Progranulin AAV gene therapy for frontotemporal dementia: translational studies and phase 1/2 trial interim results.

GRN mutations cause progranulin haploinsufficiency, which eventually leads to frontotemporal dementia (FTD-GRN). PR006 is an investigational gene therapy delivering the granulin gene (GRN) using an adeno-associated virus serotype 9 (AAV9) vector. In non-clinical studies, PR006 transduced neurons derived from induced pluripotent stem cells of patients with FTD-GRN, resulted in progranulin expression and improvement of lipofuscin, lysosomal and neuroinflammation pathologies in Grn-knockout mice, and was well tolerated except for minimal, asymptomatic dorsal root ganglionopathy in non-human primates. We initiated a first-in-human phase 1/2 open-label trial. Here we report results of a pre-specified interim analysis triggered with the last treated patient of the low-dose cohort (n = 6) reaching the 12-month follow-up timepoint. We also include preliminary data from the mid-dose cohort (n = 7). Primary endpoints were safety, immunogenicity and change in progranulin levels in cerebrospinal fluid (CSF) and blood. Secondary endpoints were Clinical Dementia Rating (CDR) plus National Alzheimer's Disease Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD) rating scale and levels of neurofilament light chain (NfL). One-time administration of PR006 into the cisterna magna was generally safe and well tolerated. All patients developed treatment-emergent anti-AAV9 antibodies in the CSF, but none developed anti-progranulin antibodies. CSF pleocytosis was the most common PR006-related adverse event. Twelve serious adverse events occurred, mostly unrelated to PR006. Deep vein thrombosis developed in three patients. There was one death (unrelated) occurring 18 months after treatment. CSF progranulin increased after PR006 treatment in all patients; blood progranulin increased in most patients but only transiently. NfL levels transiently increased after PR006 treatment, likely reflecting dorsal root ganglia toxicity. Progression rates, based on the CDR scale, were within the broad ranges reported for patients with FTD. These data provide preliminary insights into the safety and bioactivity of PR006. Longer follow-up and additional studies are needed to confirm the safety and potential efficacy of PR006. ClinicalTrials.gov identifier: NCT04408625 .

Cognitive and neuroimaging features and brain ß-amyloidosis in individuals at risk of Alzheimer's disease (INSIGHT-preAD): a longitudinal observational study.

BACKGROUND: Improved understanding is needed of risk factors and markers of disease progression in preclinical Alzheimer's disease. We assessed associations between brain ß-amyloidosis and various cognitive and neuroimaging parameters with progression of cognitive decline in individuals with preclinical Alzheimer's disease. METHODS: The INSIGHT-preAD is an ongoing single-centre observational study at the Salpêtrière Hospital, Paris, France. Eligible participants were age 70-85 years with subjective memory complaints but unimpaired cognition and memory (Mini-Mental State Examination [MMSE] score ≥27, Clinical Dementia Rating score 0, and Free and Cued Selective Reminding Test [FCSRT] total recall score ≥41). We stratified participants by brain amyloid ß deposition on 18F-florbetapir PET (positive or negative) at baseline. All patients underwent baseline assessments of demographic, cognitive, and psychobehavioural, characteristics, APOE ε4 allele carrier status, brain structure and function on MRI, brain glucose-metabolism on 18F-fluorodeoxyglucose (18F-FDG) PET, and event-related potentials on electroencephalograms (EEGs). Actigraphy and CSF investigations were optional. Participants were followed up with clinical, cognitive, and psychobehavioural assessments every 6 months, neuropsychological assessments, EEG, and actigraphy every 12 months, and MRI, and 18F-FDG and 18F-florbetapir PET every 24 months. We assessed associations of amyloid ß deposition status with test outcomes at baseline and 24 months, and with clinical status at 30 months. Progression to prodromal Alzheimer's disease was defined as an amnestic syndrome of the hippocampal type. FINDINGS: From May 25, 2013, to Jan 20, 2015, we enrolled 318 participants with a mean age of 76·0 years (SD 3·5). The mean baseline MMSE score was 28·67 (SD 0·96), and the mean level of education was high (score >6 [SD 2] on a scale of 1-8, where 1=infant school and 8=higher education). 88 (28%) of 318 participants showed amyloid ß deposition and the remainder did not. The amyloid ß subgroups did not differ for any psychobehavioural, cognitive, actigraphy, and structural and functional neuroimaging results after adjustment for age, sex, and level of education More participants positive for amyloid ß deposition had the APOE ε4 allele (33 [38%] vs 29 [13%], p<0·0001). Amyloid ß1-42 concentration in CSF significantly correlated with mean 18F-florbetapir uptake at baseline (r=-0·62, p<0·0001) and the ratio of amyloid ß1-42 to amyloid ß1-40 (r=-0·61, p<0·0001), and identified amyloid ß deposition status with high accuracy (mean area under the curve values 0·89, 95% CI 0·80-0·98 and 0·84, 0·72-0·96, respectively). No difference was seen in MMSE (28·3 [SD 2·0] vs 28·9 [1·2], p=0·16) and Clinical Dementia Rating scores (0·06 [0·2] vs 0·05 [0·3]; p=0·79) at 30 months (n=274) between participants positive or negative for amyloid ß. Four participants (all positive for amyloid ß deposition at baseline) progressed to prodromal Alzheimer's disease. They were older than other participants positive for amyloid ß deposition at baseline (mean 80·2 years [SD 4·1] vs 76·8 years [SD 3·4]) and had greater 18F-florbetapir uptake at baseline (mean standard uptake value ratio 1·46 [SD 0·16] vs 1·02 [SD 0·20]), and more were carriers of the APOE ε4 allele (three [75%] of four vs 33 [39%] of 83). They also had mild executive dysfunction at baseline (mean FCSRT free recall score 21·25 [SD 2·75] vs 29·08 [5·44] and Frontal Assessment Battery total score 13·25 [1·50] vs 16·05 [1·68]). INTERPRETATION: Brain ß-amyloidosis alone did not predict progression to prodromal Alzheimer's disease within 30 months. Longer follow-up is needed to establish whether this finding remains consistent. FUNDING: Institut Hospitalo-Universitaire and Institut du Cerveau et de la Moelle Epinière (IHU-A-ICM), Ministry of Research, Fondation Plan Alzheimer, Pfizer, and Avid.

A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer's disease.

There is increasing evidence that subjective cognitive decline (SCD) in individuals with unimpaired performance on cognitive tests may represent the first symptomatic manifestation of Alzheimer's disease (AD). The research on SCD in early AD, however, is limited by the absence of common standards. The working group of the Subjective Cognitive Decline Initiative (SCD-I) addressed this deficiency by reaching consensus on terminology and on a conceptual framework for research on SCD in AD. In this publication, research criteria for SCD in pre-mild cognitive impairment (MCI) are presented. In addition, a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings. Finally, a set of features is presented, which in accordance with current knowledge, increases the likelihood of the presence of preclinical AD in individuals with SCD. This list is referred to as SCD plus.

Distinct brain perfusion pattern associated with CSF biomarkers profile in primary progressive aphasia.

OBJECTIVE: A new classification of primary progressive aphasia (PPA) was recently proposed to differentiate between non-fluent aphasia (NF-PPA), semantic variant of PPA (S-PPA) and logopenic aphasia (LPA) by their phenotypic presentations. CSF biomarkers (BM) may differentiate PPA with atypical Alzheimer's disease (AD) that presents with LPA from PPA with frontotemporal lobe degeneration that presents with either NF-PPA or S-PPA. Single photon emission computed tomography (SPECT) was used to investigate brain hypoperfusion differences among PPA subtypes according to their CSF AD profiles. METHODS: 34 PPA patients underwent lumbar puncture and brain perfusion SPECT. PPA patients were classified into two subgroups according to the Aß(42):tau ratio: PPA BM positive (with an AD CSF profile) and PPA BM negative (not having an AD CSF profile). The biological classification was made while blind to the phenotypical presentation. The brain perfusion profiles of the PPA subgroups were compared with those of 24 healthy subjects. RESULTS: PPA BM positive patients had left-side predominant hypoperfusion in the temporoparietal cortex that extended to the dorsolateral prefrontal cortex and perisylvian region while PPA BM negative patients had hypoperfusion that was predominant in the temporal poles (p<10(-4) corrected). CONCLUSION: Distinct hypoperfusion patterns in PPA BM positive and PPA BM negative patients were observed, similar to those that have been described for S-PPA and LPA. These results support using CSF biomarkers to classify PPA.

Similar amyloid-ß burden in posterior cortical atrophy and Alzheimer's disease.

While the clinical presentation of posterior cortical atrophy is clearly distinct from typical Alzheimer's disease, neuropathological studies have suggested that most patients with posterior cortical atrophy have Alzheimer's disease with an atypical visual presentation. We analysed in vivo pathophysiological markers of Alzheimer's disease such as cerebrospinal fluid biomarkers and positron emission tomography imaging with ¹¹C-labelled Pittsburgh compound-B in posterior cortical atrophy to determine whether biochemical profile and fibrillar amyloid-ß burden topography are associated with the clinical presentation. Nine patients with posterior cortical atrophy and nine with typical Alzheimer's disease individually matched for age, duration and severity of the disease and 10 cognitively normal age-matched controls were included. ¹¹C-labelled Pittsburgh compound-B images were analysed both using volumes of interest and on a voxel-wise basis using statistical parametric mapping, taking into account the individual regional cortical atrophy. Cerebrospinal fluid biomarkers did not differ between posterior cortical atrophy and patients with Alzheimer's disease. Compared with normal controls, both posterior cortical atrophy and Alzheimer's disease groups showed increased ¹¹C-labelled Pittsburgh compound-B uptake. No significant difference was found in regional or global ¹¹C-labelled Pittsburgh compound-B binding between posterior cortical atrophy and Alzheimer's disease groups with both volumes of interest and voxel-wise basis using statistical parametric mapping methods. Our findings demonstrate that cerebrospinal fluid biomarkers and positron emission tomography imaging with ¹¹C-labelled Pittsburgh compound-B may be useful in identifying an atypical visual form of Alzheimer's disease. The similar topography of fibrillar amyloid-ß deposition between typical Alzheimer's disease and posterior cortical atrophy groups suggests that, although amyloid-ß accumulation plays a critical role in the pathogenesis of Alzheimer's disease, other factors such as neurofibrillary tangles may contribute to the different clinical features observed in posterior cortical atrophy.

Antihypertensive therapy is associated with reduced rate of conversion to Alzheimer's disease in midregional proatrial natriuretic peptide stratified subjects with mild cognitive impairment.

BACKGROUND: Hypertension is a major risk factor of Alzheimer's disease (AD); however, controlled studies on the effect of antihypertensive treatment on the risk of dementia are inconclusive. Therefore, a biological marker that predicts individual response to antihypertensive treatment would be of high clinical relevance. Midregional proatrial natriuretic peptide (MR-proANP), an inactive surrogate molecule of the mature atrial natriuretic peptide, is related to circulatory function and hypertension. METHODS: A sample population of 134 subjects with mild cognitive impairment (MCI) was followed for up to 6 years. Multivariable Cox regression analysis was conducted to predict conversion to AD based on all relevant variables. RESULTS: Baseline MR-proANP was significantly increased in the AD converter group (p < .0001). The conversion rate of patients treated with antihypertensive drugs was significantly reduced only in patients with elevated MR-proANP at baseline (p = .046). Using an optimized MR-proANP cutoff of 74 pmol/L, representing a value in the upper normal range, treatment with antihypertensive drugs reduced the conversion rate to AD by 36% (p = .035) for patients with levels >74 pmol/L. Further subgrouping by age (>/≤ 72 years at baseline) increased the positive correlation of antihypertensive treatment and MCI outcome for patients below the age of 72 years (conversion rate reduced by 74%, p = .016). CONCLUSIONS: These data seem to support the notion of a potential impact of circulatory function for the prognosis of AD at a prodromal stage. The MR-proANP levels may be useful to predict the effect of antihypertensive treatment on conversion rates to AD in subjects with MCI.

Prediction of Alzheimer's disease using midregional proadrenomedullin and midregional proatrial natriuretic peptide: a retrospective analysis of 134 patients with mild cognitive impairment.

OBJECTIVE: Development of biomarkers for early detection of Alzheimer's disease (AD) is a major clinical research goal. On the basis of the hypothesis that cardiovascular risk factors contribute to the pathogenesis of AD, we investigated whether the cardiovascular risk markers midregional proadrenomedullin (MR-proADM) and midregional proatrial natriuretic peptide (MR-proANP) predict a major clinical milestone, ie, conversion from predementia mild cognitive impairment (MCI) to manifest AD. METHOD: A group of 134 MCI patients, among 137 originally prospectively recruited at the memory disorder clinic at Malmö University Hospital, Malmö, Sweden, between July 1998 and June 2001, was clinically followed for 4-6 years. We determined whether plasma concentrations of MR-proADM and MR-proANP at baseline predicted time to conversion from MCI to clinically diagnosed AD (DSM-III-R). MCI was diagnosed according to Petersen criteria. RESULTS: During follow-up, 41.8% of MCI patients remained cognitively stable, 42.5% converted to possible and probable AD, and 15.7% converted to other forms of dementia (MCI-other). MCI converters and MCI-other patients showed increased concentrations of MR-proANP and MR-proADM compared to the stable MCI patients (P = .0001). At a cutoff of 87 pmol/L, MR-proANP yielded a sensitivity of 73.7% and a specificity of 64.3% for predicting conversion to AD. The survival analysis showed that higher values of MR-proANP and MR-proADM were associated with progression to AD. In a multivariate Cox regression model including known risk factors, MR-proANP and MR-proADM remained independent risk factors for conversion to AD for patients below the age of 72 years. CONCLUSIONS: Our study shows that plasma concentrations of MR-proANP and MR-proADM have predictive value in the progression from predementia MCI to clinical AD. Sensitivity was particularly high, which may recommend this test for first-stage screening in patients at risk for AD.

Validation of Alzheimer's disease CSF and plasma biological markers: the multicentre reliability study of the pilot European Alzheimer's Disease Neuroimaging Initiative (E-ADNI).

BACKGROUND: Alzheimer's Disease Neuroimaging Initiatives ("ADNI") aim to validate neuroimaging and biochemical markers of Alzheimer's disease (AD). Data of the pilot European-ADNI (E-ADNI) biological marker programme of cerebrospinal fluid (CSF) and plasma candidate biomarkers are reported. METHODS: Six academic EADC centres recruited 49 subjects (healthy controls, subjects with mild cognitive impairment (MCI) and AD). We measured CSF beta-amyloid 42 (CSF Abeta42), total tau-protein (t-tau), phosphorylated tau-proteins (P-tau181, P-tau231), plasma beta-amyloid 40 and 42 (Abeta40/Abeta42). Immediate fresh shipment was compared to freezing and later shipment on dry ice. RESULTS: CSF T-tau (fresh samples) was increased in AD versus controls (p=0.049), CSF Abeta42 (frozen samples) was decreased in MCI and AD (p=0.02), as well as plasma Abeta40 (fresh and frozen samples) in AD (p=0.049 and p=0.016). Pooled values of neurochemical parameters and ratios thereof were different between centres (p<0.005). Analysis of frozen samples yielded higher diagnostic accuracy than immediate fresh shipment with 100% (fresh: 100%) correctly classified in control subjects, 100% (78%) in MCI, 91% (91%) in AD. CONCLUSION: The use of frozen rather than fresh samples renders higher diagnostic accuracy within a multicentre context. We confirmed the feasibility of a multicentre AD biomarker programme for future clinical trials.

Blood-based microcirculation markers in Alzheimer's disease-diagnostic value of midregional pro-atrial natriuretic peptide/C-terminal endothelin-1 precursor fragment ratio.

BACKGROUND: There is evidence that vascular factors contribute substantially to Alzheimer's disease (AD). We have developed assays to reliably detect the circulation and microcirculation regulating factors C-terminal endothelin-1 precursor fragment (CT-proET-1), midregional pro-adrenomedullin (MR-proADM), and midregional pro-atrial natriuretic peptide (MR-proANP). We hypothesized that this set of blood-based (micro)circulation parameters is altered in AD. METHODS: Prospectively recruited volunteer cohort (94 patients with probable AD, 53 healthy control subjects [HC]). In plasma, CT-proET-1, MR-proADM, and MR-proANP were analyzed using sandwich luminescence immunoassays. Concentrations of plasma markers and their ratios (MR-proANP/CT-proET-1 and MR-proADM/CT-proET-1) were compared between groups. Diagnostic accuracy of the vasodilator/vasoconstrictor ratios were calculated in the training set (half of AD and HC groups, respectively) and the optimal cutoff was then applied to the test set (remaining half of the study population). RESULTS: In AD patients, concentrations of MR-proADM and MR-proANP were significantly increased and levels of CT-proET-1 were significantly decreased compared with HC subjects. The ratios MR-proANP/CT-proET-1 and MR-proADM/CT-proET-1 improved group separation compared with the single markers. In a logistic regression analysis, the ratios of vasodilator/vasoconstrictor significantly contributed to group separation. The highest diagnostic accuracy was found for the MR-proANP/CT-proET-1 ratio. When applied to the training (test) set, specificity was 82% (80) and sensitivity was 81% (72). CONCLUSIONS: This indicates altered expression of microcirculation parameters and supports the hypothesis of a disturbed microvascular homeostasis in AD. We generated the hypothesis that the vasodilator/vasoconstrictor ratios hold promise as a diagnostic marker of AD. The best diagnostic accuracy was achieved for the MR-proANP/CT-proET-1 ratio.

Russian Brief Pain Inventory: validation and application in cancer pain.

To validate the Russian version of the Brief Pain Inventory (BPI-R) and to examine predictors of inadequate pain management, 221 Russian patients with advanced-stage hematological malignancies or solid tumors completed the BPI-R and a Russian-language Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36-R). Factor analysis of the BPI-R found two underlying constructs, pain severity and pain interference, with Cronbach alphas of 0.93 and 0.95, respectively. Concurrent validity was established by comparing BPI-R items with SF-36-R scales. The BPI-R detected significant differences in pain severity and interference levels by Eastern Cooperative Oncology Group (ECOG) performance status, supporting known-group validity. Determination of the Pain Management Index revealed that 68% of the patients were inadequately treated by World Health Organization standards. Having advanced-stage disease and not receiving chemotherapy predicted inadequate pain management in a multivariate logistic regression model. The Russian version of the BPI is psychometrically sound in its reliability and validity.

Cancer-related symptom assessment in Russia: validation and utility of the Russian M. D. Anderson Symptom Inventory.

This multicenter cross-sectional study (n=226) validated the Russian-language M. D. Anderson Symptom Inventory (MDASI-R) in Russian cancer patients with hematological malignancies or solid tumors. The Russian-language Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36-R) also was used for validation. Factor analysis found three underlying constructs for symptom items--general, treatment-related, and affective symptoms--with Cronbach alphas of 0.86, 0.68, and 0.90, respectively. Convergent validity was established by comparing MDASI-R items with SF-36-R subscales. The MDASI-R detected significant differences in symptom severity and interference levels by performance status, supporting known-group validity. The most prevalent symptoms were fatigue, sleep disturbance, pain, sadness, and poor appetite; 53% of the sample reported one to four moderate-to-severe symptoms (>or=5 on 0-10 scale). Symptoms interfered most with work and general activity. Medical professionals underestimated the severity of pain, fatigue, and distress. The MDASI-R is valid and reliable for measuring symptom severity and interference in Russian cancer patients.