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The current clinical trial landscape targeting Alzheimer's disease (AD) is reviewed in the context of studies completed from 2019 to 2021. This review focuses on available data for observational and phase II/III clinical trial results, which will have the most impact on the field. ClinicalTrials.gov, the United States (US) comprehensive federal registry, was queried to identify completed trials. There are currently 226 interventional clinical trials and 51 observational studies completed, suspended, terminated, or withdrawn within our selected time frame. This review reveals that the role of biomarkers is expanding and although many lessons have been learned, many challenges remain when targeting disease modification of AD through amyloid and tau. In addition, to halt or slow clinical progression of AD, new clinical and observational trials are focusing on prevention as well as the role of more diverse biological processes known to influence AD pathology.

Background Highly penetrant inherited mutations in the prion protein gene (PRNP) offer a window to study the pathobiology of prion disorders. Method Clinical, neuropsychological, and neuroimaging characterization of a kindred. Results Three of four mutation carriers have progressed to a frontotemporal dementia phenotype. Declines in neuropsychological function coincided with changes in FDG-PET at the identified onset of cognitive impairment.

Posterior cortical atrophy is a neurodegenerative syndrome with a heterogeneous clinical presentation due to variable involvement of the left, right, dorsal and ventral parts of the visual system, as well as inconsistent involvement of other cognitive domains and systems. 18F-fluorodeoxyglucose (FDG)-PET is a sensitive marker for regional brain damage or dysfunction, capable of capturing the pattern of neurodegeneration at the single-participant level. We aimed to leverage these inter-individual differences on FDG-PET imaging to better understand the associations of heterogeneity of posterior cortical atrophy. We identified 91 posterior cortical atrophy participants with FDG-PET data and abstracted demographic, neurologic, neuropsychological and Alzheimer’s disease biomarker data. The mean age at reported symptom onset was 59.3 (range: 45–72 years old), with an average disease duration of 4.2 years prior to FDG-PET scan, and a mean education of 15.0 years. Females were more common than males at 1.6:1. After standard preprocessing steps, the FDG-PET scans for the cohort were entered into an unsupervised machine learning algorithm which first creates a high-dimensional space of inter-individual covariance before performing an eigen-decomposition to arrive at a low-dimensional representation. Participant values (‘eigenbrains’ or latent vectors which represent principle axes of inter-individual variation) were then compared to the clinical and biomarker data. Eight eigenbrains explained over 50% of the inter-individual differences in FDG-PET uptake with left (eigenbrain 1) and right (eigenbrain 2) hemispheric lateralization representing 24% of the variance. Furthermore, eigenbrain-loads mapped onto clinical and neuropsychological data (i.e. aphasia, apraxia and global cognition were associated with the left hemispheric eigenbrain 1 and environmental agnosia and apperceptive prosopagnosia were associated with the right hemispheric eigenbrain 2), suggesting that they captured important axes of normal and abnormal brain function. We used NeuroSynth to characterize the eigenbrains through topic-based decoding, which supported the idea that the eigenbrains map onto a diverse set of cognitive functions. These eigenbrains captured important biological and pathophysiologic data (i.e. limbic predominant eigenbrain 4 patterns being associated with older age of onset compared to frontoparietal eigenbrain 7 patterns being associated with younger age of onset), suggesting that approaches that focus on inter-individual differences may be important to better understand the variability observed within a neurodegenerative syndrome like posterior cortical atrophy., Townley et al. report that 18F-fluorodeoxyglucose PET combined with a novel decoding imaging analysis can capture the heterogenous presentation of posterior cortical atrophy. Left and right hemispheric differences accounted for 60% of the variance in this large cohort and were associated with demographic factors and clinical signs/symptoms., Graphical Abstract Graphical Abstract

OBJECTIVE: To compare the Short Test of Mental Status (STMS) to the Montreal Cognitive Assessment (MoCA) for predicting and detecting mild cognitive impairment (MCI). METHODS: Participants from the community-based Mayo Clinic Study of Aging (MCSA) (November 24, 2010 through May 19, 2012) and an academic referral Alzheimer’s Disease Research Center (ADRC) (March 16, 2015 through September 5, 2018) were analyzed. All participants were evaluated using a standardized neuropsychological battery and a multidisciplinary consensus diagnosis was assigned. The MCSA sample included 313 stable cognitively normal (CN) participants, 72 participants with normal cognition at baseline who developed incident MCI or dementia, 114 participants with prevalent MCI, and 25 participants with dementia. The ADRC included 106 stable CN participants, 8 incident MCI/dementia, 96 prevalent MCI, and 132 dementia. RESULTS: There was no significant difference between the two tests in 6 of 7 diagnostic comparisons across academic referral and community populations. The STMS had a better AUC [0.898, 95% CI: (0.865, 0.932)] for differentiating prevalent MCI from CN participants in the MCSA cohort compared to the MoCA [0.848, 95% CI: (0.808, 0.889)], P=.01. Additionally, 53% of our stable cognitively normal participants scored < 26 on the MoCA, with a specificity of 47% for diagnosing prevalent MCI. CONCLUSIONS: We provide evidence that the STMS performs similarly to the MoCA in a variety of settings and neurodegenerative syndromes. Our results suggest that the current recommended MoCA cutoff may be overly sensitive, consistent with previous studies. We also provide a conversion table for comparing the two cognitive tests.

IMPORTANCE: Highly penetrant inherited mutations in the prion protein gene (PRNP) offer a window to study the pathobiology of prion disorders. OBJECTIVE: To characterize the longitudinal clinical features, neuropsychological findings, MRI findings, and FGD-PET scan imaging findings in a subsequent generation of a family with a large 12-octapeptide repeat insertion in the PRNP gene. DESIGN: Clinical, neuropsychological, and neuroimaging characterization of a kindred. SETTING: Mayo Clinic Alzheimer Disease Research Center (Rochester, Minnesota). PARTICIPANTS: Four mutation carriers and two non-carriers in the third generation of a kindred with a large octapeptide repeat insertion in the PRNP gene. RESULTS: Three of the four mutation carriers have progressed to a frontotemporal dementia phenotype. Declines in neuropsychological function coincided with changes in FDG-PET at the identified onset of cognitive impairment. Processing speed and executive function were abnormal before the identified onset. CONCLUSIONS AND RELEVANCE: Gene silencing treatments are on the horizon and when they become available, early detection will be crucial. Longitudinal studies involving familial mutation kindreds can offer important insights into the initial neuropsychological and neuroimaging changes necessary for early detection.

We report a group of patients presenting with a progressive dementia syndrome characterized by predominant dysfunction in core executive functions, relatively young age of onset and positive biomarkers for Alzheimer’s pathophysiology. Atypical frontal, dysexecutive/behavioural variants and early-onset variants of Alzheimer’s disease have been previously reported, but no diagnostic criteria exist for a progressive dysexecutive syndrome. In this retrospective review, we report on 55 participants diagnosed with a clinically defined progressive dysexecutive syndrome with 18F-fluorodeoxyglucose-positron emission tomography and Alzheimer’s disease biomarkers available. Sixty-two per cent of participants were female with a mean of 15.2 years of education. The mean age of reported symptom onset was 53.8 years while the mean age at diagnosis was 57.2 years. Participants and informants commonly referred to initial cognitive symptoms as ‘memory problems’ but upon further inquiry described problems with core executive functions of working memory, cognitive flexibility and cognitive inhibitory control. Multi-domain cognitive impairment was evident in neuropsychological testing with executive dysfunction most consistently affected. The frontal and parietal regions which overlap with working memory networks consistently demonstrated hypometabolism on positron emission tomography. Genetic testing for autosomal dominant genes was negative in all eight participants tested and at least one APOE ε4 allele was present in 14/26 participants tested. EEG was abnormal in 14/17 cases with 13 described as diffuse slowing. Furthermore, CSF or neuroimaging biomarkers were consistent with Alzheimer’s disease pathophysiology, although CSF p-tau was normal in 24% of cases. Fifteen of the executive predominate participants enrolled in research neuroimaging protocols and were compared to amnestic (n = 110), visual (n = 18) and language (n = 7) predominate clinical phenotypes of Alzheimer’s disease. This revealed a consistent pattern of hypometabolism in parieto-frontal brain regions supporting executive functions with relative sparing of the medial temporal lobe (versus amnestic phenotype), occipital (versus visual phenotype) and left temporal (versus language phenotype). We propose that this progressive dysexecutive syndrome should be recognized as a distinct clinical phenotype disambiguated from behavioural presentations and not linked specifically to the frontal lobe or a particular anatomic substrate without further study. This clinical presentation can be due to Alzheimer’s disease but is likely not specific for any single aetiology. Diagnostic criteria are proposed to facilitate additional research into this understudied clinical presentation., We present a retrospective case series of 55 individuals presenting with a progressive dysexecutive syndrome with biomarker evidence of Alzheimer’s disease. This clinical syndrome should be recognized as a distinct clinical phenotype that is disambiguated form behavioural presentations and not linked to a particular anatomic substrate without further study., Graphical Abstract Graphical Abstract

ObjectiveTo study the in vivo binding properties of 18F-AV-1451 (tau-PET) and Pittsburgh compound B (PiB-PET) in a unique kindred with a familial prion disorder known to produce amyloid plaques composed of prion protein alongside Alzheimer disease (AD)–like tau tangles.MethodsA case series of 4 symptomatic family members with the 12-octapeptide repeat insertion in the PRNP gene were imaged with 3T MRI, PiB-PET, and tau-PET in their fourth decade of life.ResultsThere was significant neocortical uptake of the tau-PET tracer in all 4 familial prion cases. However, PiB-PET images did not demonstrate abnormally elevated signal in neocortical or cerebellar regions for any of the patients.ConclusionsIn vivo detection of molecular hallmarks of neurodegenerative diseases will be a prerequisite to well-conducted therapeutic trials. Understanding the in vivo behavior of these PET biomarkers in the setting of various neurodegenerative processes is imperative to their proper use in such trials and for research studies focused on the basic neurobiology of neurodegeneration. This study supports the high specificity of neocortical 18F-AV-1451 binding to AD-like tau and the lack of PiB binding to PrP plaques. It is uncertain how early in the disease course tau pathology appears in the brains of individuals who carry this PRNP gene mutation or how it evolves throughout the disease course, but future longitudinal 18F-AV-1451 imaging of symptomatic and asymptomatic individuals in this kindred will help address these uncertainties.

Progranulin is a highly conserved secreted protein that is expressed in multiple cell types, both in the CNS and in peripheral tissues. Both directly and via its conversion to granulins, progranulin regulates cell growth, survival, repair, and inflammation. Progranulin has a major role in regulation of lysosomal function and microglial responses in the CNS. Autosomal dominant mutations of the progranulin ( GRN ) gene leading to protein haploinsufficiency are linked to familial frontotemporal dementia with neuropathologic frontotemporal lobar degeneration (FTLD) associated with accumulation of TAR-DNA binding protein of 43kDA (TDP-43) inclusions (FTLD-TDP). Homozygous GRN mutations are linked to neuronal ceroid lipofuscinosis (NCL). These findings have stimulated interest in elucidating the normal regulation and function of progranulin and granulins and the pathomechanisms by which progranulin deficiency leads to neurodegeneration. These topics have been recently reviewed1–5 and some salient aspects are discussed here.

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapid and fatal neurodegenerative disease defined by misfolded prion proteins accumulating in the brain. A minority of cases initially present with posterior cortical atrophy (PCA) phenotype, also known as Heidenhain variant or visual variant CJD. This case provides further evidence of sCJD presenting as PCA. The case also provides evidence for early DWI changes and cortical atrophy over 30 months before neurologic decline and subsequent death. The prolonged disease course correlates with prion protein codon 129 heterozygosity and coexistence of multiple prion strains.

Postsedation neuroexcitation is sometimes attributed to intravenous injection of the sedative-hypnotic drug propofol. The movements associated with these events have strongly suggested convulsive activity, but they rarely have been comprehensively evaluated. We present video recordings of 3 healthy young patients who underwent elective surgery under conscious sedation and emerged from sedation with transient but repetitive violent motor activity and impaired consciousness. These manifestations required considerable mobilization of multiple health care workers to protect the patient from inflicting harm. All patients received propofol, and all fully recovered without adverse sequelae. We postulate that these movements are propofol related. Importantly, we found no evidence of seizures clinically or electrographically.