Symptomatology in 4-repeat tauopathies is associated with data-driven topology of [18F]-PI-2620 tau-PET signal.

In recent years in vivo visualization of tau deposits has become possible with various PET radiotracers. The tau tracer [18F]PI-2620 proved high affinity both to 3-repeat/4-repeat tau in Alzheimer's disease as well as to 4-repeat tau in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). However, to be clinically relevant, biomarkers should not only correlate with pathological changes but also with disease stage and progression. Therefore, we aimed to investigate the correlation between topology of [18F]PI-2620 uptake and symptomatology in 4-repeat tauopathies. 72 patients with possible or probable 4-repeat tauopathy, i.e. 31 patients with PSP-Richardson's syndrome (PSP-RS), 30 with amyloid-negative CBS and 11 with PSP-non-RS/CBS, underwent [18F]PI-2620-PET. Principal component analysis was performed to identify groups of similar brain regions based on 20-40 min p.i. regional standardized uptake value ratio z-scores. Correlations between component scores and the items of the PSP Rating Scale were explored. Motor signs like gait, arising from chair and postural instability showed a positive correlation with tracer uptake in mesial frontoparietal lobes and the medial superior frontal gyrus and adjacent anterior cingulate cortex. While the signs disorientation and bradyphrenia showed a positive correlation with tracer uptake in the parietooccipital junction, the signs disorientation and arising from chair were negatively correlated with tau-PET signal in the caudate nucleus and thalamus. Total PSP Rating Scale Score showed a trend towards a positive correlation with mesial frontoparietal lobes and a negative correlation with caudate nucleus and thalamus. While in CBS patients, the main finding was a negative correlation of tracer binding in the caudate nucleus and thalamus and a positive correlation of tracer binding in medial frontal cortex with gait and motor signs, in PSP-RS patients various correlations of clinical signs with tracer binding in specific cerebral regions could be detected. Our data reveal [18F]PI-2620 tau-PET topology to correlate with symptomatology in 4-repeat tauopathies. Longitudinal studies will be needed to address whether a deterioration of signs and symptoms over time can be monitored by [18F]PI-2620 in 4-repeat tauopathies and whether [18F]PI-2620 may serve as a marker of disease progression in future therapeutic trials. The detected negative correlation of tracer binding in the caudate nucleus and thalamus with the signs disorientation and arising from chair may be due to an increasing atrophy in these regions leading to partial volume effects and a relative decrease of tracer uptake in the disease course. As cerebral regions correlating with symptomatology differ depending on the clinical phenotype, a precise knowledge of clinical signs and symptoms is necessary when interpreting [18F]PI-2620 PET results.

PREDICT-juvenile-stroke: PRospective evaluation of a prediction score determining individual clinical outcome three months after ischemic stroke in young adults - a study protocol.

BACKGROUND: Although of high individual and socioeconomic relevance, a reliable prediction model for the prognosis of juvenile stroke (18-55 years) is missing. Therefore, the study presented in this protocol aims to prospectively validate the discriminatory power of a prediction score for the 3 months functional outcome after juvenile stroke or transient ischemic attack (TIA) that has been derived from an independent retrospective study using standard clinical workup data. METHODS: PREDICT-Juvenile-Stroke is a multi-centre (n = 4) prospective observational cohort study collecting standard clinical workup data and data on treatment success at 3 months after acute ischemic stroke or TIA that aims to validate a new prediction score for juvenile stroke. The prediction score has been developed upon single center retrospective analysis of 340 juvenile stroke patients. The score determines the patient's individual probability for treatment success defined by a modified Rankin Scale (mRS) 0-2 or return to pre-stroke baseline mRS 3 months after stroke or TIA. This probability will be compared to the observed clinical outcome at 3 months using the area under the receiver operating characteristic curve. The primary endpoint is to validate the clinical potential of the new prediction score for a favourable outcome 3 months after juvenile stroke or TIA. Secondary outcomes are to determine to what extent predictive factors in juvenile stroke or TIA patients differ from those in older patients and to determine the predictive accuracy of the juvenile stroke prediction score on other clinical and paraclinical endpoints. A minimum of 430 juvenile patients (< 55 years) with acute ischemic stroke or TIA, and the same number of older patients will be enrolled for the prospective validation study. DISCUSSION: The juvenile stroke prediction score has the potential to enable personalisation of counselling, provision of appropriate information regarding the prognosis and identification of patients who benefit from specific treatments. TRIAL REGISTRATION: The study has been registered at https://drks.de on March 31, 2022 ( DRKS00024407 ).

Endovascular thrombectomy for basilar artery occlusion stroke: Analysis of the German Stroke Registry-Endovascular Treatment.

BACKGROUND AND PURPOSE: Acute ischemic stroke due to basilar artery occlusion (BAO) causes the most severe strokes and has a poor prognosis. Data regarding efficacy of endovascular thrombectomy in BAO are sparse. Therefore, in this study, we performed an analysis of the therapy of patients with BAO in routine clinical practice. METHODS: Patients enrolled between June 2015 and December 2019 in the German Stroke Registry-Endovascular Treatment (GSR-ET) were analyzed. Primary outcomes were successful reperfusion (modified Thrombolysis in Cerebral Infarction [mTICI] score of 2b-3), substantial neurological improvement (≥8-point National Institute of Health Stroke Scale [NIHSS] score reduction from admission to discharge or NIHSS score at discharge ≤1), and good functional outcome at 3 months (modified Rankin Scale [mRS] score of 0-2). RESULTS: Out of 6635 GSR-ET patients, 640 (9.6%) patients (age 72.2 ± 13.3, 43.3% female) experienced BAO (median [interquartile range] NIHSS score 17 [8, 27]). Successful reperfusion was achieved in 88.4%. Substantial neurological improvement at discharge was reached by 45.5%. At 3-month follow-up, good clinical outcome was observed in 31.1% of patients and the mortality rate was 39.2%. Analysis of mTICI3 versus mTICI2b groups showed considerable better outcome in those with mTICI3 (38.9% vs. 24.4%; p = 0.005). The strongest predictors of good functional outcome were intravenous thrombolysis (IVT) treatment (odds ratio [OR] 3.04, 95% confidence interval [CI] 1.76-5.23) and successful reperfusion (OR 4.92, 95% CI 1.15-21.11), while the effect of time between symptom onset and reperfusion seemed to be small. CONCLUSIONS: Acute reperfusion strategies in BAO are common in daily practice and can achieve good rates of successful reperfusion, neurological improvement and good functional outcome. Our data suggest that, in addition to IVT treatment, successful and, in particular, complete reperfusion (mTICI3) strongly predicts good outcome, while time from symptom onset seemed to have a lower impact.

Atrial Fibrillation Risk Assessment after Embolic Stroke of Undetermined Source.

OBJECTIVE: Approximately 20% of strokes are embolic strokes of undetermined source (ESUS). Undetected atrial fibrillation (AF) remains an important cause. Yet, oral anticoagulation in unselected ESUS patients failed in secondary stroke prevention. Guidance on effective AF detection is lacking. Here, we introduce a novel, non-invasive AF risk assessment after ESUS. METHODS: Catch-Up ESUS is an investigator-initiated, observational cohort study conducted between 2018 and 2019 at the Munich University Hospital. Besides clinical characteristics, patients received ≥72 h digital electrocardiogram recordings to generate the rhythm irregularity burden. Uni- and multivariable regression models predicted the primary endpoint of incident AF, ascertained by standardized follow-up including implantable cardiac monitors. Predictors included the novel rhythm irregularity burden constructed from digital electrocardiogram recordings. We independently validated our model in ESUS patients from the University Hospital Tübingen, Germany. RESULTS: A total of 297 ESUS patients were followed for 15.6 ± 7.6 months. Incident AF (46 patients, 15.4%) occurred after a median of 105 days (25th to 75th percentile 31-33 days). Secondary outcomes were recurrent stroke in 7.7% and death in 6.1%. Multivariable-adjusted analyses identified the rhythm irregularity burden as the strongest AF-predictor (hazard ratio 3.12, 95% confidence interval 1.62-5.80, p < 0001) while accounting for the known risk factors age, CHA2 DS2 -VASc-Score, and NT-proBNP. Independent validation confirmed the rhythm irregularity burden as the most significant AF-predictor (hazard ratio 2.20, 95% confidence interval 1.45-3.33, p < 0001). INTERPRETATION: The novel, non-invasive, electrocardiogram-based rhythm irregularity burden may help adjudicating AF risk after ESUS, and subsequently guide AF-detection after ESUS. Clinical trials need to clarify if high-AF risk patients benefit from tailored secondary stroke prevention. ANN NEUROL 2023;93:479-488.

Additive value of [18F]PI-2620 perfusion imaging in progressive supranuclear palsy and corticobasal syndrome.

PURPOSE: Early after [18F]PI-2620 PET tracer administration, perfusion imaging has potential for regional assessment of neuronal injury in neurodegenerative diseases. This is while standard late-phase [18F]PI-2620 tau-PET is able to discriminate the 4-repeat tauopathies progressive supranuclear palsy and corticobasal syndrome (4RTs) from disease controls and healthy controls. Here, we investigated whether early-phase [18F]PI-2620 PET has an additive value for biomarker based evaluation of 4RTs. METHODS: Seventy-eight patients with 4RTs (71 ± 7 years, 39 female), 79 patients with other neurodegenerative diseases (67 ± 12 years, 35 female) and twelve age-matched controls (69 ± 8 years, 8 female) underwent dynamic (0-60 min) [18F]PI-2620 PET imaging. Regional perfusion (0.5-2.5 min p.i.) and tau load (20-40 min p.i.) were measured in 246 predefined brain regions [standardized-uptake-value ratios (SUVr), cerebellar reference]. Regional SUVr were compared between 4RTs and controls by an ANOVA including false-discovery-rate (FDR, p < 0.01) correction. Hypoperfusion in resulting 4RT target regions was evaluated at the patient level in all patients (mean value - 2SD threshold). Additionally, perfusion and tau pattern expression levels were explored regarding their potential discriminatory value of 4RTs against other neurodegenerative disorders, including validation in an independent external dataset (n = 37), and correlated with clinical severity in 4RTs (PSP rating scale, MoCA, activities of daily living). RESULTS: Patients with 4RTs had significant hypoperfusion in 21/246 brain regions, most dominant in thalamus, caudate nucleus, and anterior cingulate cortex, fitting to the topology of the 4RT disease spectrum. However, single region hypoperfusion was not specific regarding the discrimination of patients with 4RTs against patients with other neurodegenerative diseases. In contrast, perfusion pattern expression showed promise for discrimination of patients with 4RTs from other neurodegenerative diseases (AUC: 0.850). Discrimination by the combined perfusion-tau pattern expression (AUC: 0.903) exceeded that of the sole tau pattern expression (AUC: 0.864) and the discriminatory power of the combined perfusion-tau pattern expression was replicated in the external dataset (AUC: 0.917). Perfusion but not tau pattern expression was associated with PSP rating scale (R = 0.402; p = 0.0012) and activities of daily living (R = - 0.431; p = 0.0005). CONCLUSION: [18F]PI-2620 perfusion imaging mirrors known topology of regional hypoperfusion in 4RTs. Single region hypoperfusion is not specific for 4RTs, but perfusion pattern expression may provide an additive value for the discrimination of 4RTs from other neurodegenerative diseases and correlates closer with clinical severity than tau pattern expression.

Stimulus-dependent deliberation process in left- and right-handers obtained via current source density analysis.

The aim of the present study was to compare the activity patterns of young, healthy right- (RH, n = 25) and left-handed (LH, n = 20) subjects in high-density electroencephalograpic (EEG) recordings during a deliberation task. The deliberation task consisted of pressing one of two keys depending on a color-word Stroop task (Stroop, 1935) presented on a computer screen. Depending on the color shown and the meaning of the color word, participants responded with the index finger of the dominant or non-dominant hand. This leads to different activities in the hemispheres depending on the acting hand and on subject's handedness. Presenting the word "black" in black color, subjects were not to press any key (no-go-trial). Prior to this, subjects were tested for simple motor tasks, during which they were informed about the motor action to be performed. The temporal activity patterns obtained from RH and LH were very similar in shape and constituent components. The comparison of the three types of trials lead to the assumption that the deliberation process is based on a two-step decision: The first decision was characterized by the choice between move (match-trials, mismatch-trials) or not to move (no-go-trials). The second decision resulted in the final judgment of which index finger has to be used. The latter decision, in particular, can be tracked via the local spread of activity over the scalp. Our hypothesis is based on a comparison of activities and locations of RH and LH and yields some insights about processing a two-step decision in a deliberation task.

Retinal Infarction: A Pilot Study on the Efficacy and Safety of Intravenous Thrombolysis and Underlying Aetiologies.

Background: Treatment of non-arteritic central retinal artery occlusion is still inconsistent. Therefore, the current study aimed to evaluate the efficacy of intravenous thrombolysis (IVT) and describe the prevalence of co-occurring ischemic brain lesions in patients with acute visual loss due to ischemia. Methods: We analysed 38 consecutive patients with acute visual loss between January 2015 and June 2020. Patients presenting within 4.5 h of symptom onset without any contraindication were treated with IVT. Patients underwent neurologic and ophthalmologic examination and diagnostic workup for the underlying aetiology. Follow-up was performed after 3 and 12 months. Results: Patients treated with IVT had a significantly better functional outcome at discharge compared to patients treated conservatively. No additional ischemic brain lesions were detected (0 of 38). Three patients had extracranial carotid artery stenosis ≥50%. Atrial fibrillation was present in four patients, three of whom already received oral anticoagulation. In the remaining 31 patients no embolic source was detected. However, the number of plaques were rated mild to moderate. Within three months, one patient developed transient visual loss while another suffered a contralateral transient ischemic attack. Conclusions: IVT may represent a safe and effective treatment option in patients with isolated visual loss due to ischemia. The aetiology was atherosclerotic burden rather than embolism caused by carotid stenosis or atrial fibrillation, bringing the current diagnostic procedure and therapy into question. Randomized trials are necessary to evaluate the efficacy and safety of IV thrombolysis and clarify the aetiology of isolated visual loss due to ischemia.

Frequency and Longitudinal Course of Motor Signs In Genetic Frontotemporal Dementia.

BACKGROUND AND OBJECTIVES: Frontotemporal dementia (FTD) is a highly heritable disorder. The majority of genetic cases are caused by autosomal dominant pathogenic variants in the c9orf72, GRN and MAPT gene. As motor disorders are increasingly recognized as part of the clinical spectrum the current study aimed to describe motor phenotypes caused by genetic FTD, quantify their temporal association, and investigate their regional association with brain atrophy. METHODS: We analyzed baseline visit data of known carriers of a pathogenic variant in the c9orf72, GRN or MAPT gene from the Genetic Frontotemporal dementia Initiative cohort study. Principal component analysis with varimax rotation was performed to identify motor sign clusters that were compared with respect to frequency and severity between groups. Associations with cross-sectional atrophy patterns were determined using voxel-wise regression. We applied linear mixed effects models to assess whether groups differed in the association between motor signs and estimated time to symptom onset. RESULTS: 322 pathogenic variant carriers were included in the analysis: 122 c9orf72 (79 presymptomatic), 143 GRN (112 presymptomatic) and 57 MAPT (43 presymptomatic) pathogenic variant carriers. Principal component analysis revealed five motor clusters, which we call progressive supranuclear palsy like (PSP-like), bulbar amyotrophic lateral sclerosis (ALS) like, mixed/ALS-like, Parkinson's disease like (PD-like), and corticobasal syndrome like motor phenotypes. There was no significant group difference in the frequency of signs of different motor phenotypes. However, mixed/ALS-like motor signs were most frequent, followed by PD-like motor signs. While the PSP-like phenotype was associated with mesencephalic atrophy, the mixed/ALS-like phenotype was associated with motor cortex and corticospinal tract atrophy. The PD-like phenotype was associated with widespread cortical and subcortical atrophy. Estimated time to onset, genetic group and their interaction, influenced motor signs. In c9orf72 pathogenic variant carriers, motor signs could be detected up to 25 years prior to expected symptom onset. DISCUSSION: These results indicate the presence of multiple natural clusters of motor signs in genetic FTD, each correlated with specific atrophy patterns. Their motor severity depends on time and the affected gene. These clinico-genetic associations can guide diagnostic evaluations and the design of clinical trials for new disease-modifying and preventive treatments.

Minor stroke in large vessel occlusion: A matched analysis of patients from the German Stroke Registry-Endovascular Treatment (GSR-ET) and patients from the Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Register (SITS-ISTR).

BACKGROUND AND PURPOSE: Reperfusion treatment in patients presenting with large vessel occlusion (LVO) and minor neurological deficits is still a matter of debate. We aimed to compare minor stroke patients treated with endovascular thrombectomy (EVT) and intravenous thrombolysis (IVT) or IVT alone. METHODS: Patients enrolled in the German Stroke Registry-Endovascular Treatment (GSR-ET) and the Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Registry (SITS-ISTR) between June 2015 and December 2019 were analyzed. Minor stroke was defined as National Institutes of Health Stroke Scale (NIHSS) score ≤5, and LVO as occlusion of the internal carotid, carotid-T, middle cerebral, basilar, vertebral or posterior cerebral arteries. GSR-ET and SITS-ISTR IVT-treated patients were matched in a 1:1 ratio using propensity-score (PS) matching. The primary outcome was good functional outcome at 3 months (modified Rankin Scale score 0-2). RESULTS: A total of 272 GSR-ET patients treated with EVT and IVT (age 68.6 ± 14.0 years, 43.4% female, NIHSS score 4 [interquartile range 2-5]) were compared to 272 IVT-treated SITS-ISTR patients (age 69.4 ± 13.7, 43.4% female, NIHSS score 4 [2-5]). Good functional outcome was seen in 77.0% versus 82.9% (p = 0.119), mortality in 5.9% versus 7.9% (p = 0.413), and intracranial hemorrhage in 8.8% versus 12.5% (p = 0.308) of patients in the GSR-ET versus the SITS-ISTR IVT group, respectively. In a second PS-matched analysis, 624 GSR-ET patients (IVT rate 56.7%) and 624 SITS-ISTR patients (IVT rate 100%), good outcome was more often observed in the SITS-ISTR patients (68.2% vs. 80.9%; p < 0.001), and IVT independently predicted good outcome (odds ratio 2.16, 95% confidence interval 1.43-3.28). CONCLUSIONS: Our study suggests similar effectiveness of IVT alone compared to EVT with or without IVT in minor stroke patients. There is an urgent need for randomized controlled trials on this topic.

Detection Gap of Right-Asymmetric Neuronal Degeneration by CERAD Test Battery in Alzheimer's Disease.

Objectives: Asymmetric disease characteristics on neuroimaging are common in structural and functional imaging of neurodegenerative diseases, particularly in Alzheimer's disease (AD). However, a standardized clinical evaluation of asymmetric neuronal degeneration and its impact on clinical findings has only sporadically been investigated for F-18-fluorodeoxyglucose positron emission tomography (F-18-FDG-PET). This study aimed to evaluate the impact of lateralized neuronal degeneration on the detection of AD by detailed clinical testing. Furthermore, we compared associations between clinical evaluation and lateralized neuronal degeneration between FDG-PET hypometabolism and hippocampal atrophy. Finally, we investigated if specific subtests show associations with lateralized neuronal degeneration. Methods: One-hundred and forty-six patients with a clinical diagnosis of AD (age 71 ± 8) were investigated by FDG-PET and the "Consortium to Establish a Registry for Alzheimer's disease" (CERAD) test battery. For assessment of neuronal degeneration, FDG-PET hypometabolism in brain regions typically affected in AD were graded by visual (3D-surface projections) and semiquantitative analysis. Asymmetry of the hippocampus (left-right) in magnetic resonance tomography (MRI) was rated visually by the Scheltens scale. Measures of asymmetry were calculated to quantify lateralized neuronal degeneration and asymmetry scores were subsequently correlated with CERAD. Results: Asymmetry with left-dominant neuronal degeneration to FDG-PET was an independent predictor of cognitive impairment (visual: ß = -0.288, p < 0.001; semiquantitative: ß = -0.451, p < 0.001) when controlled for age, gender, years of education and total burden of neuronal degeneration, whereas hippocampal asymmetry to MRI was not (ß = -0.034; p = 0.731). Direct comparison of CERAD-PET associations in cases with right- and left-lateralized neuronal degeneration estimated a detection gap of 2.7 years for right-lateralized cases. Left-hemispheric neuronal degeneration was significantly associated with the total CERAD score and multiple subscores, whereas only MMSE (semiquantitative: ß = 0.429, p < 0.001) and constructional praxis (semiquantitative: ß = 0.292, p = 0.008) showed significant associations with right-hemispheric neuronal degeneration. Conclusions: Asymmetry of deteriorated cerebral glucose metabolism has a significant impact on the coupling between neuronal degeneration and cognitive function. Right dominant neuronal degeneration shows a delayed detection by global CERAD testing and requires evaluation of specific subdomains of cognitive testing.

Cognitive reserve hypothesis in frontotemporal dementia: A FDG-PET study.

BACKGROUND AND OBJECTIVE: Reserve is defined as the ability to maintain cognitive functions relatively well at a given level of pathology. Early life experiences such as education are associated with lower dementia risk in general. However, whether more years of education guards against the impact of brain alterations also in frontotemporal dementia (FTD) has not been shown in a large patient collective. Therefore, we assessed whether education is associated with relatively high cognitive performance despite the presence of [18F]-fluorodeoxyglucose positron-emission-tomography (FDG-PET) hypometabolism in FTD. METHODS: Sixty-six FTD subjects (age 67 ± 8 years) and twenty-four cognitively healthy controls (HC) were evaluated. Brain regions with FTD-related glucose hypometabolism in the contrast against HC and brain regions that correlate with the cognitive function were defined by a voxel-based analysis and individual FDG-PET values were extracted from all frontotemporal brain areas. Linear regression analysis served to test if education is associated with residualized cognitive performance and regional FDG-PET hypometabolism after controlling for global cognition. RESULTS: Compared to healthy controls, patients with FTD showed glucose hypometabolism in bilateral frontal and temporal brain areas whereas cognition was only associated with deteriorated glucose metabolism in the left temporal lobe. The education level was significantly correlated with the residualized cognitive performance (residuals from regression analysis between hypometabolism and cognitive function as a quantitative index of reserve) and also negatively correlated with left temporal FDG-PET hypometabolism after controlling for cognition. CONCLUSIONS: In patients with FTD, the education level predicts the existing left temporal FDG-PET hypometabolism at the same cognition level, supporting the cognitive reserve hypothesis in FTD.

Metabolic Correlates of Dopaminergic Loss in Dementia with Lewy Bodies.

BACKGROUND: Striatal dopamine deficiency and metabolic changes are well-known phenomena in dementia with Lewy bodies and can be quantified in vivo by 123 I-Ioflupane brain single-photon emission computed tomography of dopamine transporter and 18 F-fluorodesoxyglucose PET. However, the linkage between both biomarkers is ill-understood. OBJECTIVE: We used the hitherto largest study cohort of combined imaging from the European consortium to elucidate the role of both biomarkers in the pathophysiological course of dementia with Lewy bodies. METHODS: We compared striatal dopamine deficiency and glucose metabolism of 84 dementia with Lewy body patients and comparable healthy controls. After normalization of data, we tested their correlation by region-of-interest-based and voxel-based methods, controlled for study center, age, sex, education, and current cognitive impairment. Metabolic connectivity was analyzed by inter-region coefficients stratified by dopamine deficiency and compared to healthy controls. RESULTS: There was an inverse relationship between striatal dopamine availability and relative glucose hypermetabolism, pronounced in the basal ganglia and in limbic regions. With increasing dopamine deficiency, metabolic connectivity showed strong deteriorations in distinct brain regions implicated in disease symptoms, with greatest disruptions in the basal ganglia and limbic system, coincident with the pattern of relative hypermetabolism. CONCLUSIONS: Relative glucose hypermetabolism and disturbed metabolic connectivity of limbic and basal ganglia circuits are metabolic correlates of dopamine deficiency in dementia with Lewy bodies. Identification of specific metabolic network alterations in patients with early dopamine deficiency may serve as an additional supporting biomarker for timely diagnosis of dementia with Lewy bodies. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Identification of a rare presenilin 1 single amino acid deletion mutation (F175del) with unusual amyloid-ß processing effects.

We report the novel presenilin 1 (PSEN1) single amino acid deletion mutation F175del. Comprehensive clinical work-up, including cerebral MRI, FDG-PET, and CSF analysis, was performed in a male who had developed forgetfulness at the age of 39. Alzheimer's disease dementia was diagnosed according to established criteria. The index patient manifested rapid progressive dementia, seizures, and myoclonus, and a Pisa syndrome as a side effect of donepezil treatment. The PSEN1 mutation F175del was found on genetic testing. It was rendered very likely pathogenic as amyloid-ß (Aß) peptide 42 was elevated in a cell culture model compared to presenilin 1 wild-type controls. An additional, unusual increase in Aß39 indicates a rarely observed product line deviation in the generation of the shorter Aß species. Our observations extend the range of PSEN1 mutations to be considered in familial dementia. We demonstrate that deletion of a single conserved amino acid, which is very rare compared to missense mutations as the common cause for PSEN1-associated Alzheimer's disease, can lead to an unusual profile of Aß species.

PET Imaging of Astrogliosis and Tau Facilitates Diagnosis of Parkinsonian Syndromes.

Neurodegenerative parkinsonian syndromes comprise a number of disorders that are characterized by similar clinical features but are separated on the basis of different pathologies, i.e., aggregates of α-synuclein or tau protein. Due to the overlap of signs and symptoms a precise differentiation is often difficult, especially early in the disease course. Enormous efforts have been taken to develop tau-selective PET imaging agents, but strong off-target binding to monoamine oxidase B (MAO-B) has been observed across first generation ligands. Nonetheless, astrogliosis-related MAO-B elevation is a common histopathological known feature of all parkinsonian syndromes and might be itself an interesting imaging target. Therefore, this study aimed to investigate the performance of [18F]-THK5351, a combined MAO-B and tau tracer for differential diagnosis of parkinsonian syndromes. [18F]-THK5351 PET was performed in 34 patients: six with Parkinson's disease (PD), nine with multiple system atrophy with predominant parkinsonism (MSA-P), six with MSA with predominant cerebellar ataxia (MSA-C), and 13 with progressive supranuclear palsy (PSP) Richardson's syndrome. Volume-of-interest-based quantification of standardized-uptake-values was conducted in different parkinsonian syndrome-related target regions. PET results were subjected to multinomial logistic regression to create a prediction model discriminating among groups. Furthermore, we correlated tracer uptake with clinical findings. Elevated [18F]-THK5351 uptake in midbrain and diencephalon differentiated PSP patients from PD and MSA-C. MSA-C patients were distinguishable by high tracer uptake in the pons and cerebellar deep white matter when compared to PSP and PD patients, whereas MSA-P patients tended to show higher tracer uptake in the lentiform nucleus. A multinomial logistic regression classified 33/34 patients into the correct clinical diagnosis group. Tracer uptake in the pons, cerebellar deep white matter, and striatum was closely associated with the presence of cerebellar and parkinsonian symptoms of MSA patients. The current study demonstrates that combined MAO-B and tau binding of THK5351 facilitates differential diagnosis of parkinsonian syndromes. Furthermore, our data indicate a correlation of MSA phenotype with [18F]-THK5351 uptake in certain brain regions, illustrating their relevance for the emergence of clinical symptoms and underlining the potential of THK5351 PET as a biomarker that correlates with pathological changes as well as with disease stage.

Neuronal injury biomarkers for assessment of the individual cognitive reserve in clinically suspected Alzheimer's disease.

OBJECTIVES: Many predictive or influencing factors have emerged in investigations of the cognitive reserve model of patients with Alzheimer's disease (AD). For example, neuronal injury, which correlates with cognitive decline in AD, can be assessed by [18F]-fluorodeoxyglucose positron-emission-tomography (FDG-PET), structural magnetic resonance imaging (MRI) and total tau in cerebrospinal fluid (CSFt-tau), all according to the A/T/N-classification. The aim of this study was to calculate residual cognitive performance based on neuronal injury biomarkers as a surrogate of cognitive reserve, and to test the predictive value of this index for the individual clinical course. METHODS: 110 initially mild cognitive impaired and demented subjects (age 71 ±â€¯8 years) with a final diagnosis of AD dementia were assessed at baseline by clinical mini-mental-state-examination (MMSE), FDG-PET, MRI and CSFt-tau. All neuronal injury markers were tested for an association with clinical MMSE and the resulting residuals were correlated with years of education. We used multiple regression analysis to calculate the expected MMSE score based on neuronal injury biomarkers and covariates. The residuals of the partial correlation for each biomarker and the predicted residualized memory function were correlated with individual cognitive changes measured during clinical follow-up (27 ±â€¯13 months). RESULTS: FDG-PET correlated highly with clinical MMSE (R = -0.49, p < .01), whereas hippocampal atrophy to MRI (R = -0.15, p = .14) and CSFt-tau (R = -0.12, p = .22) showed only weak correlations. Residuals of all neuronal injury biomarker regressions correlated significantly with education level, indicating them to be surrogates of cognitive reserve. A positive residual was associated with faster cognitive deterioration at follow-up for the residuals of stand-alone FDG-PET (R = -0.36, p = .01) and the combined residualized memory function model (R = -0.35, p = .02). CONCLUSIONS: These findings suggest that subjects with higher cognitive reserve had accumulated more pathology, which subsequently caused a faster cognitive decline over time. Together with previous findings suggesting that higher reserve is associated with slower cognitive decline, we propose a biphasic reserve effect, with an initially protective phase followed by more rapid decompensation once the protection is overwhelmed.

The applause sign in frontotemporal lobar degeneration and related conditions.

The applause sign, i.e., the inability to execute the same amount of claps as performed by the examiner, was originally reported as a sign specific for progressive supranuclear palsy (PSP). Recent research, however, has provided evidence for the occurrence of the applause sign in various conditions. The aim of this study was to determine the prevalence of the applause sign and correlate its presence with neuropsychological and MRI volumetry findings in frontotemporal lobar degeneration and related conditions. The applause sign was elicited with the three clap test (TCT), with a higher score indicating poorer performance. Data were recorded from 272 patients from the cohort of the German consortium for frontotemporal lobar degeneration (FTLDc): 111 with behavioral variant frontotemporal dementia (bvFTD), 98 with primary progressive aphasia (PPA), 30 with progressive supranuclear palsy Richardson's syndrome, 17 with corticobasal syndrome (CBS) and 16 with amyotrophic lateral sclerosis with frontotemporal dementia (ALS/FTD). For comparison, 29 healthy elderly control subjects (HC) were enrolled in the study. All subjects underwent detailed language and neuropsychological assessment. In a subset of 156 subjects, atlas-based volumetry was performed. The applause sign occurred in all patient groups (40% in PSP, 29.5% in CBS, 25% in ALS/FTD, 13.3% in PPA and 9.0% in bvFTD) but not in healthy controls. The prevalence was highest in PSP patients. It was significantly more common in PSP as compared to bvFTD, PPA and HC. The comparison between the other groups failed to show a significant difference regarding the occurrence of the applause sign. The applause sign was highly correlated to a number of neuropsychological findings, especially to measures of executive, visuospatial, and language function as well as measures of disease severity. TCT scores showed an inverse correlation with the volume of the ventral diencephalon and the pallidum. Furthermore the volume of the ventral diencephalon and pallidum were significantly smaller in patients displaying the applause sign. Our study confirms the occurrence of the applause sign in bvFTD, PSP and CBS and adds PPA and ALS/FTD to these conditions. Although still suggestive of PSP, clinically it must be interpreted with caution. From the correlation with various cognitive measures we suggest the applause sign to be indicative of disease severity. Furthermore we suggest that the applause sign represents dysfunction of the pallidum and the subthalamic nucleus, structures which are known to play important roles in response inhibition.

Clinical Routine FDG-PET Imaging of Suspected Progressive Supranuclear Palsy and Corticobasal Degeneration: A Gatekeeper for Subsequent Tau-PET Imaging?

Background: F-18-fluordeoxyglucose positron emission tomography (FDG-PET) is widely used for discriminative diagnosis of tau-positive atypical parkinsonian syndromes (T+APS). This approach now stands to be augmented with more specific tau tracers. Therefore, we retrospectively analyzed a large clinical routine dataset of FDG-PET images for evaluation of the strengths and limitations of stand-alone FDG-PET. Methods: A total of 117 patients (age 68.4 ± 11.1 y) underwent an FDG-PET exam. Patients were followed clinically for a minimum of one year and their final clinical diagnosis was recorded. FDG-PET was rated visually (positive/negative) and categorized as high, moderate or low likelihood of T+APS and other neurodegenerative disorders. We then calculated positive and negative predictive values (PPV/NPV) of FDG-PET readings for the different subgroups relative to their final clinical diagnosis. Results: Suspected diagnoses were confirmed by clinical follow-up (≥1 y) for 62 out of 117 (53%) patients. PPV was excellent when FDG-PET indicated a high likelihood of T+APS in combination with low to moderate likelihood of another neurodegenerative disorder. PPV was distinctly lower when FDG-PET indicated only a moderate likelihood of T+APS or when there was deemed equal likelihood of other neurodegenerative disorder. NPV of FDG-PET with a low likelihood for T+APS was high. Conclusions: FDG-PET has high value in clinical routine evaluation of suspected T+APS, gaining satisfactory differential diagnosis in two thirds of the patients. One third of patients would potentially profit from further evaluation by more specific radioligands, with FDG-PET serving gatekeeper function for the more expensive methods.

Atrophy in the Thalamus But Not Cerebellum Is Specific for C9orf72 FTD and ALS Patients - An Atlas-Based Volumetric MRI Study.

Background: The neuropathology of patients with frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS) due to a C9orf72 mutation is characterized by two distinct types of characteristic protein depositions containing either TDP-43 or so-called dipeptide repeat proteins that extend beyond frontal and temporal regions. Thalamus and cerebellum seem to be preferentially affected by the dipeptide repeat pathology unique to C9orf72 mutation carriers. Objective: This study aimed to determine if mutation carriers showed an enhanced degree of thalamic and cerebellar atrophy compared to sporadic patients or healthy controls. Methods: Atlas-based volumetry was performed in 13 affected C9orf72 FTD, ALS and FTD/ALS patients, 45 sporadic FTD and FTD/ALS patients and 19 healthy controls. Volumes and laterality indices showing significant differences between mutation carriers and sporadic patients were subjected to binary logistic regression to determine the best predictor of mutation carrier status. Results: Compared to sporadic patients, mutation carriers showed a significant volume reduction of the thalamus, which was most striking in the occipital, temporal and prefrontal subregion of the thalamus. Disease severity measured by mini mental status examination (MMSE) and FTD modified Clinical Dementia Rating Scale Sum of Boxes (FTD-CDR-SOB) significantly correlated with volume reduction in the aforementioned thalamic subregions. No significant atrophy of cerebellar regions could be detected. A logistic regression model using the volume of the prefrontal and the laterality index of the occipital subregion of the thalamus as predictor variables resulted in an area under the curve (AUC) of 0.88 while a model using overall thalamic volume still resulted in an AUC of 0.82. Conclusion: Our data show that thalamic atrophy in C9orf72 mutation carriers goes beyond the expected atrophy in the prefrontal and temporal subregion and is in good agreement with the cortical atrophy pattern described in C9orf72 mutation carriers, indicating a retrograde degeneration of functionally connected regions. Clinical relevance of the detected thalamic atrophy is illustrated by a correlation with disease severity. Furthermore, the findings suggest MRI volumetry of the thalamus to be of high predictive value in differentiating C9orf72 mutation carriers from patients with sporadic FTD.

Additive value of amyloid-PET in routine cases of clinical dementia work-up after FDG-PET.

PURPOSE: In recent years, several [18F]-labeled amyloid-PET tracers have been developed and have obtained clinical approval. Despite their widespread scientific use, studies in routine clinical settings are limited. We therefore investigated the impact of [18F]-florbetaben (FBB)-PET on the diagnostic management of patients with suspected dementia that was still unclarified after [18F]-fluordeoxyglucose (FDG)-PET. METHODS: All subjects were referred in-house with a suspected dementia syndrome due to neurodegenerative disease. After undergoing an FDG-PET exam, the cases were discussed by the interdisciplinary dementia board, where the most likely diagnosis as well as potential differential diagnoses were documented. Because of persistent diagnostic uncertainty, the patients received an additional FBB-PET exam. Results were interpreted visually and classified as amyloid-positive or amyloid-negative, and we then compared the individual clinical diagnoses before and after additional FBB-PET. RESULTS: A total of 107 patients (mean age 69.4 ± 9.7y) were included in the study. The FBB-PET was rated as amyloid-positive in 65/107. In 83% of the formerly unclear cases, a final diagnosis was reached through FBB-PET, and the most likely prior diagnosis was changed in 28% of cases. The highest impact was observed for distinguishing Alzheimer's dementia (AD) from fronto-temporal dementia (FTLD), where FBB-PET altered the most likely diagnosis in 41% of cases. CONCLUSIONS: FBB-PET has a high additive value in establishing a final diagnosis in suspected dementia cases when prior investigations such as FDG-PET are inconclusive. The differentiation between AD and FTLD was particularly facilitated by amyloid-PET, predicting a considerable impact on patient management, especially in the light of upcoming disease-modifying therapies.

[18F]-THK5351 PET Correlates with Topology and Symptom Severity in Progressive Supranuclear Palsy.

Progressive supranuclear palsy (PSP) is a neurodegenerative movement disorder characterized by deposition of fibrillar aggregates of 4R tau-protein in neurons and glial cells of the brain. These deposits are a key neuropathological finding, allowing a diagnosis of "definite PSP," which is usually established post mortem. To date criteria for clinical diagnosis of PSP in vivo do not include biomarkers of tau pathology. For intervention trials, it is increasingly important to (i) establish biomarkers for an early diagnosis and (ii) to develop biomarkers that correlate with disease progression of PSP. [18F]-THK5351 is a novel PET-ligand that may afford in vivo visualization and quantification of tau-related alterations. We investigated binding characteristics of [18F]-THK5351 in patients with clinically diagnosed PSP and correlate tracer uptake with clinical findings. Eleven patients (68.4 ± 7.4 year; N = 6 female) with probable PSP according to current clinical criteria and nine healthy controls (71.7 ± 7.2 year; N = 4 female) underwent [18F]-THK5351 PET scanning. Voxel-wise statistical parametric comparison and volume-of-interest based quantification of standardized-uptake-values (SUV) were conducted using the cerebellar cortex as reference region. We correlated disease severity as measured with the help of the PSP Rating Scale (PSPRS) as well as several other clinical parameters with the individual PET findings. By voxel-wise mapping of [18F]-THK5351 uptake in the patient group we delineated typical distribution patterns that fit to known tau topology for PSP post mortem. Quantitative analysis indicated the strongest discrimination between PSP patients and healthy controls based on tracer uptake in the midbrain (+35%; p = 3.01E-7; Cohen's d: 4.0), followed by the globus pallidus, frontal cortex, and medulla oblongata. Midbrain [18F]-THK5351 uptake correlated well with clinical severity as measured by PSPRS (R = 0.66; p = 0.026). OCT and MRI delineated PSP patients from healthy controls by use of established discrimination thresholds but only OCT did as well correlate with clinical severity (R = 0.79; p = 0.024). Regional [18F]-THK5351 binding patterns correlated well with the established post mortem distribution of lesions in PSP and with clinical severity. The contribution of possible MAO-B binding to the [18F]-THK5351 signal needs to be further evaluated, but nevertheless [18F]-THK5351 PET may still serve as valuable biomarker for diagnosis of PSP.