Katarzyna Adamczuk

Amyloid PET in clinical practice: Its place in the multidimensional space of Alzheimer's disease

Amyloid imaging is currently introduced to the market for clinical use. We will review the evidence demonstrating that the different amyloid PET ligands that are currently available are valid biomarkers for Alzheimer-related β amyloidosis. Based on recent findings from cross-sectional and longitudinal imaging studies using different modalities, we will incorporate amyloid imaging into a multidimensional model of Alzheimers disease. Aside from the critical role in improving clinical trial design for amyloid-lowering drugs, we will also propose a tentative algorithm for when it may be useful in a memory clinic environment. Gaps in our evidence-based knowledge of the added value of amyloid imaging in a clinical context will be identified and will need to be addressed by dedicated studies of clinical utility.

Polymorphism of brain derived neurotrophic factor influences β amyloid load in cognitively intact apolipoprotein E ε4 carriers

Aside from apolipoprotein E (APOE), genetic risk factors for β amyloid deposition in cognitively intact individuals remain to be identified. Brain derived neurotrophic factor (BDNF) modulates neural plasticity, which has been implicated in Alzheimers disease. We examined in cognitively normal older adults whether the BDNF codon 66 polymorphism affects β amyloid burden and the relationship between β amyloid burden and cognitive scores, and how this relates to the effect of APOE. Amyloid load was measured by means of 18F-flutemetamol PET in 64 community-recruited cognitively intact individuals (mean age 66, S.D. 5.1). Recruitment was stratified according to a factorial design with APOE (ε4 allele present vs absent) and BDNF (met allele at codon 66 present vs absent) as factors. Individuals in the four resulting cells were matched by the number of cases, age, and gender. Among the APOE ε4 carriers, BDNF met positive subjects had a significantly higher amyloid load than BDNF met negative subjects, while BDNF met carrier status did not have an effect in APOE ε4 noncarriers. This interaction effect was localized to precuneus, orbitofrontal cortex, gyrus rectus, and lateral prefrontal cortex. In the APOE ε4/BDNF met carriers, a significant inverse relationship existed between episodic memory scores and amyloid burden but not in any of the other groups. This hypothesis-generating experiment highlights a potential role of BDNF polymorphisms in the preclinical phase of β amyloid deposition and also suggests that BDNF codon 66 polymorphisms may influence resilience against β amyloid-related effects on cognition.

BACE1 Levels Correlate with Phospho-Tau Levels in Human Cerebrospinal Fluid

Previous studies have investigated the activity and protein levels of BACE1, the β-secretase, in the brain and cerebrospinal fluid (CSF) of Alzheimers disease (AD) patients, however, results remain contradictory. We present here a highly specific and sensitive BACE1 ELISA, which allows measuring accurately BACE1 levels in human samples. We find that BACE1 levels in CSF of AD patients and other neurological disorder (OND) patients are slightly increased when compared to those of a non-neurological disorder control group (NND). BACE1 levels in CSF were well correlated with total-tau and hyperphosphorylated tau levels in the CSF, suggesting that the recorded alterations in BACE1 levels correlate with cell death and neurodegeneration.

Functional Changes in the Language Network in Response to Increased Amyloid β Deposition in Cognitively Intact Older Adults

Word finding symptoms are frequent early in the course of Alzheimers disease and relate principally to functional changes in left posterior temporal cortex. In cognitively intact older adults, we examined whether amyloid load affects the network for language and associative-semantic processing. Fifty-six community-recruited subjects (52-74 years), stratified for apolipoprotein E and brain-derived neurotrophic factor genotype, received a neurolinguistic assessment, (18)F-flutemetamol positron emission tomography, and a functional MRI of the associative-semantic system. The primary measure of amyloid load was the cerebral-to-cerebellar gray matter standardized uptake value ratio in a composite cortical volume of interest (SUVR(comp)). The primary outcome analysis consisted of a whole-brain voxelwise linear regression between SUVR(comp) and fMRI response during associative-semantic versus visuoperceptual processing. Higher activity in one region, the posterior left middle temporal gyrus, correlated positively with increased amyloid load. The correlation remained significant when only the word conditions were contrasted but not for pictures. According to a stepwise linear regression analysis, offline naming reaction times correlated positively with SUVR(comp). A binary classification into amyloid-positive and amyloid-negative cases confirmed our findings. The left posterior temporal activity increase may reflect higher demands for semantic control in the presence of a higher amyloid burden.

The interest of amyloid PET imaging in the diagnosis of Alzheimer's disease.

PURPOSE OF REVIEW This review evaluates the potential clinical utility of amyloid imaging. RECENT FINDINGS Amyloid PET is a valid in-vivo marker of neuritic plaque load and correlates with amyloid plaque surface area. Abundant diffuse plaques, however, with scant neuritic plaques can also give rise to a positive scan, most often reported in association with Lewy body disease. Specificity of amyloid PET for discriminating Alzheimers disease from healthy controls is higher than that of structural MRI. Sensitivity for discriminating Alzheimers disease from healthy controls or from frontotemporal lobar degeneration is also higher than that of fluorodeoxyglucose-PET, with higher interreader reliability. Within a same center there is high concordance between dichotomization of cases based on amyloid PET versus cerebrospinal fluid Aβ42. In a tentative algorithm, we restrict clinical-diagnostic use to dementia with age of onset before 60 years, primary progressive aphasia and corticobasal syndrome, cases with objective cognitive deficits that could be due to a neurodegenerative cause but also have significant cerebrovascular or psychiatric comorbidity, and rapidly progressive dementia. SUMMARY Empirical studies that evaluate how amyloid PET can change clinical-diagnostic thinking are starting to emerge. Key questions to be resolved are its role compared with cerebrospinal fluid markers and its impact on patient outcome.

No Association of Lower Hippocampal Volume With Alzheimer’s Disease Pathology in Late-Life Depression

OBJECTIVE Hippocampal volume is commonly decreased in late-life depression. According to the depression-as-late-life-neuropsychiatric-disorder model, lower hippocampal volume in late-life depression is associated with neurodegenerative changes. The purpose of this prospective study was to examine whether lower hippocampal volume in late-life depression is associated with Alzheimers disease pathology. METHOD Of 108 subjects who participated, complete, good-quality data sets were available for 100: 48 currently depressed older adults and 52 age- and gender-matched healthy comparison subjects who underwent structural MRI, [18F]flutemetamol amyloid positron emission tomography imaging, apolipoprotein E genotyping, and neuropsychological assessment. Hippocampal volumes were defined manually and normalized for total intracranial volume. Amyloid binding was quantified using the standardized uptake value ratio in one cortical composite volume of interest. The authors investigated group differences in hippocampal volume (both including and excluding amyloid-positive participants), group differences in amyloid uptake and in the proportion of positive amyloid scans, and the association between hippocampal volume and cortical amyloid uptake. RESULTS A significant difference was observed in mean normalized total hippocampal volume between patients and comparison subjects, but there were no group differences in cortical amyloid uptake or proportion of amyloid-positive subjects. The difference in hippocampal volume remained significant after the amyloid-positive subjects were excluded. There was no association between hippocampal volume and amyloid uptake in either patients or comparison subjects. CONCLUSIONS Lower hippocampal volume was not related to amyloid pathology in this sample of patients with late-life depression. These data counter the common belief that changes in hippocampal volume in late-life depression are due to prodromal Alzheimers disease.

Cross-modal representation of spoken and written word meaning in left pars triangularis

Abstract The correspondence in meaning extracted from written versus spoken input remains to be fully understood neurobiologically. Here, in a total of 38 subjects, the functional anatomy of cross‐modal semantic similarity for concrete words was determined based on a dual criterion: First, a voxelwise univariate analysis had to show significant activation during a semantic task (property verification) performed with written and spoken concrete words compared to the perceptually matched control condition. Second, in an independent dataset, in these clusters, the similarity in fMRI response pattern to two distinct entities, one presented as a written and the other as a spoken word, had to correlate with the similarity in meaning between these entities. The left ventral occipitotemporal transition zone and ventromedial temporal cortex, retrosplenial cortex, pars orbitalis bilaterally, and the left pars triangularis were all activated in the univariate contrast. Only the left pars triangularis showed a cross‐modal semantic similarity effect. There was no effect of phonological nor orthographic similarity in this region. The cross‐modal semantic similarity effect was confirmed by a secondary analysis in the cytoarchitectonically defined BA45. A semantic similarity effect was also present in the ventral occipital regions but only within the visual modality, and in the anterior superior temporal cortex only within the auditory modality. This study provides direct evidence for the coding of word meaning in BA45 and positions its contribution to semantic processing at the confluence of input‐modality specific pathways that code for meaning within the respective input modalities. HighlightsVoxelwise univariate and multivoxel pattern analysis of two independent fMRI datasets.Cross‐modal semantic similarity effect in the left anterodorsal pars triangularis.Semantic similarity effect for written words in the left ventromedial temporal cortex.Semantic similarity effect for spoken words in the left superior temporal gyrus.Pars triangularis is a convergence zone of written and spoken words processing streams.

Reproducibility and robustness of graph measures of the associative-semantic network.

Graph analysis is a promising tool to quantify brain connectivity. However, an essential requirement is that the graph measures are reproducible and robust. We have studied the reproducibility and robustness of various graph measures in group based and in individual binary and weighted networks derived from a task fMRI experiment during explicit associative-semantic processing of words and pictures. The nodes of the network were defined using an independent study and the connectivity was based on the partial correlation of the time series between any pair of nodes. The results showed that in case of binary networks, global graph measures exhibit a good reproducibility and robustness for networks which are not too sparse and these figures of merit depend on the graph measure and on the density of the network. Furthermore, group based binary networks should be derived from groups of sufficient size and the lower the density the more subjects are required to obtain robust values. Local graph measures are very variable in terms of reproducibility and should be interpreted with care. For weighted networks, we found good reproducibility (average test-retest variability <5% and ICC values >0.4) when using subject specific networks and this will allow us to relate network properties to individual subject information.

Chronometry of word and picture identification: Common and modality-specific effects

Based on a previous fMRI connectivity analysis, we previously proposed that long-distance connections between left inferior frontal sulcus and left occipitotemporal sulcus mediate access to visual short-term memory both for written words and pictures enhancing conscious perception and successful encoding in an amodal manner. Using a 64-channel event-related potential electrode system in 19 young cognitively intact volunteers, we determined the chronometry of common and input-modality specific effects of word and picture identification and subsequent memory retrieval. Stimulus durations were calibrated per subject, modality and run so as to reach a 50% positive identification report. The earliest main effect of a positive identification report occurred between 180 and 200 ms, was common for both input-modalities, had a positive polarity and was located at around CPz. This effect was followed between 270 and 450 ms by additional common positive-polarity effects at centrofrontal electrode sites and by common negative effects at P7/P8, TP7/TP8 and T8. Each of the later effects was closely associated not only with identification but also with subsequent memory retrieval. The earliest input-modality specific effect of conscious identification that we detected occurred from 280 till 440 ms at P8. Our findings are in line with a model where the initial stages of perceptual identification and visual short-term memory access rely on long-distance connections that are shared between written words and pictures.

Asymmetric Amyloid Deposition in the Brain Following Unilateral Electroconvulsive Therapy

ECT, electroconvulsive therapy; MADRS, Montgomery–Åsberg Depression Rating Scale; MMSE, Mini-Mental State Examination. MADRS score of 0–6 means no depression; 7–19, mild depression; 20–34, moderate depression; 35–60, severe to very severe depression. MMSE score of 24–30 means no cognitive impairment; 20–23, mild cognitive impairment; 14–19, moderate cognitive impairment; 0–13, severe cognitive impairment. .2 SD from mean, based on age-matched and educationmatched norms. Following Unilateral Electroconvulsive Therapy