The metabolic spatial covariance pattern of definite idiopathic normal pressure hydrocephalus: an FDG PET study with principal components analysis.

Identification of patients with idiopathic normal pressure hydrocephalus (iNPH) in a collective with suspected neurodegenerative disease is essential. This study aimed to determine the metabolic spatial covariance pattern of iNPH on FDG PET using an established technique based on scaled subprofile model principal components analysis (SSM-PCA).We identified 11 patients with definite iNPH. By applying SSM-PCA to the FDG PET data, they were compared to 48 age-matched healthy controls to determine the whole-brain voxel-wise metabolic spatial covariance pattern of definite iNPH (iNPH-related pattern, iNPHRP). The iNPHRP score was compared between groups of patients with definite iNPH, possible iNPH (N = 34), Alzheimer's (AD, N = 38), and Parkinson's disease (PD, N = 35) applying pairwise Mann-Whitney U tests and correction for multiple comparisons.SSM-PCA of FDG PET revealed an iNPHRP that is characterized by relative negative voxel weights at the vicinity of the lateral ventricles and relative positive weights in the paracentral midline region. The iNPHRP scores of patients with definite iNPH were substantially higher than in patients with AD and PD (both p < 0.05) and non-significantly higher than those of patients with possible iNPH. Subject scores of the iNPHRP discriminated definite iNPH from AD and PD with 96% and 100% accuracy and possible iNPH from AD and PD with 83% and 86% accuracy.We defined a novel metabolic spatial covariance pattern of iNPH that might facilitate the differential diagnosis of iNPH versus other neurodegenerative disorders. The knowledge of iNPH-associated alterations in the cerebral glucose metabolism is of high relevance as iNPH constitutes an important differential diagnosis to dementia and movement disorders.

Cognitive Deficits in Parkinson's Disease Are Associated with Neuronal Dysfunction and Not White Matter Lesions.

Background: Cognitive deficits considerably contribute to the patient's burden in Parkinson's disease (PD). While cognitive decline is linked to neuronal dysfunction, the additional role of white matter lesions (WML) is discussed controversially. Objective: To investigate the influence of WML, in comparison to neuronal dysfunction, on cognitive deficits in PD. Methods: We prospectively recruited patients with PD who underwent neuropsychological assessment using the Mattis Dementia Rating Scale 2 (DRS-2) or Parkinson Neuropsychometric Dementia Assessment (PANDA) and both MRI and PET with [18F]fluorodeoxyglucose (FDG). WML-load and PD cognition-related covariance pattern (PDCP) as a measure of neuronal dysfunction were read out. Relationship between cognitive performance and rank-transformed WML was analyzed with linear regression, controlling for the patients' age. PDCP subject scores were investigated likewise and in a second step adjusting for age and WML load. Results: Inclusion criteria were met by 76 patients with a mean (± SD) age of 63.5 ± 9.0 years and disease duration of 10.7 ± 5.4 years. Neuropsychological testing revealed front executive and parietal deficits and a median DRS-2 score of 137 (range 119-144)/144 and PANDA score of 22 (range 3-30)/30. No association between WML and cognition was observed, whereas PDCP subject scores showed a trend-level negative correlation with the DRS-2 (P = 0.060) as well as a negative correlation with PANDA (P = 0.049) which persisted also after additional correction for WML (P = 0.039). Conclusion: The present study indicates that microangiopathic WML do not have a relevant impact on neurocognitive performance in PD whereas neuronal dysfunction does.

More extensive hypometabolism and higher mortality risk in patients with right- than left-predominant neurodegeneration of the anterior temporal lobe.

BACKGROUND: Left-predominant neurodegeneration of the anterior temporal lobe (ATL) and the associated syndrome termed semantic variant primary progressive aphasia (svPPA) are well characterized. Less is known about right-predominant neurodegeneration of the ATL, which has been associated with the clinical syndrome named right temporal variant of frontotemporal dementia (rtvFTD). Here, we assessed glucose metabolism across the brain, cognitive performance, and mortality in patients with right-predominant neurodegeneration of the ATL. METHODS: Patients with predominant hypometabolism of the ATL on FDG PET (as a measure of neurodegeneration) were retrospectively identified and categorized into those with asymmetrical right, left, or symmetric bilateral involvement (N = 10, 17, and 8). We compared whole-brain, normalized regional glucose metabolism using SPM12, cognitive performance on the CERAD Neuropsychological Assessment Battery, and mortality risk (age- and sex-adjusted Cox proportional hazard model) between groups. RESULTS: Hypometabolism was most pronounced and extensive in patients with right-predominant neurodegeneration of the ATL. Beyond the right temporal lobe, right frontal and left temporal lobes were affected in these patients. Cognitive performance was similarly impaired in all three groups, with predominant naming and hippocampal-dependent memory deficits. Mortality risk was 6.1 times higher in patients with right- than left-predominant ATL neurodegeneration (p < 0.05). Median survival duration after PET was shortest in patients with right- and longest in patients with left-predominant ATL neurodegeneration (5.7 vs 8.3 years after examination). DISCUSSION: More extensive neurodegeneration and shorter survival duration in patients with right- than left-predominant neurodegeneration of the ATL might indicate that the former consult memory clinics at a later disease stage, when symptoms like naming and episodic memory deficits have already emerged. At the time of diagnosis, the shorter survival duration of patients with right- than left-predominant ATL neurodegeneration should be kept in mind when counseling patients and caregivers.

Nigral glucose metabolism as a diagnostic marker of neurodegenerative parkinsonian syndromes.

Parkinson's disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP) are characterized by nigrostriatal degeneration. We used [18F]FDG PET to assess glucose metabolism of the substantia nigra (SN) in patients with these diseases and evaluated its ability to discriminate neurodegenerative parkinsonian syndromes (NP) from controls. We retrospectively evaluated [18F]FDG PET scans of 171 patients with NP (n = 115 PD, n = 35 MSA, n = 21 PSP) and 48 controls (13 healthy controls [HC] and 35 control patients). Mean normalized bilateral [18F]FDG uptake in the SN was calculated and compared between groups with covariance and receiver operating characteristic (ROC) analyses (selection of the optimal cut-off required a minimum specificity of 90% to meet the clinical need of a confirmatory test). PD patients were additionally stratified by the expression of the well-established PD-related metabolic pattern (PDRP; elevated expression defined as 2 standard deviations above the mean value of HC). [18F]FDG uptake was significantly lower in NP (Cohen's d = 1.09, p < 0.001) and its subgroups (PD, d = 1.10, p < 0.001; MSA, d = 0.97, p < 0.001; PSP, d = 1.79, p < 0.001) than in controls. ROC analysis for discriminating NP vs. controls revealed an area under the curve of 0.81 and a sensitivity and specificity of 56 and 92%. Moreover, nigral metabolism was below the cut-off in 60% of PD patients without elevated PDRP expression. Glucose metabolism of the SN can distinguish patients with NP from controls with good diagnostic accuracy and can be used as a marker of nigral degeneration. Its evaluation is particularly valuable in PD patients without elevated PDRP expression and may thus help to narrow the diagnostic gap of [18F]FDG PET in neurodegenerative parkinsonism (i.e., identification of patients with PD without cortical involvement).

Neural activity of the auditory cortex predicts speech recognition of patients with asymmetric hearing loss after cochlear implantation.

Patients with asymmetric hearing loss show an asymmetry of glucose metabolism of the primary auditory cortex (PAC). We investigated whether this asymmetry could serve as an objective predictor for speech recognition with CI. Nine patients underwent 18FDG PET prior to CI surgery. Average normalized 18FDG uptake of 25% of voxels with highest uptake was calculated for the PAC employing a probabilistic atlas and cerebellar cortex as reference. Differences in glucose metabolism of the PAC were assessed by an asymmetry index (AI-PAC). We tested the correlation between outcome of CI surgery (6 months post implantation), AI-PAC and clinical predictors. Pre-operative AI-PAC showed a positive correlation with speech recognition with CI (significant for sentences and numbers; trend for monosyllabic words). With a pre-operative AI-PAC ≥ 4.2%, patients reached good CI outcome in sentence recognition of 59-90% and number recognition of 90-100% and less favorable CI outcome in monosyllabic word recognition of 25-45%. Age at symptom onset was significantly associated with all measures of speech recognition, while deafness duration was only associated with sentence recognition. AI-PAC allows for a reliable and quantitative pre-operative prediction of early improvement in speech recognition after CI. 18FDG PET may be a valuable addition to the objective pre-operative assessment of CI candidates. Further studies in larger cohorts and with longer follow-up times are needed.

Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum.

IMPORTANCE: One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design. OBJECTIVE: To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria. EXPOSURES: Alzheimer disease biomarkers detected on PET or in CSF. MAIN OUTCOMES AND MEASURES: Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations. RESULTS: Among the 19 097 participants (mean [SD] age, 69.1 [9.8] years; 10 148 women [53.1%]) included, 10 139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P = .04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P = .004), subjective cognitive decline (9%; 95% CI, 3%-15%; P = .005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P = .004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P = .18). CONCLUSIONS AND RELEVANCE: This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.

PET/CT background noise and its effect on speech recognition.

Positron emission tomography (PET) has been successfully used to investigate central nervous processes, including the central auditory pathway. Unlike early water-cooled PET-scanners, novel PET/CT scanners employ air cooling and include a CT system, both of which result in higher background noise levels. In the present study, we describe the background noise generated by two state-of-the-art air-cooled PET/CT scanners. We measured speech recognition in background noise: recorded PET noise and a speech-shaped noise applied in clinical routine to subjects with normal hearing. Background noise produced by air-cooled PET/CT is considerable: 75.1 dB SPL (64.5 dB(A)) for the Philips Gemini TF64 and 76.9 dB SPL (68.4 dB(A)) for the Philips Vereos PET/CT (Philips Healthcare, The Netherlands). Subjects with normal hearing exhibited better speech recognition in recorded PET background noise compared with clinically applied speech-shaped noise. Speech recognition in both background noises correlated significantly. Background noise generated by PET/CT scanners should be considered when PET is used for the investigation of the central auditory pathway. Speech in PET noise is better than in speech-shaped noise because of the minor masking effect of the background noise of the PET/CT.

DAT SPECT Predicts Survival in Patients Assessed for Differential Diagnosis of Dementia.

BACKGROUND: Dopamine transporter (DAT) SPECT is an established diagnostic procedure in dementia diagnostics, yet its prognostic value is currently unknown. OBJECTIVE: We evaluated the prognostic value of DAT SPECT in patients assessed for differential diagnosis of dementia. METHODS: We included all patients who had received DAT SPECT for differential diagnosis of dementia from 10/2008 to 06/2016 at our site and whose survival status could be obtained in 09/2019. Clinical SPECT reports, categorizing scans into positive or negative for nigrostriatal degeneration (NSD), were tested for their prognostic value (Cox regressions, adjusted for age and sex). In addition, an automated region-of-interest analysis (striatum, occipital cortex as reference) was performed. RESULTS: Median follow-up of 97 included patients was 6.6 years. Patients with NSD had a significantly higher mortality risk than those without NSD (HR = 3.6 [2.0-6.7], p < 0.001). Results were confirmed by region-of-interest analysis: higher mortality risk was associated with lower striatal DAT binding (HR = 1.8 per standard deviation loss). CONCLUSION: Beyond its established utility in dementia diagnostics, DAT SPECT also conveys important prognostic information.

Slow but Evident Recovery from Neocortical Dysfunction and Cognitive Impairment in a Series of Chronic COVID-19 Patients.

Cognitive impairment is a frequent complaint in coronavirus disease 2019 (COVID-19) and can be related to cortical hypometabolism on 18F-FDG PET at the subacute stage. However, it is unclear if these changes are reversible. Methods: We prospectively assessed the Montreal Cognitive Assessment scores and 18F-FDG PET scans of 8 COVID-19 patients at the subacute stage (once no longer infectious) and the chronic stage (˜6 mo after symptom onset). The expression of the previously established COVID-19-related covariance pattern was analyzed at both stages to examine the time course of post-COVID-19 cognitive impairment. For further validation, we also conducted a conventional group analysis. Results: Follow-up 18F-FDG PET revealed that there was a significant reduction in the initial frontoparietal and, to a lesser extent, temporal hypometabolism and that this reduction was accompanied by a significant improvement in cognition. The expression of the previously established COVID-19-related pattern was significantly lower at follow-up and correlated inversely with Montreal Cognitive Assessment performance. However, both 18F-FDG PET and cognitive assessment suggest a residual impairment. Conclusion: Although a significant recovery of regional neuronal function and cognition can be clearly stated, residuals are still measurable in some patients 6 mo after manifestation of COVID-19. Given the current pandemic situation and tremendous uncertainty concerning the long-term effects of COVID-19, the present study provides novel insights of the highest medical and socioeconomic relevance.

Cognitive impairment and altered cerebral glucose metabolism in the subacute stage of COVID-19.

During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, neurological symptoms increasingly moved into the focus of interest. In this prospective cohort study, we assessed neurological and cognitive symptoms in hospitalized coronavirus disease-19 (COVID-19) patients and aimed to determine their neuronal correlates. Patients with reverse transcription-PCR-confirmed COVID-19 infection who required inpatient treatment primarily because of non-neurological complications were screened between 20 April 2020 and 12 May 2020. Patients (age > 18 years) were included in our cohort when presenting with at least one new neurological symptom (defined as impaired gustation and/or olfaction, performance < 26 points on a Montreal Cognitive Assessment and/or pathological findings on clinical neurological examination). Patients with ≥2 new symptoms were eligible for further diagnostics using comprehensive neuropsychological tests, cerebral MRI and 18fluorodeoxyglucose (FDG) PET as soon as infectivity was no longer present. Exclusion criteria were: premorbid diagnosis of cognitive impairment, neurodegenerative diseases or intensive care unit treatment. Of 41 COVID-19 inpatients screened, 29 patients (65.2 ± 14.4 years; 38% female) in the subacute stage of disease were included in the register. Most frequently, gustation and olfaction were disturbed in 29/29 and 25/29 patients, respectively. Montreal Cognitive Assessment performance was impaired in 18/26 patients (mean score 21.8/30) with emphasis on frontoparietal cognitive functions. This was confirmed by detailed neuropsychological testing in 15 patients. 18FDG PET revealed pathological results in 10/15 patients with predominant frontoparietal hypometabolism. This pattern was confirmed by comparison with a control sample using voxel-wise principal components analysis, which showed a high correlation (R2 = 0.62) with the Montreal Cognitive Assessment performance. Post-mortem examination of one patient revealed white matter microglia activation but no signs of neuroinflammation. Neocortical dysfunction accompanied by cognitive decline was detected in a relevant fraction of patients with subacute COVID-19 initially requiring inpatient treatment. This is of major rehabilitative and socioeconomic relevance.

Validation of the Alzheimer Disease Dementia Conversion-Related Pattern as an ATN Biomarker of Neurodegeneration.

OBJECTIVE: To determine whether the Alzheimer disease (AD) dementia conversion-related pattern (ADCRP) on [18F]FDG PET can serve as a valid predictor for the development of AD dementia, the individual expression of the ADCRP (subject score) and its prognostic value were examined in patients with mild cognitive impairment (MCI) and biologically defined AD. METHODS: A total of 269 patients with available [18F]FDG PET, [18F]AV-45 PET, phosphorylated and total tau in CSF, and neurofilament light chain in plasma were included. Following the AT(N) classification scheme, where AD is defined biologically by in vivo biomarkers of ß-amyloid (Aß) deposition ("A") and pathologic tau ("T"), patients were categorized to the A-T-, A+T-, A+T+ (AD), and A-T+ groups. RESULTS: The mean subject score of the ADCRP was significantly higher in the A+T+ group compared to each of the other group (all p < 0.05) but was similar among the latter (all p > 0.1). Within the A+T+ group, the subject score of ADCRP was a significant predictor of conversion to dementia (hazard ratio, 2.02 per z score increase; p < 0.001), with higher predictive value than of alternative biomarkers of neurodegeneration (total tau and neurofilament light chain). Stratification of A+T+ patients by the subject score of ADCRP yielded well-separated groups of high, medium, and low conversion risks. CONCLUSIONS: The ADCRP is a valuable biomarker of neurodegeneration in patients with MCI and biologically defined AD. It shows great potential for stratifying the risk and estimating the time to conversion to dementia in patients with MCI and underlying AD (A+T+). CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that [18F]FDG PET predicts the development of AD dementia in individuals with MCI and underlying AD as defined by the AT(N) framework.

Principal-Component Analysis-Based Measures of PET Data Closely Reflect Neuropathologic Staging Schemes.

Voxel-based principal-component analysis allows for an identification of patterns of glucose metabolism and amyloid deposition related to the conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD). The present study aimed to validate these AD conversion-related patterns (ADCRPs) against neuropathologic findings. Methods: We included patients from the Alzheimer's Disease Neuroimaging Initiative who underwent autopsy and for whom 18F-FDG PET (30 AD, 6 MCI, 2 cognitively normal) and amyloid-ß (Aß) PET (17 AD, 3 MCI, 2 cognitively normal) were available. Pattern expression scores (PESs) of the 18F-FDG- and Aß-ADCRP were compared with Braak tangle stage and Thal amyloid phase, respectively. Mean 18F-FDG uptake and mean 18F-AV-45 SUV ratio (SUVr) in regions of hypometabolism and elevated amyloid load typical of AD, respectively, were used as volume-of-interest-based PET measures. The diagnostic performance for identifying none-to-low vs. intermediate-to-high AD neuropathologic change (ADNC) was assessed for all biomarkers. Results: We observed significant associations between PES of 18F-FDG-ADCRP and Braak stage (ρ > 0.48, P < 0.005) and between PES of Aß-ADCRP and Thal phase (ρ > 0.66, P < 0.001). PES of 18F-FDG-ADCRP, PES of Aß-ADCRP, and their combination identified intermediate-to-high ADNC with an area under the receiver-operating-characteristic curve (AUC) of 0.80, 0.95, and 0.98 (n = 22), respectively. Mean 18F-FDG uptake and mean 18F-AV-45 SUVr in AD-typical regions were also significantly associated with Braak stage (|ρ| > 0.45, P < 0.01) and Thal phase (ρ > 0.55, P < 0.01), respectively. Volume-of-interest-based PET measures discriminated between ADNC stages with an AUC of 0.79, 0.88, and 0.90 for mean 18F-FDG uptake, mean 18F-AV-45 SUVr, and their combination (n = 22), respectively. Contemplating all subjects with available 18F-FDG PET and neuropathology information (n = 38), PES of 18F-FDG-ADCRP was a significant predictor of intermediate-to-high ADNC (AUC = 0.72), whereas mean 18F-FDG uptake was not (AUC = 0.66), although the difference between methods was not significant. Conclusion: PES of 18F-FDG-ADCRP, a measure of neurodegeneration, shows close correspondence with the extent of tau pathology, as assessed by Braak tangle stage. PES of Aß-ADCRP is a valid biomarker of underlying amyloid pathology, as demonstrated by its strong correlation with Thal phase. The combination of ADCRPs performed better than 18F-FDG-ADCRP alone, although there was only negligible improvement compared with Aß-ADCRP.

Brain activation patterns during visuomotor adaptation in motor experts and novices: An FDG PET study with unrestricted movements.

BACKGROUND: Speed of performance improvements and the strength of memory consolidation in humans vary with movement expertise. Underlying neural mechanisms of behavioural differences between levels of movement expertise are so far unknown. NEW METHOD: In this study, PET with [18F]fluorodeoxyglucose (FDG) was proposed as a powerful novel methodology to assess learning-related brain activity patterns during large non-restricted movements (ball throwing with a right hand). 24 male handball players ('Experts') and 24 male participants without handball experience ('Novices') performed visuomotor adaptations to prismatic glasses with or without strategic manoeuvres (i.e., explicit or implicit adaptation). RESULTS: Regional changes in FDG uptake as a marker of neuronal activity, relative to a control condition, were assessed. Prismatic adaptation, in general, was associated with decreased occipital neuronal activity as a possible response to misleading visual information. In 'Experts', the adaptation was associated with altered neuronal activity in a network comprising the right parietal cortex and the left cerebellum. In 'Novices', implicit adaptation resulted in an activation of the middle frontal and inferior temporal gyrus. COMPARISON WITH EXISTING METHODS: This study demonstrates the versatility of FDG PET for studying brain activations patterns in experimental settings with unrestricted movements that are not accessible by other techniques (e.g., fMRI or EEG). CONCLUSIONS: Observed results are consistent with the involvement of different functional networks related to strategic manoeuvres and expertise levels. This strengthens the assumption of different mechanisms underlying behavioural changes associated with movement expertise. Furthermore, the present study underscores the value of FDG PET for studying brain activation patterns during unrestricted movements.

Impact of age and sex correction on the diagnostic performance of dopamine transporter SPECT.

PURPOSE: The specific binding ratio (SBR) of 123I-FP-CIT (FP-CIT) in the putamen decreases with age by about 5% per decade and most likely is about 10% higher in females. However, the clinical utility of age and sex correction of the SBR is still a matter of debate. This study tested the impact of age and sex correction on the diagnostic performance of the putamen SBR in three independent patient samples. METHODS: Research sample: 207 healthy controls (HC) and 438 Parkinson's disease (PD) patients. Clinical sample A: 183 patients with neurodegenerative parkinsonian syndrome (PS) and 183 patients with non-neurodegenerative PS from one site. Clinical sample B: 84 patients with neurodegenerative PS and 38 patients with non-neurodegenerative PS from another site. Correction for age and sex of the putamen SBR was based on linear regression in the HC or non-neurodegenerative PS, separately in each sample. The area under the ROC curve (AUC) was used as performance measure. RESULTS: The putamen SBR was higher in females compared to males (PPMI: 14%, p < 0.0005; clinical sample A: 7%, p < 0.0005; clinical sample B: 6%, p = 0.361). Age-related decline of the putamen SBR ranged between 3.3 and 10.4% (p ≤ 0.019). In subjects ≥ 50 years, age and sex explained < 10% of SBR between-subjects variance. Correction of the putamen SBR for age and sex resulted in slightly decreased AUC in the PPMI sample (0.9955 versus 0.9969, p = 0.025) and in clinical sample A (0.9448 versus 0.9519, p = 0.057). There was a small, non-significant AUC increase in clinical sample B (0.9828 versus 0.9743, p = 0.232). CONCLUSION: These findings do not support age and sex correction of the putaminal FP-CIT SBR in the diagnostic workup of parkinsonian syndromes. This most likely is explained by the fact that the proportion of between-subjects variance caused by age and sex is considerably below the symptom threshold of about 50% reduction in neurodegenerative PS.

Differential diagnosis of parkinsonism: a head-to-head comparison of FDG PET and MIBG scintigraphy.

[18F]fluorodeoxyglucose (FDG) PET and [123I]metaiodobenzylguanidine (MIBG) scintigraphy may contribute to the differential diagnosis of neurodegenerative parkinsonism. To identify the superior method, we retrospectively evaluated 54 patients with suspected neurodegenerative parkinsonism, who were referred for FDG PET and MIBG scintigraphy. Two investigators visually assessed FDG PET scans using an ordinal 6-step score for disease-specific patterns of Lewy body diseases (LBD) or atypical parkinsonism (APS) and assigned the latter to the subgroups multiple system atrophy (MSA), progressive supranuclear palsy (PSP), or corticobasal syndrome. Regions-of-interest analysis on anterior planar MIBG images served to calculate the heart-to-mediastinum ratio. Movement disorder specialists blinded to imaging results established clinical follow-up diagnosis by means of guideline-derived case vignettes. Clinical follow-up (1.7 ± 2.3 years) revealed the following diagnoses: n = 19 LBD (n = 17 Parkinson's disease [PD], n = 1 PD dementia, and n = 1 dementia with Lewy bodies), n = 31 APS (n = 28 MSA, n = 3 PSP), n = 3 non-neurodegenerative parkinsonism; n = 1 patient could not be diagnosed and was excluded. Receiver operating characteristic analyses for discriminating LBD vs. non-LBD revealed a larger area under the curve for FDG PET than for MIBG scintigraphy at statistical trend level for consensus rating (0.82 vs. 0.69, p = 0.06; significant for investigator #1: 0.83 vs. 0.69, p = 0.04). The analysis of PD vs. MSA showed a similar difference (0.82 vs. 0.69, p = 0.11; rater #1: 0.83 vs. 0.69, p = 0.07). Albeit the notable differences in diagnostic performance did not attain statistical significance, the authors consider this finding clinically relevant and suggest that FDG PET, which also allows for subgrouping of APS, should be preferred.

Amyloid biomarkers as predictors of conversion from mild cognitive impairment to Alzheimer's dementia: a comparison of methods.

BACKGROUND: Amyloid-ß (Aß) PET is an established predictor of conversion from mild cognitive impairment (MCI) to Alzheimer's dementia (AD). We compared three PET (including an approach based on voxel-wise Cox regression) and one cerebrospinal fluid (CSF) outcome measures in their predictive power. METHODS: Datasets were retrieved from the ADNI database. In a training dataset (N = 159), voxel-wise Cox regression and principal component analyses were used to identify conversion-related regions (Cox-VOI and AD conversion-related pattern (ADCRP), respectively). In a test dataset (N = 129), the predictive value of mean normalized 18F-florbetapir uptake (SUVR) in AD-typical brain regions (composite SUVR) or the Cox-VOI and the pattern expression score (PES) of ADCRP and CSF Aß42/Aß40 as predictors were compared by Cox models (corrected for age and sex). RESULTS: All four Aß measures were significant predictors (p < 0.001). Prediction accuracies (Harrell's c) showed step-wise significant increases from Cox-SUVR (c = 0.71; HR = 1.84 per Z-score increase), composite SUVR (c = 0.73; HR = 2.18), CSF Aß42/Aß40 (c = 0.75; HR = 3.89) to PES (c = 0.77; HR = 2.71). CONCLUSION: The PES of ADCRP is the most predictive Aß PET outcome measure, comparable to CSF Aß42/Aß40, with a slight but statistically significant advantage.

Intrinsic Alertness Is Impaired in Patients with Nigrostriatal Degeneration: A Prospective Study with Reference to [123I]FP-CIT SPECT and [18F]FDG PET.

BACKGROUND: Variations in alertness and attention are common in Lewy body diseases (LBD) and among the core features of dementia with Lewy bodies (DLB). Dopamine transporter SPECT is an accurate biomarker of nigrostriatal degeneration (NSD) in LBD. OBJECTIVE: The present study investigated performance on a computerized alertness test as a potential measure of attention in patients with NSD compared to patients without NSD. METHODS: Thirty-six patients with cognitive impairment plus at least one core feature of DLB referred for [123I]FP-CIT SPECT imaging were prospectively recruited. Performance in a computerized test of intrinsic alertness was compared between patients with and those without NSD as assessed by [123I]FP-CIT SPECT. RESULTS: Reaction times to auditory stimuli (adjusted for age, sex, and education) were significantly longer in patients with NSD compared to those with a normal [123I]FP-CIT SPECT scan (p < 0.05). Statistical analyses revealed no significant differences comparing reaction times to visual stimuli or dispersion of reaction times between groups. Exploratory analysis in a subgroup of patients with available [18F]FDG PET revealed that longer reaction times were associated with decreased glucose metabolism in the prefrontal cortex (statistical parametric mapping, adjusted for age and sex; p < 0.005, cluster extent > 50 voxels). CONCLUSION: Computerized assessment of auditory reaction times is able to detect alertness deficits in patients with NSD and might help to measure alertness deficits in patients with LBD and NSD. Future studies in larger samples are needed to evaluate the diagnostic utility of computerized alertness assessment for the differential diagnosis of LBD.

[123I]FP-CIT SPECT in Clinically Uncertain Parkinsonism Predicts Survival: A Data-Driven Analysis.

BACKGROUND: Dopamine transporter SPECT is an established method to investigate nigrostriatal integrity in case of clinically uncertain parkinsonism. OBJECTIVE: The present study explores whether a data-driven analysis of [123I]FP-CIT SPECT is able to stratify patients according to mortality after SPECT. METHODS: Patients from our clinical registry were included if they had received [123I]FP-CIT SPECT between 10/2008 and 06/2016 for diagnosis of parkinsonism and if their vital status could be determined in 07/2017. Specific binding ratios (SBR) of the whole striatum, its asymmetry (asymmetry index, AI; absolute value), and the rostrocaudal gradient of striatal binding (C/pP: caudate SBR divided by posterior putamen SBR) were used as input for hierarchical clustering of patients. We tested differences in survival between these groups (adjusted for age) with a Cox proportional hazards model. RESULTS: Data from 518 patients were analyzed. Median follow-up duration was 3.3 years [95% C.I. 3.1 to 3.7]. Three subgroups identified by hierarchical clustering were characterized by relatively low striatal SBR, high AI, and low C/pP (group 1), low striatal SBR, high AI, and high C/pP (group 2), and high striatal SBR, low AI, and low C/pP (group 3). Mortality was significantly higher in group 1 compared to each of the other two groups (p = 0.029 and p = 0.003, respectively). CONCLUSION: Data-driven analysis of [123I]FP-CIT SPECT identified a subgroup of patients with significantly increased mortality during follow-up. This suggests that [123I]-FP-CIT SPECT might not only serve as a diagnostic tool to verify nigrostriatal degeneration but also provide valuable prognostic information.

Whole-brain irradiation with hippocampal sparing and dose escalation on metastases: neurocognitive testing and biological imaging (HIPPORAD) - a phase II prospective randomized multicenter trial (NOA-14, ARO 2015-3, DKTK-ROG).

BACKGROUND: Whole brain radiation therapy (WBRT) is the standard therapy for multiple brain metastases. However, WBRT has a poor local tumor control and is associated with a decline in neurocognitive function (NCF). Aim of this trial is to assess the efficacy and safety of a new treatment method, the WBRT with hippocampus avoidance (HA) combined with the simultaneous integrated boost (SIB) on metastases/resection cavities (HA-WBRT+SIB). METHODS: This is a prospective, randomized, two-arm phase II multicenter trial comparing the impact of HA on NCF after HA-WBRT+SIB versus WBRT+SIB in patients with multiple brain metastases. The study design is double-blinded. One hundred thirty two patients are to be randomized with a 1:1 allocation ratio. Patients between 18 and 80 years old are recruited, with at least 4 brain metastases of solid tumors and at least one, but not exceeding 10 metastases ≥5 mm. Patients must be in good physical condition and have no metastases/resection cavities in or within 7 mm of the hippocampus. Patients with dementia, meningeal disease, cerebral lymphomas, germ cell tumors, or small cell carcinomas are excluded. Previous irradiation and resection of metastases, as well as the number and size of metastases to be boosted have to comply with certain restrictions. Patients are randomized between the two treatment arms: HA-WBRT+SIB and WBRT+SIB. WBRT is to be performed with 30 Gy in 12 daily fractions and the SIB with 51 Gy/42 Gy in 12 daily fractions on 95% of volume for metastases/resection cavities. In the experimental arm, the dose to the hippocampi is restricted to 9 Gy in 98% of the volume and 17Gy in 2% of the volume. NCF testing is scheduled before WBRT, after 3 (primary endpoint), 9, 18 months and yearly thereafter. Clinical and imaging follow-ups are performed 6 and 12 weeks after WBRT, after 3, 9, 18 months and yearly thereafter. DISCUSSION: This is a protocol of a randomized phase II trial designed to test a new strategy of WBRT for preventing cognitive decline and increasing tumor control in patients with multiple brain metastases. TRIAL REGISTRATION: The HIPPORAD trial is registered with the German Clinical Trials Registry (DRKS00004598, registered 2 June 2016).

Automated voxel- and region-based analysis of gray matter and cerebrospinal fluid space in primary dementia disorders.

PURPOSE: Previous studies showed voxel-based volumetry as a helpful tool in detecting pathologic brain atrophy. Aim of this study was to investigate whether the inclusion of CSF volume improves the imaging based diagnostic accuracy using combined automated voxel- and region-based volumetry. METHODS: In total, 120 individuals (30 healthy elderly, 30 frontotemporal dementia (FTD), 30 Alzheimer's dementia (AD) and 30 Lewy body dementia (LBD) patients) were analyzed with voxel-based morphometry and compared to a reference group of 360 healthy elderly controls. Abnormal GM and CSF volumes were visualized via z-scores. Volumetric results were finally evaluated by ROC analyses. RESULTS: Based on the volume of abnormal GM and CSF voxels high accuracy was shown in separating dementia from normal ageing (AUC 0.93 and 0.91, respectively) within 5 different brain regions per hemisphere (frontal, medial temporal, temporal, parietal, occipital). Accuracy for separating FTD and AD was higher based on CSF volume (FTD: AUC 0.80 vs. 0.75 in frontal regions; AD: AUC 0.78 vs. 0.68 in parietal regions based on CSF and GM respectively). CONCLUSIONS: Differentiation of dementia patients from normal ageing persons shows high accuracy when based on automatic volumetry alone. Evaluating volumes of abnormal CSF performed better than volumes of abnormal GM, especially in AD and FTD patients.