At-Home Administration of Gantenerumab by Care Partners to People with Early Alzheimer's Disease: Feasibility, Safety and Pharmacodynamic Impact.

BACKGROUND: Monoclonal antibodies that target amyloid-beta and remove amyloid plaques can slow cognitive and functional decline in early Alzheimer's disease. Gantenerumab is a subcutaneously administered fully-human anti-amyloid-beta monoclonal antibody with highest affinity for aggregated amyloid-beta. Since the phase 3 GRADUATE trials did not meet the primary endpoint (change from baseline to Week 116 in Clinical Dementia Rating scale - Sum of Boxes), development of gantenerumab in sporadic Alzheimer's disease was stopped and all ongoing trials were terminated early due to sponsor decision. Subcutaneous administration at the clinic or at home by care partner would be an important option for other therapies in this class in order to increase flexibility and reduce overall burden. The insights obtained from the experience with gantenerumab home administration by care partner in the phase 2 GRADUATION trial will serve to guide the ongoing efforts with other anti-amyloid-beta antibodies. OBJECTIVES: To evaluate the pharmacodynamic effects on brain amyloid load of once weekly subcutaneous administration of gantenerumab and the safety and feasibility of home administration by care partners. DESIGN: Phase 2, open-label, single arm study. SETTING: Multicenter trial conducted in 33 sites in 8 countries from November 2020 to March 2023. PARTICIPANTS: Participants aged 50 to 90 with early symptomatic Alzheimer's disease (mild cognitive impairment/mild dementia due to Alzheimer's disease), and evidence of amyloid positron emission tomography positivity. INTERVENTION: Participants could receive up to 255 mg gantenerumab once-weekly, administered subcutaneously at site or at home by healthcare professionals or non-healthcare-professional care partners. MEASUREMENTS: The primary endpoint was the change from baseline to Week 52 and to Week 104 in brain amyloid load as measured by PET centiloid levels. The secondary endpoints were responses to the home administration questionnaire, plasma concentrations and safety. RESULTS: The overall number of participants enrolled was 192, with a mean (standard deviation) amyloid PET load at baseline of 101.80 (29.80) centiloids. At the time of early study termination by sponsor, 149 participants had valid Week 52 amyloid PET data (primary endpoint), and 12 participants had an early termination PET within the pre-defined time range of Week 104. The mean change in amyloid PET from baseline to Week 52 and Week 104 was -26.19 centiloids (range: -75.6-15.8; n=149) and -35.48 centiloids (range: -63.2--7.0; n=12), respectively. Responses to the home administration questionnaire at Week 52 (n=148) indicated that the majority of care partners (88-97%) considered administration of study drug at home easy (30.4%) or very easy (57.4%), and convenient (25.7%) or very convenient (70.9%). Care partners felt confident (31.1%) or very confident (62.2%) and satisfied (29.7%) or very satisfied (64.9%) with giving the injection at home. Responses by care partners at Week 36 (n=72), Week 76 (n=126) and Week 104 (n=29) and participant (patient) assessment of convenience and satisfaction at these time points were similar. There were no new safety findings associated with gantenerumab administered subcutaneously once weekly at 255 mg or safety issues associated with at-home injections by non-healthcare professional care partners. CONCLUSIONS: Once-weekly subcutaneous home administration of the anti-amyloid-beta antibody gantenerumab by non-healthcare-professional care partners to participants with early Alzheimer's disease was feasible, safe, well tolerated, and considered as a convenient option by both the care partners and participants with Alzheimer's disease. Although gantenerumab's development has been stopped due to lack of efficacy, this approach has the potential to reduce the frequency of hospital/outpatient clinic visits required for treatment with other anti-amyloid-ß antibodies and can increase flexibility of drug administration for people living with Alzheimer's disease and their families.

Elecsys Cerebrospinal Fluid Assays Accurately Distinguish Alzheimer's Disease from Frontotemporal Lobar Degeneration.

BACKGROUND: Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) are heterogeneous in their clinical presentation and underlying pathology, but they often have overlapping features. Diagnostic accuracy is critical for guiding patient management. Cerebrospinal fluid (CSF) diagnostic assays for the differentiation of AD and FTLD may increase diagnostic accuracy. OBJECTIVES: In this study, we aimed to understand the potential role of CSF biomarkers and biomarker ratios, measured using Elecsys® CSF immunoassays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland), in the differential diagnosis of AD and FTLD. DESIGN: This study was conducted at a single center in Munich, Germany between July 2019 and July 2020. Patient CSF samples were retrospectively collected from the study center biobank. PARTICIPANTS: A total of 130 patients with cognitive impairment were included in the study; 86 patients were diagnosed with AD and 44 with FTLD (behavioral variant frontotemporal dementia, semantic variant of primary progressive aphasia, and non-fluent variant of primary progressive aphasia), based on core clinical criteria and a non-CSF biomarker, a typical pattern of regional hypometabolism on [18F] fluorodeoxyglucose positron emission tomography. MEASUREMENTS: Patient CSF biomarker concentrations were measured using Elecsys CSF immunoassays. Receiver operating characteristic analyses were conducted to determine areas under the curve (AUCs) for CSF biomarker performance. Sensitivity and specificity analyses were conducted to evaluate the performance of established cut-offs (Aß42 ≤1000 pg/mL, pTau181/Aß42 ratio >0.024, and tTau/Aß42 ratio >0.28) and optimized cut-offs based on Youden's index. RESULTS: AUC-based performance was similarly good for the pTau181/Aß42 ratio (AUC=0.841; 95% CI: 0.759-0.923), pTau181/Aß40 ratio (AUC=0.837; 95% CI: 0.754-0.919), Aß42/Aß40 ratio (AUC=0.829; 95% CI: 0.746-0.912), tTau/Aß42 ratio (AUC=0.822; 95% CI: 0.736-0.908), pTau181/Aß42/Aß40 ratio (AUC=0.817; 95% CI: 0.734-0.901), and Aß42 (AUC=0.812; 95% CI: 0.722-0.902). Performance was slightly lower for the tTau/Aß42/Aß40 ratio (AUC=0.799; 95% CI: 0.713-0.885), pTau181 alone (AUC=0.793; 95% CI: 0.707-0.880), tTau/Aß40 ratio (AUC=0.751; 95% CI: 0.657-0.844), and tTau alone (AUC=0.706; 95% CI: 0.613-0.799). The highest qualitative performance was observed with the pTau181/Aß42 ratio with an established cut-off value of >0.024 and optimized cut-off value of >0.022: sensitivity and specificity values were 0.892 and 0.773, respectively. CONCLUSIONS: Elecsys CSF immunoassays demonstrate good diagnostic accuracy in differentiating patients with AD from those with FTLD. These immunoassays have the potential to support clinical decision making, i.e. in diagnosing patients with FTLD by excluding patients with amyloid positivity, which is indicative of underlying AD.

Behavioral variant frontotemporal dementia: advanced disease stages and death. A step to palliative care.

OBJECTIVE: The aim of the present study was to gain insight into the living and care situation in advanced behavioral variant frontotemporal dementia (bvFTD), to describe symptoms and findings in advanced bvFTD, and to evaluate somatic comorbidities and circumstances of death. METHODS: Standardized interviews were conducted with family caregivers of 83 patients with bvFTD. Forty-four percent of the patients were already deceased at the time of the interview. RESULTS: At the time of the interview or death, respectively, 47% of the patients lived in a nursing home. The median time between symptom onset and nursing home admission was 5.0 ± 5.5 years. In moderate and severe dementia stages almost all patients suffered from severe disabilities including impairment of language, gait, swallowing, and of the ability to care for themselves. Sixteen percent of the patients had got enteral tube feeding. Comorbid somatic diseases were diagnosed in 46% of the patients. Twenty-three percent of the deceased patients had been admitted into a hospital before death. Cardiovascular disease and respiratory disease, mostly pneumonia, were the most frequent causes of death. CONCLUSIONS: Advanced bvFTD is characterized by severe cognitive impairment and physical disabilities. BvFTD leads to a premature death. Our findings stress the importance of strategies that maximize patient comfort in advanced disease stages and allow for a peaceful death. Copyright © 2016 John Wiley & Sons, Ltd.

Impact of beta-amyloid-specific florbetaben PET imaging on confidence in early diagnosis of Alzheimer's disease.

BACKGROUND: Early diagnosis of Alzheimer's disease (AD) may be corroborated by imaging of beta-amyloid plaques using positron emission tomography (PET). Here, we performed an add-on questionnaire study to evaluate the relevance of florbetaben imaging (BAY 949172) in diagnosis and consecutive management of probable AD patients. METHODS: AD patients with a clinical diagnosis in accordance with the NINCDS-ADRDA criteria or controls were imaged using florbetaben. Referring physicians were asked on a voluntary basis about their confidence in initial diagnosis, significance of PET imaging results, and their anticipated consequences for future patient care. RESULTS: 121 questionnaires for probable AD patients and 80 questionnaires for controls were evaluated. In 18% of patients who had initially received the diagnosis of probable AD, PET scans were rated negative, whereas in controls 18% of scans were positive. An increase in confidence in the initial diagnosis was frequently reported (80%). Imaging results had a significant impact on the intended patient care, as judged by the referring physicians; this was most prominent in those patients with a contradicting scan and/or a low confidence in the initial diagnosis. CONCLUSION: Florbetaben amyloid imaging increases the overall confidence in diagnosis of AD and may frequently influence clinical decisions and patient management.

CSF soluble amyloid precursor proteins in the diagnosis of incipient Alzheimer disease.

OBJECTIVE: To explore if soluble amyloid precursor proteins (sAPP) in CSF improve the identification of patients with incipient Alzheimer disease (AD) in a group of patients with mild cognitive impairment (MCI). METHODS: A cohort study with follow-up assessments of 58 patients with MCI with baseline CSF sampling was conducted: 21 patients had progressed to probable AD (MCI-AD), 27 still had MCI, 8 had reverted to normal (MCI-NAD), and 2 patients with frontotemporal dementia (FTD) were excluded. Sixteen additional patients with FTD were included to explore the specificity of the CSF markers. CSF concentrations of sAPPα, sAPPß, tau, and Aß(1-42) were measured with sensitive and specific ELISAs. Associations between diagnostic status, CSF protein concentrations, and other patient characteristics were explored using multiple logistic regression analyses with stepwise variable selection. The optimal sensitivity and specificity of the best models were derived from receiver operating characteristic curves. RESULTS: The MCI-AD group had significantly higher sAPPß concentrations than the MCI-NAD and the FTD groups. A combination of sAPPß, tau, and age differentiated the MCI-AD and the MCI-NAD groups with a sensitivity of 80.00% and a specificity of 81.00%. The best model for the differentiation of the MCI-AD and the FTD groups included sAPPß and tau, and showed a sensitivity of 95.20% and a specificity of 81.20%. Aß(1-42) and sAPPα did not significantly contribute to the models. CONCLUSION: These findings suggest that sAPPß may be clinically useful, and superior to Aß(1-42), in the early and differential diagnosis of incipient AD.

[Visualization of amyloid with positron emission tomography. Useful improvement in the diagnosis of dementia?]. / Amyloiddarstellung mittels Positronenemissionstomographie. Ein nützlicher Fortschritt in der Demenzdiagnostik?

Imaging techniques for in vivo visualization of cerebral amyloid using positron emission tomography (PET) have been tested in clinical trails over the past 5 years. Based on a selected overview of the literature including our own studies the various radiopharmaceuticals are presented and the current status of research on the validity of amyloid PET imaging as well as its suitability for early and differential diagnosis of Alzheimer's disease (AD) are described. The findings available up to now support the validity of amyloid PET imaging and suggest a possible benefit in differential diagnosis. However, there are as yet no studies with large sample sizes. The possible use for the early diagnosis of AD should be viewed critically, particularly due to the lack of treatment options.

Effect of APOE genotype on amyloid plaque load and gray matter volume in Alzheimer disease.

OBJECTIVE: To examine the influence of the APOE genotype on levels of beta-amyloid (Abeta) plaque load and atrophy in patients with Alzheimer disease (AD) in vivo. METHODS: Thirty-two patients with moderate AD were divided into carriers and noncarriers of the epsilon4 allele. These groups were matched for age, disease duration, education, and cognitive impairment. In all subjects, [11C]PIB-PET was performed for measurement of cerebral Abeta plaque deposition and cranial MRI for the assessment of gray matter volume by voxel-based morphometry (VBM) and for correction of partial volume effects (PVE) in the PET data. Voxel-based comparisons (SPM5) were performed between patient groups and healthy control populations and completed with multiple regression analyses between imaging data and epsilon4 allele frequency. RESULTS: Compared to controls, AD-typical patterns of [11C]PIB retention and atrophy were detected in both epsilon4-positive and epsilon4-negative patient groups. In direct comparison, significantly stronger and more extended [11C]PIB uptake was found in epsilon4-positive patients in bilateral temporoparietal and frontal cortex, surviving PVE correction. VBM analysis demonstrated comparable levels of atrophy in both patient groups. Regression analyses revealed a linear association between higher epsilon4 allele frequency and stronger temporoparietal Abeta plaque deposition, independently of other confounds. No major correlation between epsilon4 allele frequency and gray matter decrease was observed. CONCLUSION: These results indicate that the epsilon4-positive APOE genotype not only represents a risk factor for Alzheimer disease (AD), but also results in higher levels of Abeta plaque deposition in epsilon4-positive patients with AD compared to age-matched epsilon4-negative patients with similar levels of cognitive impairment and brain atrophy. The potential role of Abeta plaque imaging for patient inclusion and follow-up in anti-amyloid therapy trials is strengthened by these findings.

[Current immune therapy for Alzheimer's disease]. / Aktueller Stand der Immuntherapie bei Alzheimer-Krankheit.

New treatment strategies have developed since publication in 1991 of the amyloid hypothesis on the pathogenesis of Alzheimer's disease. In contrast to previous methods, these strategies are not for countering the effects of neuronal loss at the transmitter level. Instead, they are meant to influence the neurodegenerative process itself. They incorporate amyloid precursor protein-splitting proteases (secretase inhibitors), substances for reducing the aggregation of beta-amyloid 42 (Abeta42) and stimulating specific immune reactions against it. Particularly Abeta42 and the clinical research are examined. Ethical and economic questions resulting from successful immunization against Abeta are discussed.

Decline of cerebral glucose metabolism in frontotemporal dementia: a longitudinal 18F-FDG-PET-study.

OBJECTIVE: To identify the pattern of progression of decline of cerebral glucose metabolism in frontotemporal dementia (FTD, frontal variant). METHODS: 22 patients with mild FTD underwent 18F-FDG-positron emission tomography at baseline and at follow-up in average 19.5 months later. Patient scans were compared with scans from 15 healthy age-matched control subjects on a voxel-by-voxel basis using SPM-99. RESULTS: As compared with healthy control subjects at baseline patients with FTD showed a significant symmetrical hypometabolism of the frontal lobes sparing the motor cortex, of the caudate nuclei, insula and thalamus bilaterally. At follow-up further significant reductions in glucose metabolism were observed in the parietal and temporal cortices. CONCLUSIONS: In early stages of FTD the neurodegenerative process is limited to the frontal lobes. During the progression of the disease, the pathological changes pass over the lobar borders and spread into the parietal and temporal cortices.

Longitudinal changes of cerebral glucose metabolism in semantic dementia.

BACKGROUND: Semantic dementia (SD). OBJECTIVE: To identify the pattern of decline of cerebral glucose metabolism in SD using cerebral (18)F-fluoro-2-desoxy-D-glucose positron emission tomography scanning ((18)F-FDG-PET). METHODS: Eight patients with SD underwent (18)F-FDG-PET at baseline and at re-examination in average 15 months later. RESULTS: Compared with healthy control subjects, patients with SD showed a significant asymmetrical (left > right) hypometabolism of the temporal lobes, particularly of the anterior poles, at baseline. At follow-up, we observed a deterioration of cognitive abilities. However, in addition to the temporal lobes no other cortical or subcortical region showed a significant reduction of glucose metabolism except the anterior cingulate cortex (pcorr < 0.05). CONCLUSION: Subtle functional changes suffice to produce significant neuropsycho- logical deterioration.

[Validation of a Short Telephone Test (T3MS) for the Diagnosis of Cognitive Impairment]. / Validierung eines kurzen telefonischen Tests (T3MS) für die Erkennung kognitiver Störungen.

The identification of cognitive impairment in general practice requires short but accurate tests. For epidemiologic surveys and genetic family studies cognitive tests are desirable which can be administered over the telephone. We assessed the ability of a telephone version of the Modified Mini Mental State Examination (T3MS) to identify mild cognitive impairment (MCI) and mild dementia in Alzheimer's disease (AD) and compared it with the diagnostic accuracy of the conventional Mini Mental State Examination (MMSE). The study refers to 34 patients of the outpatient clinic for cognitive disorders of the technical university of Munich of whom 18 had MCI and 16 had mild dementia in AD, respectively. The study also included 14 cognitively unimpaired age-matched probands. The T3MS and MMST were validated against an expert diagnosis base on a comprehensive diagnostic workup. Statistical analysis was performed using the receiver-operator-characteristics (ROC) method. The T3MS outperformed the MMST in the distinction between MCI patients and cognitively unimpaired individuals. In the separation between cognitively unimpaired probands and patients with mild AD the T3MS achieved a sensitivity and specificity of 100 %. The T3MS is a short and practical but accurate telephone test for the identification of mild dementia in AD for use in epidemiological surveys and genetic family studies. The interview achieves higher diagnostic precision than the MMSE and contributes to a valid assessment of cognitive performance. For the identification of mild cognitive impairment, however, the T3MS was less appropriate.

Progression to dementia in clinical subtypes of mild cognitive impairment.

OBJECTIVE: To examine the outcome among patients diagnosed with different types of mild cognitive impairment (MCI). PATIENTS: A follow-up examination (average follow-up period: 3.49 +/- 2.2 years) was performed in 81 cognitively impaired, non-demented patients aged >55 years at baseline. RESULTS: 8 of 32 patients with amnestic MCI (25%), 22 of 41 patients with multiple-domain MCI (54%), and 3 of 8 patients with single non-memory MCI (37.5%) progressed to dementia. The clinical type of MCI is significantly associated with the likelihood of conversion to dementia. DISCUSSION: When the clinical syndrome of MCI evolves on a neurodegenerative basis, the multiple-domain type of MCI has a less favorable prognosis than the amnestic type and may represent a more advanced prodromal stage of dementia.

Schooling mediates brain reserve in Alzheimer's disease: findings of fluoro-deoxy-glucose-positron emission tomography.

BACKGROUND: Functional imaging studies report that higher education is associated with more severe pathology in patients with Alzheimer's disease, controlling for disease severity. Therefore, schooling seems to provide brain reserve against neurodegeneration. OBJECTIVE: To provide further evidence for brain reserve in a large sample, using a sensitive technique for the indirect assessment of brain abnormality (18F-fluoro-deoxy-glucose-positron emission tomography (FDG-PET)), a comprehensive measure of global cognitive impairment to control for disease severity (total score of the Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Battery) and an approach unbiased by predefined regions of interest for the statistical analysis (statistical parametric mapping (SPM)). METHODS: 93 patients with mild Alzheimer's disease and 16 healthy controls underwent 18F-FDG-PET imaging of the brain. A linear regression analysis with education as independent and glucose utilisation as dependent variables, adjusted for global cognitive status and demographic variables, was conducted in SPM2. RESULTS: The regression analysis showed a marked inverse association between years of schooling and glucose metabolism in the posterior temporo-occipital association cortex and the precuneus in the left hemisphere. CONCLUSIONS: In line with previous reports, the findings suggest that education is associated with brain reserve and that people with higher education can cope with brain damage for a longer time.

Frontotemporal dementia, semantic dementia, and Alzheimer's disease: the contribution of standard neuropsychological tests to differential diagnosis.

CERAD-NAB (Consortium to Establish a Registry for Alzheimer's Disease-Neuropsychological Assessment Battery) data were compared between 51 patients with frontotemporal dementia, 13 with semantic dementia, and 69 with Alzheimer's disease. There were statistically significant differences between the 3 groups. Compared with patients with Alzheimer's disease, patients with frontotemporal dementia were more impaired on Animal Fluency but not on any other CERAD-NAB subtest. Patients with semantic dementia performed worse in Animal Fluency and Boston Naming Test compared with frontotemporal dementia and Alzheimer's disease. Multiple logistic regression analysis revealed that in the differentiation between frontotemporal dementia and Alzheimer's disease, the combination of Animal Fluency and Boston Naming Test correctly classified 90.5% of patients. In segregating semantic dementia and Alzheimer's disease, the combination of Boston Naming Test and Mini Mental State Examination resulted in a correct classification of 96.3%. These findings demonstrate that the Mini Mental State Examination and the language subtests of the CERAD-NAB are valuable clinical instruments for the differential diagnosis between early frontotemporal dementia, semantic dementia, and Alzheimer's disease.

Cerebral glucose metabolism in patients with AD and different APOE genotypes.

OBJECTIVE: To examine the influence of the APOE epsilon4 allele on cerebral glucose metabolism in a large series of patients with Alzheimer disease (AD). METHODS: Eighty-three patients (41 APOE epsilon4 positive and 42 epsilon4 negative) were selected from a pre-existing databank of patients with AD (n > 1,000). The patients were carefully matched for age, age at onset, approximate disease duration, educational level, and overall degree of cognitive impairment. Cerebral [18F]fluorodeoxyglucose PET imaging was performed in all patients by a standardized protocol. Statistical comparison of patient PET data vs a healthy control population was performed as well as an analysis of differences between groups (SPM99; Wellcome Department of Cognitive Imaging, London, UK). RESULTS: A similar pattern of cerebral hypometabolism was detected in the epsilon4-positive and -negative patient groups vs healthy volunteers in regions typically affected by AD (bilateral temporal, parietal, posterior cingulate, and prefrontal cortical areas). The comparison between epsilon4-positive and -negative patients additionally revealed stronger abnormalities in epsilon4 carriers in parietal, temporal, and posterior cingulate cortical regions. CONCLUSIONS: A generally similar pattern of cerebral hypometabolism was detected in APOE epsilon4-positive and -negative patients with Alzheimer disease. However, in direct comparison of the two matched groups, the abnormalities in the epsilon4-positive group were demonstrated to be more pronounced.

Cerebral metabolic patterns at early stages of frontotemporal dementia and semantic dementia. A PET study.

OBJECTIVE: To determine the patterns of cerebral glucose metabolism in frontotemporal dementia (FTD) and semantic dementia (SD). METHODS: 25 patients with mild FTD and 9 patients with mild SD as well as 15 healthy age-matched control subjects underwent 18F-FDG- positron emission tomography. Patient scans were compared with control scans using SPM-99. RESULTS: As compared with healthy control subjects patients with FTD showed an extensive symmetrical hypometabolism of the frontal lobes (height threshold P <0.01) which spared the motor cortex. Patients with SD showed a hypometabolism in the whole left temporal lobe and in the right temporal pole. CONCLUSIONS: In the clinical syndromes of FTD and SD two distinct patterns of cerebral metabolism were identified. FTD was associated with frontal hypometabolism, whereas in SD cerebral glucose metabolism was exclusively reduced in the temporal lobes. Our findings are consistent with the notion that FTD and SD begin as strictly lobar neuronal degenerations and that a spread of pathological changes is not seen until more advanced stages.

Region-specific decline of cerebral glucose metabolism in patients with frontotemporal dementia: a prospective 18F-FDG-PET study.

OBJECTIVE: The aim of this study was to examine the pattern of glucose uptake and the changes over time of metabolic deficits in patients with frontotemporal dementia (FTD). METHODS: 10 patients who had received the clinical diagnosis of FTD underwent positron emission tomography scanning at the time of their first examination (baseline) and at follow-up (after 17.1 +/- 6.0 months). For statistical analysis, we used the SPM 99 software. First, we compared the data of the patients at baseline with an age-matched healthy control group. Second, we compared glucose uptake at follow-up with baseline measurements. RESULTS: Compared with normal controls, FTD patients showed significant metabolic deficits primarily in frontal cortical areas, but also in the caudate nuclei and the thalami. At follow-up, a significant progression of metabolic deficit was exclusively observed in the orbitofrontal parts of the frontal lobe and in the subcortical structures. DISCUSSION: These findings demonstrate that the clinical progression in patients with FTD is accompanied by a region-specific decline in cerebral glucose metabolism.