Positron emission tomography imaging and clinical progression in relation to molecular pathology in the first Pittsburgh Compound B positron emission tomography patient with Alzheimer’s disease

The accumulation of β-amyloid in the brain is an early event in Alzheimer’s disease. This study presents the first patient with Alzheimer’s disease who underwent positron emission tomography imaging with the amyloid tracer, Pittsburgh Compound B to visualize fibrillar β-amyloid in the brain. Here we relate the clinical progression, amyloid and functional brain positron emission tomography imaging with molecular neuropathological alterations at autopsy to gain new insight into the relationship between β-amyloid accumulation, inflammatory processes and the cholinergic neurotransmitter system in Alzheimer’s disease brain. The patient underwent positron emission tomography studies with 18F-fluorodeoxyglucose three times (at ages 53, 56 and 58 years) and twice with Pittsburgh Compound B (at ages 56 and 58 years), prior to death at 61 years of age. The patient showed a pronounced decline in cerebral glucose metabolism and cognition during disease progression, while Pittsburgh Compound B retention remained high and stable at follow-up. Neuropathological examination of the brain at autopsy confirmed the clinical diagnosis of pure Alzheimer’s disease. A comprehensive neuropathological investigation was performed in nine brain regions to measure the regional distribution of β-amyloid, neurofibrillary tangles and the levels of binding of 3H-nicotine and 125I-α-bungarotoxin to neuronal nicotinic acetylcholine receptor subtypes, 3H-L-deprenyl to activated astrocytes and 3H-PK11195 to microglia, as well as butyrylcholinesterase activity. Regional in vivo 11C-Pittsburgh Compound B-positron emission tomography retention positively correlated with 3H-Pittsburgh Compound B binding, total insoluble β-amyloid, and β-amyloid plaque distribution, but not with the number of neurofibrillary tangles measured at autopsy. There was a negative correlation between regional fibrillar β-amyloid and levels of 3H-nicotine binding. In addition, a positive correlation was found between regional 11C-Pittsburgh Compound B positron emission tomography retention and 3H-Pittsburgh Compound B binding with the number of glial fibrillary acidic protein immunoreactive cells, but not with 3H-L-deprenyl and 3H-PK-11195 binding. In summary, high 11C-Pittsburgh Compound B positron emission tomography retention significantly correlates with both fibrillar β-amyloid and losses of neuronal nicotinic acetylcholine receptor subtypes at autopsy, suggesting a closer involvement of β-amyloid pathology with neuronal nicotinic acetylcholine receptor subtypes than with inflammatory processes

Functional brain activity in Alzheimer patients as studied by multi-tracer positron emission tomography : effects of treatment with cholinesterase inhibitors

Alzheimer’s disease (AD) is a progressive neurodegenerative disease accompanied by cognitive impairment and disturbances in several neurotransmitter systems, especially the cholinergic system. Studies have correlated the cognitive impairment observed in AD patients with a deficit in central cholinergic neurotransmission. The most successful therapeutic agents for symptomatic treatment of AD patients are cholinesterase inhibitors (ChEIs), e.g. donepezil, rivastigmine and galantamine, which are targeted towards enhancing cholinergic neurotransmission. One of the most valuable tools for evaluating cholinergic neurotransmission in AD patients is positron emission tomography (PET). PET with high spatial resolution, has successfully been used in the early diagnosis, differential diagnosis and evaluation of drug treatment in patients suffering from AD. The overall aim of this thesis was to utilize the multi-tracer PET technique to measure brain glucose metabolism, nicotinic acetylcholine receptor (nAChR) density, acetylcholinesterase (AChE) activity and amyloid load of patients with mild AD. These brain functional aspects were measured during the natural course of the disease or during treatment with ChEIs and/or anti-amyloid therapy in conjunction with assessment of changes in CSF biomarkers, ChE activity as well as with cognitive performance of the patients. In this thesis, it was demonstrated that cortical nAChRs as assessed by a dual tracer PET model with administration of 15O-water and (S)(-)11C-nicotine in mild AD patients (n = 27) are associated with the cognitive function of attention rather than with episodic memory. The effect of different ChEIs on cortical nAChRs was also evaluated in this thesis. Rivastigmine treated mild AD patients (n = 10) showed a significant increase of nAChRs in several cortical brain regions after 3 months compared with baseline, while the increase was not significant after 12 months of treatment. In a randomized double-blind placebo-controlled study, mild AD patients (n = 18) treated with galantamine demonstrated no change in cortical nAChRs after both short- (3 months) and long-term (12 months) treatment. However, it should be noted that individual subjects with higher plasma galantamine levels also demonstrated an increase in cortical nAChR binding. Additionally, patients treated with galantamine for 12 months demonstrated a 30–40% decrease in cortical AChE activity (as assessed by 11C-PMP-PET) and a 30-36% decrease in CSF AChEsynaptic activity. In addition to rivastigmine and galantamine, the effects of (-)-phenserine, a new ChEI, were evaluated in mild AD patients (n = 20) in a randomized double-blind placebo-controlled study. Phenserine is a tentative AD drug that demonstrates an additional mechanism of action as an inhibitor of the formation of beta-amyloid precursor protein (beta-APP). Mild AD patients treated with (-)-phenserine demonstrated an increase in cerebral glucose metabolism as evaluated by 18F-FDGPET after 3 months compared with baseline. We also observed that cortical amyloid load, measured by 11C-PIB-PET, was inversely correlated with CSF beta-amyloid (Abeta) levels, suggesting that (-)- phenserine treatment influenced both brain and CSF amyloid. After treatment with galantamine and (-)-phenserine we observed the highest level of improvement of cognitive performance up to 3 to 6 months, and maintenance of cognitive performance was observed after 12 months’ treatment, indicating stabilization of the disease. Attention was shown to be the main cognitive domain improved by the treatment. Positive correlations were also observed between the changes in number of cortical nicotinic receptors, AChE inhibition and changes in cognitive measures of attention. In conclusion, the present findings demonstrate that utilizing the multi-tracer PET method is important in the investigation of functional activity, neurotransmitters and pathology in the brains of patients with AD, in conjunction with measures of cognitive function, to evaluate the efficacy of the currently available ChEI treatments and future treatment strategies

Clinical impact of (18)F-FDG-PET among memory clinic patients with uncertain diagnosis.

PURPOSE: To assess the clinical impact and incremental diagnostic value of (18)F-fluorodeoxyglucose (FDG-PET) among memory clinic patients with uncertain diagnosis. METHODS: The study population consisted of 277 patients who, despite extensive baseline cognitive assessment, MRI, and CSF analyses, had an uncertain diagnosis of mild cognitive impairment (MCI) (n = 177) or dementia (n = 100). After baseline diagnosis, each patient underwent an FDG-PET, followed by a post-FDG-PET diagnosis formulation. We evaluated (i) the change in diagnosis (baseline vs. post-FDG-PET), (ii) the change in diagnostic accuracy when comparing each baseline and post-FDG-PET diagnosis to a long-term follow-up (3.6 ± 1.8 years) diagnosis used as reference, and (iii) comparative FDG-PET performance testing in MCI and dementia conditions. RESULTS: FDG-PET led to a change in diagnosis in 86 of 277 (31%) patients, in particular in 57 of 177 (32%) MCI and in 29 of 100 (29%) dementia patients. Diagnostic change was greater than two-fold in the sub-sample of cases with dementia "of unclear etiology" (change in diagnosis in 20 of 32 (63%) patients). In the dementia group, after results of FDG-PET, diagnostic accuracy improved from 77 to 90% in Alzheimer's disease (AD) and from 85 to 94% in frontotemporal lobar degeneration (FTLD) patients (p 5 and < 5, respectively). CONCLUSION: Within a selected clinical population, FDG-PET has a significant clinical impact, both in early and differential diagnosis of uncertain dementia. FDG-PET provides significant incremental value to detect AD and FTLD over a clinical diagnosis of uncertain dementia

Age, Frailty, and Comorbidity as Prognostic Factors for Short-Term Outcomes in Patients With Coronavirus Disease 2019 in Geriatric Care

Objectives: To analyze whether frailty and comorbidities are associated with in-hospital mortality and discharge to home in older adults hospitalized for coronavirus disease 2019 (COVID-19). Design: Single-center observational study. Setting and Participants: Patients admitted to geriatric care in a large hospital in Sweden between March 1 and June 11, 2020; 250 were treated for COVID-19 and 717 for other diagnoses. Methods: COVID-19 diagnosis was clinically confirmed by positive reverse transcription polymerase chain reaction test or, if negative, by other methods. Patient data were extracted from electronic medical records, which included Clinical Frailty Scale (CFS), and were further used for assessments of the Hospital Frailty Risk Score (HFRS) and the Charlson Comorbidity Index (CCI). In-hospital mortality and home discharge were followed up for up to 25 and 28 days, respectively. Multivariate Cox regression models adjusted for age and sex were used. Results: Among the patients with COVID-19, in-hospital mortality rate was 24% and home discharge rate was 44%. Higher age was associated with in-hospital mortality (hazard ratio [HR] 1.05 per each year, 95% confidence interval [CI] 1.01.1.08) and lower probability of home discharge (HR 0.97, 95% CI 0.95.0.99). CFS (&gt;5) and CCI, but not HFRS, were predictive of in-hospital mortality (HR 1.93, 95% CI 1.02.3.65 and HR 1.27, 95% CI 1.02.1.58, respectively). Patients with CFS &gt;5 had a lower probability of being discharged home (HR 0.38, 95% CI 0.25.0.58). CCI and HFRS were not associated with home discharge. In general, effects were more pronounced in men. Acute kidney injury was associated with in-hospital mortality and hypertension with discharge to home. Other comorbidities (diabetes, cardiovascular disease, lung diseases, chronic kidney disease and dementia) were not associated with either outcome. Conclusions and Implications: Of all geriatric patients with COVID-19, 3 out of 4 survived during the study period. Our results indicate that in addition to age, the level of frailty is a useful predictor of short-term COVID-19 outcomes in geriatric patients. (C) 2020 AMDA - The Society for Post-Acute and Long-Term Care Medicine

Targeted delivery of nerve growth factor to the cholinergic basal forebrain of Alzheimer's disease patients : application of a second-generation encapsulated cell biodelivery device

Background: Targeted delivery of nerve growth factor (NGF) has emerged as a potential therapy for Alzheimer's disease (AD) due to its regenerative effects on basal forebrain cholinergic neurons. This hypothesis has been tested in patients with AD using encapsulated cell biodelivery of NGF (NGF-ECB) in a first-in-human study. We report our results from a third-dose cohort of patients receiving second-generation NGF-ECB implants with improved NGF secretion. Methods: Four patients with mild to moderate AD were recruited to participate in an open-label, phase Ib dose escalation study with a 6-month duration. Each patient underwent stereotactic implant surgery with four NGF-ECB implants targeted at the cholinergic basal forebrain. The NGF secretion of the second-generation implants was improved by using the Sleeping Beauty transposon gene expression technology and an improved three-dimensional internal scaffolding, resulting in production of about 10 ng NGF/device/day. Results: All patients underwent successful implant procedures without complications, and all patients completed the study, including implant removal after 6 months. Upon removal, 13 of 16 implants released NGF, 8 implants released NGF at the same rate or higher than before the implant procedure, and 3 implants failed to release detectable amounts of NGF. Of 16 adverse events, none was NGF-, or implant-related. Changes from baseline values of cholinergic markers in cerebrospinal fluid (CSF) correlated with cortical nicotinic receptor expression and Mini Mental State Examination score. Levels of neurofilament light chain (NFL) protein increased in CSF after NGF-ECB implant, while glial fibrillary acidic protein (GFAP) remained stable. Conclusions: The data derived from this patient cohort demonstrate the safety and tolerability of sustained NGF release by a second-generation NGF-ECB implant to the basal forebrain, with uneventful surgical implant and removal of NGF-ECB implants in a new dosing cohort of four patients with AD