Strong Relation Between an EEG Functional Connectivity Measure and Postmenstrual Age: A New Potential Tool for Measuring Neonatal Brain Maturation.

Fetal and neonatal brain connectivity development is highly complex. Studies have shown that functional networks change dramatically during development. The purpose of the current study was to determine how the mean phase lag index (mPLI), a measure of functional connectivity (FC), assessed with electroencephalography (EEG), changes with postmenstrual age (PMA) during the early stages of brain development after birth. Neonates (N = 131) with PMA 27.6-45.3 weeks who underwent an EEG for a medical reason were retrospectively studied. For each recording, global FC was assessed by obtaining a whole-head average of all local PLI values (pairwise between sensor space EEG signals). Global FC results were consequently correlated with PMA values in seven frequency bands. Local results were obtained for the frequency band with the strongest global association. There was a strong negative correlation between mPLI and PMA in most frequency bands. The strongest association was found in the delta frequency band (R = -0.616, p < 0.001) which was therefore topographically explored; the strongest correlations were between pairs of electrodes with at least one electrode covering the central sulcus. Even in this heterogeneous group of neonates, global FC strongly reflects PMA. The decrease in PLI may reflect the process of segregation of specific brain regions with increasing PMA. This was mainly found in the central brain regions, in parallel with myelination of these areas during early development. In the future, there may be a role for PLI in detecting atypical FC maturation. Moreover, PLI could be used to develop biomarkers for brain maturation and expose segregation processes in the neonatal brain.

Early onset APOE E4-negative Alzheimer's disease patients show faster cognitive decline on non-memory domains.

Age at onset and APOE E4-genotype have been shown to influence clinical manifestation of Alzheimer's disease (AD). We investigated rate of decline in specific cognitive domains according to age at onset and APOE E4-genotype in patients with AD. 199 patients with probable AD underwent at least two annual neuropsychological assessments. Patients were classified according to age-at-onset (≤ 65 years vs >65 years) and APOE genotype (positive vs negative). The neuropsychological test battery compromised tests for memory, language, attention, executive and visuo-spatial functioning. For each domain compound z-scores were calculated, based on the baseline performance of patients. Average duration of follow-up was 1.5 ± 1 years. We used linear mixed models (LMM) to estimate effects of age, APOE and age⁎APOE on cognitive decline over time. At baseline, patients were 65 ± 8 years, 98(49%) were female and MMSE was 22 ± 4. LMM showed that early onset patients declined faster on executive functioning (ß ± SE:-0.09 ± 0.06) than late onset patients, but age was not related to decline in the other cognitive domains. APOE E4 negative patients declined faster on language than APOE E4 positive patients (ß ± SE:-0.1 ± 0.06). When we took age and APOE genotype into account simultaneously, we found that compared to late onset-E4 positive patients, early onset-E4 negative patients declined faster on language (ß ± SE:-0.36 ± 0.1), attention (ß ± SE:-0.42 ± 0.1), executive (ß ± SE:-0.41 ± 0.1) and visuo-spatial functioning (ß ± SE:-0.43 ± 0.1). Late onset-E4 negative and early onset-E4 positive patients showed intermediate rates of decline. We found no differences in decline on memory. We found that patients who develop AD despite absence of the two most important risk factors, show steepest cognitive decline on non-memory cognitive domains.

Regional atrophy is associated with impairment in distinct cognitive domains in Alzheimer's disease.

BACKGROUND: In Alzheimer's disease (AD), some patients present with cognitive impairment other than episodic memory disturbances. We evaluated whether occurrence of posterior atrophy (PA) and medial temporal lobe atrophy (MTA) could account for differences in cognitive domains affected. METHODS: In 329 patients with AD, we assessed five cognitive domains: memory, language, visuospatial functioning, executive functioning, and attention. Magnetic resonance imaging (MRI) was rated visually for the presence of MTA and PA. Two-way analyses of variance were performed with MTA and PA as independent variables, and cognitive domains as dependent variables. Gender, age, and education were covariates. As PA is often encountered in younger patients, analyses were repeated after stratification for age of onset (early onset, ≤65 years). RESULTS: The mean age of the participants was 67 years, 175 (53%) were female, and the mean Mini-Mental State Examination (score±standard deviation) was 20±5 points. Based on dichotomized magnetic resonance imaging ratings, 84 patients (26%) had MTA and PA, 98 (30%) had MTA, 57 (17%) had PA, and 90 (27%) had neither. MTA was associated with worse performance on memory, language, and attention (all, P<.05), and PA was associated with worse performance on visuospatial and executive functioning (both, P<.05). Stratification for age showed in patients with late-onset AD (n=173) associations between MTA and impairment on memory, language, visuospatial functioning, and attention (all, P<.05); in early-onset AD (n=156), patients with PA tended to perform worse on visuospatial functioning. CONCLUSIONS: Regional atrophy is related to impairment in specific cognitive domains in AD. The prevalence of PA in a large set of patients with AD and its association with cognitive functioning provides support for the usefulness of this visual rating scale in the diagnostic evaluation of AD.

Quantitative regional validation of the visual rating scale for posterior cortical atrophy.

OBJECTIVES: Validate the four-point visual rating scale for posterior cortical atrophy (PCA) on magnetic resonance images (MRI) through quantitative grey matter (GM) volumetry and voxel-based morphometry (VBM) to justify its use in clinical practice. METHODS: Two hundred twenty-nine patients with probable Alzheimer's disease and 128 with subjective memory complaints underwent 3T MRI. PCA was rated according to the visual rating scale. GM volumes of six posterior structures and the total posterior region were extracted using IBASPM and compared among PCA groups. To determine which anatomical regions contributed most to the visual scores, we used binary logistic regression. VBM compared local GM density among groups. RESULTS: Patients were categorised according to their PCA scores: PCA-0 (n = 122), PCA-1 (n = 143), PCA-2 (n = 79), and PCA-3 (n = 13). All structures except the posterior cingulate differed significantly among groups. The inferior parietal gyrus volume discriminated the most between rating scale levels. VBM showed that PCA-1 had a lower GM volume than PCA-0 in the parietal region and other brain regions, whereas between PCA-1 and PCA-2/3 GM atrophy was mostly restricted to posterior regions. CONCLUSIONS: The visual PCA rating scale is quantitatively validated and reliably reflects GM atrophy in parietal regions, making it a valuable tool for the daily radiological assessment of dementia. KEY POINTS: • Visual rating scale reflects grey matter atrophy in posterior brain regions. • Different PCA scores corresponded well to different quantitative degrees of atrophy. • Inferior parietal gyrus volume influenced assessment based on the visual rating scale. • This simple visual rating scale makes it useful for radiological dementia assessment.

Visual ratings of atrophy in MCI: prediction of conversion and relationship with CSF biomarkers.

Medial temporal lobe atrophy (MTA) and cerebrospinal fluid (CSF) markers of Alzheimer's disease (AD) pathology may aid the early detection of AD in mild cognitive impairment (MCI). However, the relationship between structural and pathological markers is not well understood. Furthermore, while posterior atrophy (PA) is well recognized in AD, its value in predicting conversion from late-onset amnestic MCI to AD is unclear. In this study we used visual ratings of MTA and PA to assess their value in predicting conversion to AD in 394 MCI patients. The relationship of atrophy patterns with CSF Aß1-42, tau, and p-tau(181) was further investigated in 114 controls, 192 MCI, and 99 AD patients. There was a strong association of MTA ratings with conversion to AD (p < 0.001), with a weaker association for PA ratings (p = 0.047). Specific associations between visual ratings and CSF biomarkers were found; MTA was associated with lower levels of Aß1-42 in MCI, while PA was associated with elevated levels of tau in MCI and AD, which may reflect widespread neuronal loss including posterior regions. These findings suggest both that posterior atrophy may predict conversion to AD in late-onset MCI, and that there may be differential relationships between CSF biomarkers and regional atrophy patterns.

Cognitive correlates of cerebrospinal fluid biomarkers in frontotemporal dementia.

OBJECTIVE: In this study we investigated the relationships between cerebrospinal fluid (CSF) biomarkers (tau and amyloid-ß1-42 [Aß1-42]) and cognition or behavior in patients with frontotemporal dementia (the behavioral variant, bvFTD). METHODS: We included 58 patients with bvFTD. All patients underwent a neuropsychological assessment and lumbar puncture. Relationships between CSF biomarkers and cognition or behavior were assessed with linear regression analysis. RESULTS: After correction for age, sex, and education, CSF tau levels were found to be negatively related to the Visual Association Test (standardized ß = -0.3, P < .05), whereas CSF Aß1-42 levels were found to be positively related to the Mini-Mental State Examination (ß = 0.3, P < .05), the frontal assessment battery (ß = 0.5, P < .05), and digit span backwards test (ß = 0.3, P = .01). We did not find relations between CSF biomarkers and behavior (measured by the neuropsychiatric inventory). After excluding all patients with a CSF biomarker profile often seen in Alzheimer's disease (high levels of tau and low levels of Aß1-42), we still found relations between CSF Aß1-42 levels and Visual Association Test object naming (ß = 0.4, P < .05), as well as between CSF Aß1-42 levels and the frontal assessment battery (ß = 0.5, P < .05, but there was no relation between CSF tau and cognition. CONCLUSION: Low CSF Aß1-42 levels are associated with worse general cognitive function and worse executive function in patients with bvFTD. Our results provide circumstantial evidence for a pathophysiological role of Aß1-42 in bvFTD.

Episodic memory and the medial temporal lobe: not all it seems. Evidence from the temporal variants of frontotemporal dementia.

BACKGROUND: Disproportionate medial temporal lobe atrophy (MTA) is an early finding in Alzheimer's disease (AD). Episodic memory impairment in AD is associated with the degree of MTA. Episodic memory impairment and MTA are also found in semantic dementia (SD) and in right temporal lobe atrophy (RTLA), the temporal variants of frontotemporal dementia, but their relationship is unclear. OBJECTIVE: To compare episodic memory impairment among patients with these temporal variants of frontotemporal dementia with that of patients with AD with the same degree of MTA. METHODS: Episodic memory was tested with the visual association test, and semantic memory (SM) with animal fluency and the visual association naming test. MTA was measured using a visual rating scale. Each patient with SD or RTLA was matched for MTA with two patients with AD. Comparisons of episodic memory and SM were made for patients with SD versus matched patients with AD; patients with RTLA versus matched patients with AD and for SD, RTLA and all patients with AD. RESULTS: 27 patients with SD and 11 with RTLA were matched with 54 and 22 patients with AD, respectively. Episodic memory was less impaired in patients with SD than in those with AD (8 versus 2; p<0.001) and in patients with RTLA than in those with AD (10 versus 4.5; p=0.009). Semantic memory was more affected in patients with SD than in those with AD, and the Mini Mental State Examination score was higher in patients with RTLA than in those with AD. Comparison of the three diagnostic groups showed that episodic memory was most impaired in AD, whereas SM was most impaired in SD. CONCLUSION: Since episodic memory impairment is more severe in AD than in SD and RTLA, despite a comparable degree of MTA, atrophy of the medial temporal lobe alone cannot account for episodic memory dysfunction.

Early onset Alzheimer's disease is associated with a distinct neuropsychological profile.

Alzheimer's disease (AD) in younger patients is associated with a higher prevalence of atypical symptoms. We examined neuropsychological performance according to age-at-onset. We assessed cognition in 172 patients with AD (81 early and 91 late onset) in five cognitive domains (memory, language, visuo-spatial functioning, executive functioning, attention). Dementia severity was assessed using the Mini-Mental State Examination (MMSE) and global cognitive decline using Cambridge Cognitive Examination (CAMCOG). Analyses of variance were performed with age-at-onset as between-subjects factor, and gender and education as covariates. Analysis was repeated after stratification for dementia severity (based on median MMSE). In early onset AD, age (mean ± SD) was 60 ± 4 years; 44 (54%) were female. In late onset AD, age was 72 ± 5 years; 47 (52%) were female. Dementia severity and global cognitive decline did not differ between groups (early onset: MMSE: 20 ± 5, CAMCOG: 69 ± 15, late onset: MMSE: 21 ± 5, CAMCOG: 70 ± 15; p > 0.05). Early onset patients performed worse than late onset patients on visuo-spatial functioning (p < 0.01), executive functioning (p < 0.001), and attention (p < 0.01). Late onset patients performed worse on memory, although not significantly (p = 0.11). Stratification for dementia severity showed that in mildly demented early onset patients, memory function was remarkably preserved compared to late onset patients (p < 0.01). In moderate AD, differences in memory function disappeared, but early onset patients performed worse on visuo-spatial functioning (p < 0.01), executive functioning (p < 0.001), and attention (p < 0.01) than late onset patients. Adjustment for APOE left results unchanged. In conclusion, early onset AD presents with a different cognitive profile and the disease course seems different. Relative sparing of memory function in early stages stresses the need to adequately test other cognitive domains.

Posterior cerebral atrophy in the absence of medial temporal lobe atrophy in pathologically-confirmed Alzheimer's disease.

Medial temporal lobe atrophy (MTA) is a recognized marker of Alzheimer's disease (AD), however, it can be prominent in frontotemporal lobar degeneration (FTLD). There is an increasing awareness that posterior atrophy (PA) is important in AD and may aid the differentiation of AD from FTLD. Visual rating scales are a convenient way of assessing atrophy in a clinical setting. In this study, 2 visual rating scales measuring MTA and PA were used to compare atrophy patterns in 62 pathologically-confirmed AD and 40 FTLD patients. Anatomical correspondence of MTA and PA was assessed using manually-delineated regions of the hippocampus and posterior cingulate gyrus, respectively. Both MTA and PA scales showed good inter- and intrarater reliabilities (kappa > 0.8). MTA scores showed a good correspondence with manual hippocampal volumes. Thirty percent of the AD patients showed PA in the absence of MTA. Adding the PA to the MTA scale improved discrimination of AD from FTLD, and early-onset AD from normal aging. These results underline the importance of considering PA in AD diagnosis, particularly in younger patients where medial temporal atrophy may be less conspicuous.

Visual assessment of posterior atrophy development of a MRI rating scale.

OBJECTIVE: To develop a visual rating scale for posterior atrophy (PA) assessment and to analyse whether this scale aids in the discrimination between Alzheimer's disease (AD) and other dementias. METHODS: Magnetic resonance imaging of 118 memory clinic patients were analysed for PA (range 0-3), medial temporal lobe atrophy (MTA) (range 0-4) and global cortical atrophy (range 0-3) by different raters. Weighted-kappas were calculated for inter- and intra-rater agreement. Relationships between PA and MTA with the MMSE and age were estimated with linear-regression analysis. RESULTS: Intra-rater agreement ranged between 0.93 and 0.95 and inter-rater agreement between 0.65 and 0.84. Mean PA scores were higher in AD compared to controls (1.6 ± 0.9 and 0.6 ± 0.7, p < 0.01), and other dementias (0.8 ± 0.8, p < 0.01). PA was not associated with age compared to MTA (B = 1.1 (0.8) versus B = 3.1 (0.7), p < 0.01)). PA and MTA were independently negatively associated with the MMSE (B = -1.6 (0.5), p < 0.01 versus B = -1.4 (0.5), p < 0.01). CONCLUSION: This robust and reproducible scale for PA assessment conveys independent information in a clinical setting and may be useful in the discrimination of AD from other dementias.

Clinical characteristics of patients with frontotemporal dementia with and without lobar atrophy on MRI.

INTRODUCTION: The presence of frontal and/or temporal atrophy on neuroimaging has been designated as supportive in the clinical consensus criteria for behavioral variant frontotemporal dementia (bvFTD). As magnetic resonance imaging (MRI) has a relatively low sensitivity for bvFTD, a substantial proportion of patients may present with a normal MRI. Thus, there may be clinical differences between patients with and without lobar abnormalities on MRI. We compared clinical characteristics of bvFTD patients with frontotemporal lobar atrophy on MRI to those lacking the typical pattern at presentation. METHODS: MRIs of 49 patients from our memory clinic, diagnosed with bvFTD were rated for the presence or absence of frontal and/or temporal atrophy. Demographic, behavioral, and cognitive features were compared between subjects with and without typical bvFTD atrophy pattern. RESULTS: Twenty-three patients showed lobar atrophy on MRI, whereas 26 patients lacked the characteristic frontotemporal lobar atrophy, including 13 patients with a normal MRI and 13 with other abnormalities. Disinhibition occurred more often in the group with frontal and/or temporal atrophy on MRI compared with the group with other abnormalities, whereas imitation did not occur in patients lacking the typical bvFTD atrophy pattern. No differences were found in neuropsychologic profiles. There was a trend for a lower mean Clinical Dementia Rating and less severe language impairment in patients with a normal MRI compared with the group with frontal and/or temporal atrophy. CONCLUSIONS: The clinical phenotype of FTD cannot be predicted by the presence or absence of lobar atrophy on MRI, although imitation and disinhibition are more prevalent in bvFTD patients with characteristic MRI abnormalities. Furthermore, patients with a normal MRI seem to be less severely demented in comparison to patients with frontal and/or temporal atrophy.

Dementia mimicking Alzheimer's disease Owing to a tau mutation: CSF and PET findings.

The objective of the study was to illustrate the utility of positron emission tomography (PET) imaging using [C]PIB and [F]FDDNP together with cerebrospinal fluid (CSF) measures of amyloid-beta1 to 42 (Abeta42), total tau (t-tau) and tau phosphorylated at threonine 181 (p-tau) in the in vivo diagnosis of specific dementia syndromes. Two siblings fulfilling diagnostic criteria for familial Alzheimer's disease (AD) were investigated using [C]PIB and [F]FDDNP PET in combination with CSF measures of Abeta42, t-tau and p-tau. PET data were compared with paired [C]PIB and [F]FDDNP data from age-matched sporadic AD patients (n=9) and healthy controls (n=6). [C]PIB retention and CSF levels of Abeta42 in both patients resembled those of controls suggesting the presence of nonamyloid pathology. Genetic testing confirmed the absence of mutations in the presenilin 1 gene in 1 patient; subsequent testing revealed the R406W tau mutation in both individuals leading to a diagnosis of frontotemporal dementia [F]FDDNP retention broadly correlated with CSF levels of t-tau and p-tau. Despite both individuals harbouring the same mutation, [F]FDDNP retention and CSF t-tau and p-tau were elevated in 1 patient, but not in the other. [C]PIB imaging and CSF measures of Abeta42 are useful in refuting the presence of underlying amyloid pathology. This, in combination with elevated levels of CSF t-tau and p-tau, has potential value in differential diagnosis of frontotemporal dementia from AD.

Early-versus late-onset Alzheimer's disease: more than age alone.

Alzheimer's disease (AD) is the most common cause of dementia at older age. Although less prevalent before the age of 65 years, it is still the most frequent cause of early-onset dementia followed by frontotemporal dementia. The typical presentation of AD is memory dysfunction, however, presentations with prominent cognitive impairment in other domains besides memory, like prominent apraxia, language problems, or executive dysfunction, may occur and are relatively more common in early-onset AD. In this retrospective descriptive study, we determined the prevalence of non-memory presentations in a large sample of early-onset AD patients compared to late-onset AD. The clinical files of 270 patients with AD starting before the age of 65 years and 90 patients with late-onset AD ( 65 years) were reviewed to assess clinical characteristics. Patients were classified as memory presentation and non-memory presentation according to their clinical presentation. The mean age of the early-onset group was 56 +/- 5 years and 74 +/- 6 years for the late-onset group. A third of the early-onset AD group presented with non-memory symptoms compared to only 6% in the late-onset group (p < 0.001). Within the group with non-memory presentations, apraxia/visuospatial dysfunction was the most prevalent presenting symptom (12%). Patients with early-onset AD often present with a non-memory phenotype, of which apraxia/visuospatial dysfunction is the most common presenting symptom. Atypical presentations of AD should be considered in the clinical differential diagnosis of early-onset dementia.

Progression of mild cognitive impairment to dementia: contribution of cerebrovascular disease compared with medial temporal lobe atrophy.

BACKGROUND AND PURPOSE: We sought to determine the predictive value of magnetic resonance imaging measures of vascular disease (white matter hyperintensities [WMHs], lacunes, microbleeds, and infarcts) compared with atrophy on the progression of mild cognitive impairment to dementia. METHODS: We included 152 consecutive patients with mild cognitive impairment. Baseline magnetic resonance imaging was used to determine the presence of medial temporal lobe atrophy and vascular disease (presence of lacunes, microbleeds, and infarcts was determined, and WMHs were rated on a semiquantitative scale). Patients were followed up for 2+/-1 years. RESULTS: Seventy-two (47%) patients progressed to dementia during follow-up. Of these, 56 (37%) patients were diagnosed with Alzheimer's disease, and 16 (10%) patients were diagnosed with a non-Alzheimer dementia (including vascular dementia, frontotemporal lobar degeneration, and Parkinson dementia). Converters were older and had a lower Mini-Mental State Examination score at baseline. On baseline magnetic resonance imaging, patients who progressed to a non-Alzheimer dementia showed more severe WMHs and had a higher prevalence of lacunes in the basal ganglia and microbleeds compared with nonconverters. Cox proportional-hazard models showed that, adjusted for age and sex, baseline medial temporal lobe atrophy (hazard ratio=2.9; 95% CI, 1.7 to 5.3), but not vascular disease, was associated with progression to Alzheimer's disease. By contrast, deep WMHs (hazard ratio=5.7; 95% CI, 1.2 to 26.7) and periventricular hyperintensities (hazard ratio=6.5; 95% CI, 1.4 to 29.8) predicted progression to non-Alzheimer dementia. Furthermore, microbleeds (hazard ratio=2.6; 95% CI, 0.9 to 7.5) yielded a >2-fold increased, though nonsignificant, risk of non-Alzheimer dementia. CONCLUSIONS: Medial temporal lobe atrophy and markers of cerebrovascular disease predict the development of different types of dementia in mild cognitive impairment patients.

Early-onset dementia is associated with higher mortality.

BACKGROUND/AIMS: Our objective was to compare the mortality risks of patients with early- and late-onset dementia with non-demented controls of the same age range and to analyse the mortality risks in subtypes of dementia. METHODS: We included 1,203 subjects from our memory clinic. Patients with dementia were subdivided into 2 groups, with early- (<65 years) or late-onset dementia (>or=65 years), and compared with non-demented controls of the same age range. We used Cox proportional hazard models to estimate mortality risks. RESULTS: When compared to non-demented controls of the same age range, the patients with early-onset dementia had a strongly elevated mortality risk [hazard ratio (95% confidence interval) = 43.3 (3.1-600.4)], while those with late-onset dementia had a moderately increased mortality risk compared to older controls [hazard ratio (95% confidence interval) = 3.4 (1.8-6.2)]. An additional analysis showed that, adjusted for age, Alzheimer's disease seemed to have the most benign course, with a fourfold increased mortality risk. Dementia with Lewy bodies and vascular dementia (frequently seen at older age) and frontotemporal lobar degeneration and 'other dementias' (often found at younger age) had a six- to eightfold increased mortality risk. CONCLUSION: Dementia is a risk factor for death. Especially in young patients the impact of dementia on mortality is high.