untreated AD group presented progressive increased activation in the left middle temporal gyrus and bilateral precuneus at the 3-month examination compared to baseline, whereas the treated group exhibited stable patterns of brain activity. Donepezil treatment is associated with stabilization of connectivity of medial temporal regions during resting state and of brain efficiency during a cognitive demand, on the whole reducing progressive dysfunctional reorganizations observed during the natural course of the disease.

[Landscape test for assessing visual memory in Alzheimer's disease]. / Test de paisajes para la valoración de la memoria visual en la enfermedad de Alzheimer.

INTRODUCTION: Visual episodic memory is affected in the early phases of Alzheimer's disease (AD). AIMS: To design a visual memory test free of any verbal content, to offer its normative values in the elderly population in Spain, to validate the test in a group of patients with mild AD and to determine its capacity to discriminate between subjects with AD and controls. SUBJECTS AND METHODS: The study involved a sample of 263 subjects (137 controls and 126 patients with AD) over 50 years of age. The landscape test consists of a first part in which participants are shown 25 photographs of landscapes. Five minutes later, the previous 25 photos are shown again together with 25 new pictures, and the subject must recognise the ones that have already been seen. The statistical analysis was performed using the Student t test for independent measures, ANCOVA, linear regression, Pearson's correlation and the ROC curve. RESULTS: In the control group, sex and schooling did not have any significant effect on the results, although differences were found between the youngest group (50-59 years) and the oldest age group (equal to or above 80 years). Findings show that there is a significant difference between the mean scores on the landscape test obtained by the two groups (control: 44.06 ± 3.2; AD: 34.25 ± 6.6; p < 0.001). The area under the curve from the landscape test was 0.904, with a sensitivity of 0.82 and a specificity of 0.85. CONCLUSIONS: The landscapes test is a simple, sensitive and novel instrument for assessing visual memory in early AD.

[Cognitive reserve questionnaire. Scores obtained in a healthy elderly population and in one with Alzheimer's disease]. / Cuestionario de reserva cognitiva. Valores obtenidos en poblacion anciana sana y con enfermedad de Alzheimer.

INTRODUCTION: The term cognitive reserve describes the capacity of the adult brain to minimise the clinical manifestation of a neurodegenerative process. The acquisition of cognitive reserve has been linked to the performance of certain intellectual and cognitive activities throughout the whole of the individual's life. AIMS: To create a new cognitive reserve questionnaire (CRQ), to establish its relation with the cognitive functions and to obtain the standard values in the cognitively healthy elderly Spanish population. SUBJECTS AND METHODS: The sample consisted of 55 cognitively healthy controls and 53 patients with Alzheimer's disease. All the subjects were asked to complete the CRQ, which consists of eight items with several different possible answers, together with a brief neuropsychological battery. RESULTS: Age had no significant influence on the score obtained on the CRQ in either of the groups, yet the number of years of schooling did exert a significant effect. In both groups significant correlations were found between the score on the CRQ and performance in neuropsychological tests that measure executive functioning. CONCLUSIONS: The CRQ is a useful questionnaire for assessing the degree of cognitive reserve in healthy controls and in patients in the early stages of Alzheimer's disease. The CRQ is associated with the cognitive performance of executive functioning.

[Relearning vocabulary. A comparative analysis between a case of dementia and Alzheimer's disease with predominant compromise of language]. / Reaprendizaje de vocabulario. Análisis comparativo entre un caso de demencia semántica y enfermedad de Alzheimer con afectación predominante del lenguaje.

INTRODUCTION: Semantic dementia is characterised by a progressive loss of semantic content that initially affects the capacity to name things, and is associated with asymmetric atrophy of the anterior temporal lobes. In Alzheimer's disease (AD) with predominant compromise of language, anomia is also the main symptom. The study examined the capacity to relearn vocabulary of two patients, each exhibiting one of these two forms of degenerative anomia. CASE REPORTS: The two cases presented similar ages, gender, levels of schooling and degree of compromise. Their capacity to name a list of 40 pictures was evaluated at baseline, following 20 sessions of relearning, at one month and at six months. The patient with semantic dementia named 25/40 objects at baseline, 40/40 after relearning, 35/40 at one month and 27/40 at six months. The patient with AD named 29/40 at baseline, 30/40 after relearning, 29/40 at one month and 32/40 at six months. No intrusions were observed following relearning. CONCLUSIONS: The patient with semantic dementia was able to relearn all the vocabulary she was shown, even though she lost everything she had acquired after treatment was interrupted. The AD patient did not improve her naming capacity with therapy. These differences suggest that the learning and consolidation circuits are affected in different ways. Subjects with semantic dementia, but not those with AD, could benefit from word relearning strategies with this method.