Purpose of ReviewThis review summarises the most recent evidence regarding the effects of dietary flavonoids on age-related cognitive decline and neurodegenerative diseases.Recent FindingsRecent evidence indicates that plant-derived flavonoids may exert powerful actions on mammalian cognition and protect against the development of age-related cognitive decline and pathological neurodegeneration. The neuroprotective effects of flavonoids have been suggested to be due to interactions with the cellular and molecular architecture of brain regions responsible for memory.SummaryMechanisms for the beneficial effects of flavonoids on age-related cognitive decline and dementia are discussed, including modulating signalling pathways critical in controlling synaptic plasticity, reducing neuroinflammation, promoting vascular effects capable of stimulating new nerve cell growth in the hippocampus, bidirectional interactions with gut microbiota and attenuating the extracellular accumulation of pathological proteins. These processes are known to be important in maintaining optimal neuronal function and preventing age-related cognitive decline and neurodegeneration.

Behavioural variant frontotemporal dementia (bvFTD) and Alzheimer’s disease (AD) dementia are characterised by progressive brain atrophy. Longitudinal MRI volumetry may help to characterise ongoing structural degeneration and support the differential diagnosis of dementia subtypes. Automated, observer-independent atlas-based MRI volumetry was applied to analyse 102 MRI data sets from 15 bvFTD, 14 AD, and 10 healthy elderly control participants with consecutive scans over at least 12 months. Anatomically defined targets were chosen a priori as brain structures of interest. Groups were compared regarding volumes at clinic presentation and annual change rates. Baseline volumes, especially of grey matter compartments, were significantly reduced in bvFTD and AD patients. Grey matter volumes of the caudate and the gyrus rectus were significantly smaller in bvFTD than AD. The bvFTD group could be separated from AD on the basis of caudate volume with high accuracy (79% cases correct). Annual volume decline was markedly larger in bvFTD and AD than controls, predominantly in white matter of temporal structures. Decline in grey matter volume of the lateral orbitofrontal gyrus separated bvFTD from AD and controls. Automated longitudinal MRI volumetry discriminates bvFTD from AD. In particular, greater reduction of orbitofrontal grey matter and temporal white matter structures after 12 months is indicative of bvFTD.

Our results replicate previous findings showing only moderate discriminability between AD and bvFTD at clinical presentation on EF and memory measures. More importantly, we also show that longitudinal trajectories strongly overlap for both dementias on these measures. Disinhibition emerged as the sole measure that in the long run was significantly more impaired in bvFTD. Future studies should use tests designed to target cortical regions that are specifically impaired in bvFTD, such as the ventromedial prefrontal cortex, to improve the accurate discrimination of these diseases. (JINS, 2017, 23, 34-43).

Diagnostic distinction of primary progressive aphasias (PPA) remains challenging, in particular for the logopenic (lvPPA) and nonfluent/agrammatic (naPPA) variants. Recent findings highlight that episodic memory deficits appear to discriminate these PPA variants from each other, as only lvPPA perform poorly on these tasks while having underlying amyloid pathology similar to that seen in amnestic dementias like Alzheimer's disease (AD). Most memory tests are, however, language based and thus potentially confounded by the prevalent language deficits in PPA. The current study investigated this issue across PPA variants by contrasting verbal and non-verbal episodic memory measures while controlling for their performance on a language subtest of a general cognitive screen. A total of 203 participants were included (25 lvPPA; 29 naPPA; 59 AD; 90 controls) and underwent extensive verbal and non-verbal episodic memory testing, with a subset of patients (n = 45) with confirmed amyloid profiles as assessed by Pittsburgh Compound B and PET. The most powerful discriminator between naPPA and lvPPA patients was a non-verbal recall measure (Rey Complex Figure delayed recall), with 81% of PPA patients classified correctly at presentation. Importantly, AD and lvPPA patients performed comparably on this measure, further highlighting the importance of underlying amyloid pathology in episodic memory profiles. The findings demonstrate that non-verbal recall emerges as the best discriminator of lvPPA and naPPA when controlling for language deficits in high load amyloid PPA cases.

The trajectory of perceived burden differs across the FTD-ALS spectrum, with SD and ALSFTD caregivers demonstrating an increased burden that develops over time, compared to a persistently high level for bvFTD caregivers, evident throughout the disease course. The evolution of burden in these three syndromes likely reflects the initial presentation and clinical characterization that develops with time. Psycho-education programs for caregivers, which provide better coping strategies for challenging behaviors, may reduce levels of burden experienced with disease progression.

Recent evidence has questioned the integrity of episodic memory in behavioural variant frontotemporal dementia (bvFTD), where recall performance is impaired to the same extent as in Alzheimer’s disease (AD). While these deficits appear to be mediated by divergent patterns of brain atrophy, there is evidence to suggest that certain prefrontal regions are implicated across both patient groups. In this study we sought to further elucidate the dorsolateral (DLPFC) and ventromedial (VMPFC) prefrontal contributions to episodic memory impairment in bvFTD and AD. Performance on episodic memory tasks and neuropsychological measures typically tapping into either DLPFC or VMPFC functions was assessed in 22 bvFTD, 32 AD patients and 35 age- and education-matched controls. Behaviourally, patient groups did not differ on measures of episodic memory recall or DLPFC-mediated executive functions. BvFTD patients were significantly more impaired on measures of VMPFC-mediated executive functions. Composite measures of the recall, DLPFC and VMPFC task scores were covaried against the T1 MRI scans of all participants to identify regions of atrophy correlating with performance on these tasks. Imaging analysis showed that impaired recall performance is associated with divergent patterns of PFC atrophy in bvFTD and AD. Whereas in bvFTD, PFC atrophy covariates for recall encompassed both DLPFC and VMPFC regions, only the DLPFC was implicated in AD. Our results suggest that episodic memory deficits in bvFTD and AD are underpinned by divergent prefrontal mechanisms. Moreover, we argue that these differences are not adequately captured by existing neuropsychological measures.

Behavioral variant frontotemporal dementia (bvFTD) has only recently been associated with significant striatal atrophy, whereas the striatum appears to be relatively preserved in Alzheimer’s disease (AD). Considering the critical role the striatum has in cognition and behavior, striatal degeneration, together with frontal atrophy, could be responsible of some characteristic symptoms in bvFTD and emerges therefore as promising novel diagnostic biomarker to distinguish bvFTD and AD. Previous studies have, however, only taken either cortical or striatal atrophy into account when comparing the two diseases. In this study, we establish for the first time a profile of fronto-striatal atrophy in 23 bvFTD and 29 AD patients at presentation, based on the structural connectivity of striatal and cortical regions. Patients are compared to 50 healthy controls by using a novel probabilistic connectivity atlas, which defines striatal regions by their cortical white-matter connectivity, allowing us to explore the degeneration of the frontal and striatal regions that are functionally linked. Comparisons with controls revealed that bvFTD showed substantial fronto-striatal atrophy affecting the ventral as well as anterior and posterior dorso-lateral prefrontal cortices and the related striatal subregions. In contrast, AD showed few fronto-striatal atrophy, despite having significant posterior dorso-lateral prefrontal degeneration. Direct comparison between bvFTD and AD revealed significantly more atrophy in the ventral striatal–ventromedial prefrontal cortex regions in bvFTD. Consequently, deficits in ventral fronto-striatal regions emerge as promising novel and efficient diagnosis biomarker for bvFTD. Future investigations into the contributions of these fronto-striatal loops on bvFTD symptomology are needed to develop simple diagnostic and disease tracking algorithms.

Our objective was to distinguish ALS, ALS-FTD and bvFTD via a novel visual MRI cortical atrophy scale that can be employed in a clinical setting. MRI images of 100 participants (33 ALS, 11 ALS-FTD, 22 bvFTD and 34 controls) were rated in four brain areas: orbitofrontal cortex, anterior temporal pole, anterior cingulate, and motor cortex. Areas were rated on a 5- point Likert scale by two raters blinded to the diagnosis. Results demonstrated that bvFTD patients showed the highest levels of atrophy across all regions, while ALS patients had the lowest atrophy scores. ALS-FTD patients have higher atrophy ratings compared to ALS patients for the motor cortex, anterior cingulate and anterior temporal lobe, with a statistical trend for the orbitofrontal cortex. ALS-FTD patients were not significantly different from bvFTD for any of the brain regions. These findings were confirmed in a post hoc VBM analysis of the same participants. Our study demonstrates that a simple visual MRI rating scale can reliably distinguish ALS, ALS-FTD and bvFTD atrophy patterns in a clinical setting. Motor cortex, anterior cingulate and anterior temporal atrophy emerged as good diagnostic markers for ALS-FTD. Employment of this MRI rating scale can complement clinical diagnostics of patients in the ALS-FTD continuum.