Blood Biomarkers from Research Use to Clinical Practice: What Must Be Done? A Report from the EU/US CTAD Task Force.

Timely and accurate diagnosis of Alzheimer's disease (AD) in clinical practice remains challenging. PET and CSF biomarkers are the most widely used biomarkers to aid diagnosis in clinical research but present limitations for clinical practice (i.e., cost, accessibility). Emerging blood-based markers have the potential to be accurate, cost-effective, and easily accessible for widespread clinical use, and could facilitate timely diagnosis. The EU/US CTAD Task Force met in May 2022 in a virtual meeting to discuss pathways to implementation of blood-based markers in clinical practice. Specifically, the CTAD Task Force assessed: the state-of-art for blood-based markers, the current use of blood-based markers in clinical trials, the potential use of blood-based markers in clinical practice, the current challenges with blood-based markers, and the next steps needed for broader adoption in clinical practice.

Memory consolidation and the hippocampus: further evidence from studies of autobiographical memory in semantic dementia and frontal variant frontotemporal dementia.

Studies of autobiographical memory in semantic dementia have found relative preservation of memories for recent rather than remote events. As semantic dementia is associated with progressive atrophy to temporal neocortex, with early asymmetric sparing of the hippocampus, this neuropsychological pattern suggests that the hippocampal complex plays a role in the acquisition and retrieval of recent memories, but is not necessary for the recall of older episodic events. In an alternative view of memory consolidation, however, the hippocampus plays a role in the retrieval of all autobiographical memories, regardless of the age of the memory [Curr. Opin. Neurobiol. 7(1997)217]. This 'multiple trace theory' predicts that patients with semantic dementia should show no effects of time in their autobiographical recall. In this article, we ask whether it is possible to reconcile the data from semantic dementia with the multiple trace theory by investigating whether the time-dependent pattern of autobiographical retrieval seen in the disease is due to (i) patients showing this effect being exceptional in their presentation; and/or (ii) patients with semantic dementia exhibiting impaired strategic retrieval from concomitant frontal damage. A series of experiments in patients with semantic dementia, the frontal variant of frontotemporal dementia and Alzheimer's disease clearly demonstrates that neither of these two factors can explain the documented effect of time seen in semantic dementia. Nonetheless, we discuss how damage to semantic knowledge could result in an autobiographical memory deficit and suggest that data from semantic dementia may be consistent with both views of hippocampal involvement in long-term memory.

The role of conceptual knowledge in object use evidence from semantic dementia.

It has been reported that patients with semantic dementia function well in everyday life and sometimes show striking preservation of the ability to use objects, even those specific objects for which the patient has degraded conceptual information. To explore this phenomenon in nine cases of semantic dementia, we designed a set of semantic tests regarding 20 everyday objects and compared performance on these with the patients' ability to demonstrate the correct use of the same items. We also administered a test of mechanical problem solving utilizing novel tools, on which the patients had completely normal ability. All but the mildest affected patient showed significant deficits of naming and on the visually based semantic matching tasks. Object use was markedly impaired and, most importantly, correlated strongly with naming and semantic knowledge. In a small number of instances, there was appropriate use of an object for which the patient's knowledge on the semantic matching tasks was no better than chance; but this typically applied to objects with a rather obvious relationship between appearance and use, or was achieved by trial and error. The results suggest that object use is heavily dependent upon object-specific conceptual knowledge, supplemented to some degree by a combination of visual affordances and mechanical problem solving.

Which neuropsychiatric and behavioural features distinguish frontal and temporal variants of frontotemporal dementia from Alzheimer's disease?

OBJECTIVES: To investigate the prevalence of changes in mood, personality, and behaviour in frontotemporal dementia (FTD) and Alzheimer's disease (AD) and hence, which features reliably distinguish between them. To establish whether the frontal and temporal variants of FTD are characterised by different behavioural changes. METHODS: A questionnaire was designed to assess a wide range of neuropsychiatric changes; it incorporated features reported in previous studies of FTD and components of the neuropsychiatric inventory.(1) This was completed by 37 carers of patients with Alzheimer's disease (AD) and 33 patients with frontotemporal dementia (FTD), comprising 20 with temporal variant FTD (tv FTD) or semantic dementia and 13 with frontal variant FTD (fv FTD). An exploratory principal components factor analysis and discriminant function analysis was applied. RESULTS: Factor analysis showed four robust and meaningful symptom clusters: factor 1-stereotypic and eating behaviour; factor 2-executive dysfunction and self care; factor 3-mood changes; factor 4-loss of social awareness. Only stereotypic and altered eating behaviour and loss of social awareness reliably differentiated AD from FTD with no effect of disease severity. By contrast, executive dysfunction, poor self care, and restlessness showed a significant effect of disease severity only, with the more impaired patients scoring more highly. Changes in mood were found to be equally prevalent in the three patient groups. Analysis of individual symptoms showed increased rates of mental rigidity and depression in the patients with semantic dementia compared with those with fv FTD. Conversely, the latter group showed greater disinhibition. Discriminant function analysis correctly classified 71.4% overall and 86.5% of the patients with AD. CONCLUSIONS: This questionnaire disclosed striking differences between patients with FTD and AD, but only stereotypic behaviour, changes in eating preference, disinhibition, and features of poor social awareness reliably separated the groups. The patients with fv FTD and semantic dementia were behaviourally very similar, reflecting the involvement of a common network, the ventral frontal lobe, temporal pole, and amygdala. Dysexecutive symptoms and poor self care were found to be affected by the severity of the disease, reflecting perhaps spread to dorsolateral prefrontal areas relatively late in the course of both FTD and AD. This questionnaire may be of value in the diagnosis and the monitoring of therapies.

Non-verbal semantic impairment in semantic dementia.

The clinical presentation of patients with semantic dementia is dominated by anomia and poor verbal comprehension. Although a number of researchers have argued that these patients have impaired comprehension of non-verbal as well as verbal stimuli, the evidence for semantic deterioration is mainly derived from tasks that include some form of verbal input or output. Few studies have investigated semantic impairment using entirely non-verbal assessments and the few exceptions have been based on results from single cases ([3]: Breedin SD, Saffran EM, Coslett HB. Reversal of the concreteness effect in a patient with semantic dementia. Cognitive Neuropsychology 1994;11:617-660, [12]: Graham KS, Becker JT, Patterson K, Hodges JR. Lost for words: a case of primary progressive aphasia? In: Parkin A, editor. Case studies in the neuropsychology of memory, East Sussex: Lawrence Erlbaum, 1997. pp. 83-110, [21]: Lambon Ralph MA, Howard D. Gogi aphasia or semantic dementia? Simulating and assessing poor verbal comprehension in a case of progressive fluent aphasia. Cognitive Neuropsychology, (in-press). This study employed sound recognition and semantic association tasks to investigate the nature of the verbal and non-verbal comprehension deficit in 10 patients with semantic dementia. The patients were impaired on both verbal and non-verbal conditions of the assessments, and their accuracy on these tasks was directly related to their scores on a range of other tests requiring access to semantic memory. Further analyses revealed that performance was graded by concept and sound familiarity and, in addition, identified significant item consistency across the different conditions of the tasks. These results support the notion that the patients' deficits across all modalities were due to degradation within a single, central network of conceptual knowledge. There were also reliable differences between conditions. The sound-picture matching task proved to be more sensitive to semantic impairment than the word-picture matching equivalent, and the patients performed significantly better on the picture than word version of a semantic association test. We propose that these differences arise directly from the nature of the mapping between input modality and semantic memory. Words and sounds have an arbitrary relationship with meaning while pictures benefit from a degree of systematicity with conceptual knowledge about the object.