Functional neuroanatomical associations of working memory in early-onset Alzheimer's disease.

OBJECTIVE: To characterize metabolic correlates of working memory impairment in clinically defined subtypes of early-onset Alzheimer's disease. BACKGROUND: Established models of working memory suggest a key role for frontal lobe function, yet the association in Alzheimer's disease between working memory impairment and visuospatial and language symptoms suggests that temporoparietal neocortical dysfunction may be responsible. METHODS: Twenty-four patients with predominantly early-onset Alzheimer's disease were clinically classified into groups with predominantly amnestic, multidomain or visual deficits. Patients underwent neuropsychological evaluation focused on the domains of episodic and working memory, T1-weighted magnetic resonance imaging and brain fluorodeoxyglucose positron emission tomography. Fluorodeoxyglucose positron emission tomography data were analysed by using a region-of-interest approach. RESULTS: Patients with multidomain and visual presentations performed more poorly on tests of working memory compared with amnestic Alzheimer's disease. Working memory performance correlated with glucose metabolism in left-sided temporoparietal, but not frontal neocortex. Carriers of the apolipoprotein E4 gene showed poorer episodic memory and better working memory performance compared with noncarriers. CONCLUSIONS: Our findings support the hypothesis that working memory changes in early-onset Alzheimer's disease are related to temporoparietal rather than frontal hypometabolism and show dissociation from episodic memory performance. They further support the concept of subtypes of Alzheimer's disease with distinct cognitive profiles due to prominent neocortical dysfunction early in the disease course. Copyright © 2017 John Wiley & Sons, Ltd.

Metabolic regional and network changes in Alzheimer's disease subtypes.

Clinical variants of Alzheimer's disease (AD) include the common amnestic subtype as well as subtypes characterised by leading visual processing impairments or by multimodal neurocognitive deficits. We investigated regional metabolic patterns and networks between AD subtypes. The study comprised 9 age-matched controls and 25 patients with mild to moderate AD. Methods included clinical and neuropsychological assessment, high-resolution FDG PET and T1-weighted 3D MR imaging with PET-MR coregistration, grey matter segmentation, atlas-based regions-of-interest, linear mixed effects and regional correlation analysis. Regional metabolic patterns differed significantly between groups, but significant hypometabolism in the posterior cingulate cortex (PCC) was common to all subtypes. The most distinctive regional abnormality was occipital hypometabolism in the visual subtype. In controls, two large clusters of positive regional metabolic correlations were observed. The most pronounced breakdown of the normal correlation pattern was found in amnestic patients who, in contrast, showed the least regional focal metabolic deficits. The normal positive correlation between PCC and hippocampus was lost in all subtypes. In conclusion, PCC hypometabolism and metabolic correlation breakdown between PCC and hippocampus are the common functional core of all AD subtypes. Network alterations exceed focal regional impairment and are most prominent in the amnestic subtype.

Effect of Deep Brain Stimulation on Regional Cerebral Blood Flow in Patients with Medically Refractory Tourette Syndrome.

In this study, alterations in brain perfusion have been investigated in patients with Tourette syndrome (TS) compared with control subjects. In addition, we investigated the effects of deep brain stimulation (DBS) in both globus pallidus internus (GPi) and centromedian-parafascicular/ventralis oralis internus nuclei of the thalamus (CM/Voi) and sham (SHAM) stimulation on cerebral blood flow. In a prospective controlled, randomized, double-blind setting, five severely affected adult patients with TS with predominant motor or vocal tics (mean total tic score on the Yale Global Tic Severity Scale: 39) underwent serial brain perfusion single photon emission computed tomography with (99m)Tc-ECD. Results were compared with data from six age-matched control subjects. All patients were investigated at four different time points: once before DBS implantation (preOP) and three times postoperatively. Postoperative scans were performed in a randomized order, each after 3 months of either GPi, CM/Voi, or SHAM stimulation. At each investigation, patients were injected at rest while awake, but scanned during anesthesia. This procedure ensured that neither anesthesia nor movement artifacts influenced our results. Control subjects were investigated only once at baseline (without DBS or anesthesia). At baseline, cerebral blood flow was significantly reduced in patients with TS (preOP) compared with controls in the central region, frontal, and parietal lobe, specifically in Brodmann areas 1, 4-9, 30, 31, and 40. Significantly increased perfusion was found in the cerebellum. When comparing SHAM stimulation to preOP condition, we found significantly decreased perfusion in basal ganglia and thalamus, but increased perfusion in different parts of the frontal cortex. Compared with SHAM condition both GPi and thalamic stimulation resulted in a significant decrease in cerebral blood flow in basal ganglia and cerebellum, while perfusion in the frontal cortex was significantly increased. Our results provide substantial evidence that, in TS, brain perfusion is altered in the frontal cortex and the cerebellum and that these changes can be reversed by both GPi and CM/Voi DBS.

Positron Emission Tomography Imaging Reveals Auditory and Frontal Cortical Regions Involved with Speech Perception and Loudness Adaptation.

Considerable progress has been made in the treatment of hearing loss with auditory implants. However, there are still many implanted patients that experience hearing deficiencies, such as limited speech understanding or vanishing perception with continuous stimulation (i.e., abnormal loudness adaptation). The present study aims to identify specific patterns of cerebral cortex activity involved with such deficiencies. We performed O-15-water positron emission tomography (PET) in patients implanted with electrodes within the cochlea, brainstem, or midbrain to investigate the pattern of cortical activation in response to speech or continuous multi-tone stimuli directly inputted into the implant processor that then delivered electrical patterns through those electrodes. Statistical parametric mapping was performed on a single subject basis. Better speech understanding was correlated with a larger extent of bilateral auditory cortex activation. In contrast to speech, the continuous multi-tone stimulus elicited mainly unilateral auditory cortical activity in which greater loudness adaptation corresponded to weaker activation and even deactivation. Interestingly, greater loudness adaptation was correlated with stronger activity within the ventral prefrontal cortex, which could be up-regulated to suppress the irrelevant or aberrant signals into the auditory cortex. The ability to detect these specific cortical patterns and differences across patients and stimuli demonstrates the potential for using PET to diagnose auditory function or dysfunction in implant patients, which in turn could guide the development of appropriate stimulation strategies for improving hearing rehabilitation. Beyond hearing restoration, our study also reveals a potential role of the frontal cortex in suppressing irrelevant or aberrant activity within the auditory cortex, and thus may be relevant for understanding and treating tinnitus.

18F-florbetapir PET in patients with frontotemporal dementia and Alzheimer disease.

UNLABELLED: Pathologic deposition of amyloid ß (Aß) protein is a key component in the pathogenesis of Alzheimer disease (AD) but not a feature of frontotemporal dementia (FTD). PET ligands for Aß protein are increasingly used in diagnosis and research of dementia syndromes. Here, we report a PET study using (18)F-florbetapir in healthy controls and patients with AD and FTD. METHODS: Ten healthy controls (mean age ± SD, 62.5 ± 5.2 y), 10 AD patients (mean age ± SD, 62.6 ± 4.5), and 8 FTD patients (mean age ± SD, 62.5 ± 9.6) were recruited to the study. All patients underwent detailed clinical and neuropsychologic assessment and T1-weighted MR imaging and were genotyped for apolipoprotein E status. All participants underwent dynamic (18)F-florbetapir PET on a high-resolution research tomograph, and FTD patients also underwent (18)F-FDG PET scans. Standardized uptake value ratios (SUVRs) were extracted for predefined gray and white matter regions of interest using cerebellar gray matter as a reference region. Static PET images were evaluated by trained raters masked to clinical status and regional analysis. RESULTS: Total cortical gray matter (18)F-florbetapir uptake values were significantly higher in AD patients (median SUVR, 1.73) than FTD patients (SUVR, 1.13, P = 0.002) and controls (SUVR, 1.26, P = 0.04). (18)F-Florbetapir uptake was also higher in AD patients than FTD patients and controls in the frontal, parietal, occipital, and cingulate cortices and in the central subcortical regions. Only 1 FTD patient (homozygous for apolipoprotein E ε4) displayed high cortical (18)F-florbetapir retention, whereas (18)F-FDG PET demonstrated mesiofrontal hypometabolism consistent with the clinical diagnosis of FTD. Most visual raters classified 1 control (10%) and 8 AD (80%) and 2 FTD (25%) patients as amyloid-positive, whereas ratings were tied in another 2 FTD patients and 1 healthy control. CONCLUSION: Cortical (18)F-florbetapir uptake is low in most FTD patients, providing good discrimination from AD. However, visual rating of FTD scans was challenging, with a higher rate of discordance between interpreters than in AD and control subjects.

Alzheimer Disease Biomarkers as Outcome Measures for Clinical Trials in MCI.

BACKGROUND: The aim of this study was to compare the performance and power of the best-established diagnostic biological markers as outcome measures for clinical trials in patients with mild cognitive impairment (MCI). METHODS: Magnetic resonance imaging, F-18 fluorodeoxyglucose positron emission tomography markers, and Alzheimer's Disease Assessment Scale-cognitive subscale were compared in terms of effect size and statistical power over different follow-up periods in 2 MCI groups, selected from Alzheimer's Disease Neuroimaging Initiative data set based on cerebrospinal fluid (abnormal cerebrospinal fluid Aß1-42 concentration-ABETA+) or magnetic resonance imaging evidence of Alzheimer disease (positivity to hippocampal atrophy-HIPPO+). Biomarkers progression was modeled through mixed effect models. Scaled slope was chosen as measure of effect size. Biomarkers power was estimated using simulation algorithms. RESULTS: Seventy-four ABETA+ and 51 HIPPO+ MCI patients were included in the study. Imaging biomarkers of neurodegeneration, especially MR measurements, showed highest performance. For all biomarkers and both MCI groups, power increased with increasing follow-up time, irrespective of biomarker assessment frequency. CONCLUSION: These findings provide information about biomarker enrichment and outcome measurements that could be employed to reduce MCI patient samples and treatment duration in future clinical trials.

Anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis show distinct patterns of brain glucose metabolism in 18F-fluoro-2-deoxy-d-glucose positron emission tomography.

BACKGROUND: Pathogenic autoantibodies targeting the recently identified leucine rich glioma inactivated 1 protein and the subunit 1 of the N-methyl-D-aspartate receptor induce autoimmune encephalitis. A comparison of brain metabolic patterns in 18F-fluoro-2-deoxy-d-glucose positron emission tomography of anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis patients has not been performed yet and shall be helpful in differentiating these two most common forms of autoimmune encephalitis. METHODS: The brain 18F-fluoro-2-deoxy-d-glucose uptake from whole-body positron emission tomography of six anti-N-methyl-D-aspartate receptor encephalitis patients and four patients with anti-leucine rich glioma inactivated 1 protein encephalitis admitted to Hannover Medical School between 2008 and 2012 was retrospectively analyzed and compared to matched controls. RESULTS: Group analysis of anti-N-methyl-D-aspartate encephalitis patients demonstrated regionally limited hypermetabolism in frontotemporal areas contrasting an extensive hypometabolism in parietal lobes, whereas the anti-leucine rich glioma inactivated 1 protein syndrome was characterized by hypermetabolism in cerebellar, basal ganglia, occipital and precentral areas and minor frontomesial hypometabolism. CONCLUSIONS: This retrospective 18F-fluoro-2-deoxy-d-glucose positron emission tomography study provides novel evidence for distinct brain metabolic patterns in patients with anti-leucine rich glioma inactivated 1 protein and anti-N-methyl-D-aspartate receptor encephalitis.

Summary metrics to assess Alzheimer disease-related hypometabolic pattern with 18F-FDG PET: head-to-head comparison.

UNLABELLED: In the recently revised diagnostic criteria for Alzheimer disease (AD), the National Institute on Aging and Alzheimer Association suggested that confidence in diagnosing dementia due to AD and mild cognitive impairment (MCI) due to AD could be improved by the use of certain biomarkers, such as (18)F-FDG PET evidence of hypometabolism in AD-affected brain regions. Three groups have developed automated data analysis techniques to characterize the AD-related pattern of hypometabolism in a single measurement. In this study, we sought to directly compare the ability of these three (18)F-FDG PET data analysis techniques--the PMOD Alzheimer discrimination analysis tool, the hypometabolic convergence index, and a set of meta-analytically derived regions of interest reflecting AD hypometabolism pattern (metaROI)--to distinguish moderate or mild AD dementia patients and MCI patients who subsequently converted to AD dementia from cognitively normal older adults. METHODS: One hundred sixty-six (18)F-FDG PET patients from the AD Neuroimaging Initiative, 308 from the Network for Efficiency and Standardization of Dementia Diagnosis, and 176 from the European Alzheimer Disease Consortium PET study were categorized, with masking of group classification, as AD, MCI, or healthy control. For each AD-related (18)F-FDG PET index, receiver-operating-characteristic curves were used to characterize and compare subject group classifications. RESULTS: The 3 techniques were roughly comparable in their ability to distinguish each of the clinical groups from cognitively normal older adults with high sensitivity and specificity. Accuracy of classification (in terms of area under the curve) in each clinical group varied more as a function of dataset than by technique. All techniques were differentially sensitive to disease severity, with the classification accuracy for MCI due to AD to moderate AD varying from 0.800 to 0.949 (PMOD Alzheimer tool), from 0.774 to 0.967 (metaROI), and from 0.801 to 0.983 (hypometabolic convergence index). CONCLUSION: The 3 tested techniques have the potential to help detect AD in research and clinical settings. Additional efforts are needed to clarify their ability to address particular scientific and clinical questions. Their incremental diagnostic value over other imaging and biologic markers makes them easier to implement by other groups for these purposes.

Cholinergic system function and cognition in mild cognitive impairment.

Evidence for cholinergic dysfunction in very early stages of neurodegeneration like mild cognitive impairment (MCI) is inconclusive. Previous positron emission tomography (PET) studies based on small samples investigated if it is related to memory impairment. We examined whether cortical acetylcholine esterase (AChE) activity is reduced at this stage and correlated with cognitive function. N-[(11)C]-methyl-4-piperidyl acetate ([11C]MP4A), a positron emission tomography tracer for measuring cerebral AChE activity in vivo, was applied in 21 controls and 17 MCI patients. Parametric images of AChE activity were analyzed using standard atlas regions. Principal components analysis (PCA) of regional values of AChE activity and correlation analysis with neuropsychological test results was performed. Cortical AChE activity showed a significant decline in MCI patients compared with controls which was most pronounced in temporal regions. They formed the main part of a principal component that was related significantly to verbal and nonverbal memory, language comprehension and executive function. Cholinergic dysfunction is an early hallmark even before onset of dementia at the clinical stage of MCI. Its impact especially on temporal neocortex is associated with impaired neuropsychological function.

Evaluation of a calibrated (18)F-FDG PET score as a biomarker for progression in Alzheimer disease and mild cognitive impairment.

UNLABELLED: Increasingly, clinical trials are being planned in patients with mild cognitive impairment (MCI) to prevent or delay the onset of dementia in Alzheimer disease (AD) by disease-modifying intervention. Inclusion of imaging techniques as biomarkers for patient selection and assessment of outcome is expected to increase trial efficacy. PET using (18)F-FDG provides objective information about the impairment of synaptic function and could, with appropriate standardization, qualify as a biomarker. METHODS: We evaluated a predefined quantitative measure (PET score) that is extracted automatically from (18)F-FDG PET scans using a sample of controls (n = 44), patients with MCI (n = 94), and patients with mild AD (n = 40) from the Alzheimer Disease Neuroimaging Initiative (ADNI). Subjects received 4 scans and clinical assessments over 2 y. RESULTS: PET scores provide much higher test-retest reliability than standard neuropsychologic test scores (Alzheimer's Disease Assessment Scale-Cognitive [ADAS-cog] and Mini-Mental State Examination) and superior signal strength for measuring progression. At the same time, they are related linearly to ADAS-cog scores, thus providing a valid measure of cognitive impairment. In addition, PET scores at study entry in MCI patients significantly predict clinical progression to dementia with a higher accuracy than Mini-Mental State Examination and ADAS-cog. CONCLUSION: (18)F-FDG PET scores are a valid imaging biomarker to monitor the progression of MCI to AD. Their superior test-retest reliability and signal strength will allow the reduction in the number of subjects needed or shortening of study duration substantially.

11C-flumazenil positron emission tomography demonstrates reduction of both global and local cerebral benzodiazepine receptor binding in a patient with Stiff Person Syndrome.

Stiff Person Syndrome (SPS) is a rare autoimmune disorder associated with antibodies against glutamic acid decarboxylase (GAD-Ab), the key enzyme in gamma-aminobutyric acid synthesis (GABA). In order to investigate the role of cerebral benzodiazepinereceptor binding in SPS, we performed [(11)C]flumazenil (FMZ) positron emission tomography (PET) in a female patient with SPS compared to nine healthy controls. FMZ is a radioligand to the postsynaptic central benzodiazepine receptor which is co-localized with the GABA-A receptor. In the SPS patient, we found a global reduction of cortical FMZ binding. In addition, distinct local clusters of reduced radiotracer binding were observed. These data provide first in vivo evidence for a reduced postsynaptic GABA-A receptor availability which may reflect the loss of GABAergic neuronal inhibition in SPS.