Stephanie Wong

In vivo and post-mortem memory circuit integrity in frontotemporal dementia and Alzheimer’s disease

Behavioural variant frontotemporal dementia can present with episodic memory deficits as severe as those in Alzheimers disease. Little is known of the integrity of grey matter areas and white matter tracts of the Papez memory circuit in these diseases. The integrity of the Papez circuit (hippocampus, fornix, mammillary bodies, anterior thalamus, cingulate cortex) was investigated in vivo and at post-mortem in behavioural variant frontotemporal dementia and Alzheimers disease cohorts using voxel-based morphometry, diffusion tensor imaging and manual volumetric tracing. Our findings indicate that behavioural variant frontotemporal dementia and Alzheimers disease show similar degrees of hippocampal atrophy in vivo, but patients with behavioural variant frontotemporal dementia show greater hippocampal atrophy at post-mortem, with the frontotemporal lobar degeneration with TDP-43 inclusions subtype being particularly affected. Cingulate cortex findings show an expected atrophy pattern with behavioural variant frontotemporal dementia being affected more anteriorly and Alzheimers disease showing more posterior atrophy. More importantly, subcortical Papez circuit regions (fornix and anterior thalamus) were affected in behavioural variant frontotemporal dementia only, with atrophy in these regions determining the degree of amnesia in behavioural variant frontotemporal dementia. Hippocampal atrophy does not appear to be an efficient diagnostic marker for underlying behavioural variant frontotemporal dementia or Alzheimers disease pathology, although for behavioural variant frontotemporal dementia, episodic memory deficits in conjunction with marked hippocampal atrophy emerge as potential biomarkers for frontotemporal lobar degeneration with TDP-43 inclusions pathology. Sub-regions of the Papez circuit were differentially affected in behavioural variant frontotemporal dementia and Alzheimers disease with subcortical regions determining the degree of episodic memory deficits in behavioural variant frontotemporal dementia. Subcortical atrophy should be taken into account when establishing whether the severe amnesia observed in a patient is likely to be due to behavioural variant frontotemporal dementia or Alzheimers disease pathology.

Lost in spatial translation - A novel tool to objectively assess spatial disorientation in Alzheimer's disease and frontotemporal dementia.

Spatial disorientation is a prominent feature of early Alzheimers disease (AD) attributed to degeneration of medial temporal and parietal brain regions, including the retrosplenial cortex (RSC). By contrast, frontotemporal dementia (FTD) syndromes show generally intact spatial orientation at presentation. However, currently no clinical tasks are routinely administered to objectively assess spatial orientation in these neurodegenerative conditions. In this study we investigated spatial orientation in 58 dementia patients and 23 healthy controls using a novel virtual supermarket task as well as voxel-based morphometry (VBM). We compared performance on this task with visual and verbal memory function, which has traditionally been used to discriminate between AD and FTD. Participants viewed a series of videos from a first person perspective travelling through a virtual supermarket and were required to maintain orientation to a starting location. Analyses revealed significantly impaired spatial orientation in AD, compared to FTD patient groups. Spatial orientation performance was found to discriminate AD and FTD patient groups to a very high degree at presentation. More importantly, integrity of the RSC was identified as a key neural correlate of orientation performance. These findings confirm the notion that i) it is feasible to assess spatial orientation objectively via our novel Supermarket task; ii) impaired orientation is a prominent feature that can be applied clinically to discriminate between AD and FTD and iii) the RSC emerges as a critical biomarker to assess spatial orientation deficits in these neurodegenerative conditions.

Beyond the temporal pole: limbic memory circuit in the semantic variant of primary progressive aphasia

Despite accruing evidence for relative preservation of episodic memory in the semantic variant of primary progressive aphasia (previously semantic dementia), the neural basis for this remains unclear, particularly in light of their well-established hippocampal involvement. We recently investigated the Papez network of memory structures across pathological subtypes of behavioural variant frontotemporal dementia and demonstrated severe degeneration of all relay nodes, with the anterior thalamus in particular emerging as crucial for intact episodic memory. The present study investigated the status of key components of Papez circuit (hippocampus, mammillary bodies, anterior thalamus, cingulate cortex) and anterior temporal cortex using volumetric and quantitative cell counting methods in pathologically-confirmed cases with semantic variant of primary progressive aphasia (n = 8; 61-83 years; three males), behavioural variant frontotemporal dementia with TDP pathology (n = 9; 53-82 years; six males) and healthy controls (n = 8, 50-86 years; four males). Behavioural variant frontotemporal dementia cases with TDP pathology were selected because of the association between the semantic variant of primary progressive aphasia and TDP pathology. Our findings revealed that the semantic variant of primary progressive aphasia and behavioural variant frontotemporal dementia show similar degrees of anterior thalamic atrophy. The mammillary bodies and hippocampal body and tail were preserved in the semantic variant of primary progressive aphasia but were significantly atrophic in behavioural variant frontotemporal dementia. Importantly, atrophy in the anterior thalamus and mild progressive atrophy in the body of the hippocampus emerged as the main memory circuit regions correlated with increasing dementia severity in the semantic variant of primary progressive aphasia. Quantitation of neuronal populations in the cingulate cortices confirmed the selective loss of anterior cingulate von Economo neurons in behavioural variant frontotemporal dementia. We also show that by end-stage these neurons selectively degenerate in the semantic variant of primary progressive aphasia with preservation of neurons in the posterior cingulate cortex. Overall, our findings demonstrate for the first time, severe atrophy, although not necessarily neuronal loss, across all relay nodes of Papez circuit with the exception of the mammillary bodies and hippocampal body and tail in the semantic variant of primary progressive aphasia. Despite the longer disease course in the semantic variant of primary progressive aphasia compared with behavioural variant frontotemporal dementia, we suggest here that the neural preservation of crucial memory relays (hippocampal→mammillary bodies and posterior cingulate→hippocampus) likely reflects the conservation of specific episodic memory components observed in most patients with semantic variant of primary progressive aphasia.

Uncovering the Neural Bases of Cognitive and Affective Empathy Deficits in Alzheimer’s Disease and the Behavioral-Variant of Frontotemporal Dementia

Loss of empathy is a core presenting feature of the behavioral-variant of frontotemporal dementia (bvFTD), resulting in socioemotional difficulties and behavioral transgressions. In contrast, interpersonal functioning remains relatively intact in Alzheimers disease (AD), despite marked cognitive decline. The neural substrates mediating these patterns of loss and sparing in social functioning remain unclear, yet are relevant for our understanding of the social brain. We investigated cognitive versus affective aspects of empathy using the Interpersonal Reactivity Index (IRI) in 25 AD and 24 bvFTD patients and contrasted their performance with 22 age- and education-matched controls. Cognitive empathy was comparably compromised in AD and bvFTD, whereas affective empathy was impaired exclusively in bvFTD. While controlling for overall cognitive dysfunction ameliorated perspective-taking deficits in AD, empathy loss persisted across cognitive and affective domains in bvFTD. Voxel-based morphometry analyses revealed divergent neural substrates of empathy loss in each patient group. Perspective-taking deficits correlated with predominantly left-sided temporoparietal atrophy in AD, whereas widespread bilateral frontoinsular, temporal, parietal, and occipital atrophy was implicated in bvFTD. Reduced empathic concern in bvFTD was associated with atrophy in the left orbitofrontal, inferior frontal, and insular cortices, and the bilateral mid-cingulate gyrus. Our findings suggest that social cognitive deficits in AD arise largely as a consequence of global cognitive dysfunction, rather than a loss of empathy per se. In contrast, loss of empathy in bvFTD reflects the deterioration of a distributed network of frontoinsular and temporal structures that appear crucial for monitoring and processing social information.

Contrasting prefrontal cortex contributions to episodic memory dysfunction in behavioural variant frontotemporal dementia and Alzheimer's disease.

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.

Neural substrates of episodic memory dysfunction in behavioural variant frontotemporal dementia with and without C9ORF72 expansions

The recently discovered hexanucleotide repeat expansion, C9ORF72, has been shown to be among the most common cause of familial behavioural variant frontotemporal dementia (bvFTD) and to be present in a significant minority of apparently sporadic cases. While mounting evidence points to prominent episodic memory dysfunction in bvFTD cases, recent reports have also suggested an amnestic profile in C9ORF72 mutation carriers. No study to date, however, has formally characterised the extent to which episodic memory is impaired in C9ORF72 mutation versus sporadic cases, or the underlying neural substrates of such deficits. We conducted a comparison of C9ORF72 (n = 8) and sporadic (n = 15) bvFTD cases using a battery of verbal and visual episodic memory tasks, and contrasted their performance with that of Alzheimers disease (AD, n = 15) and healthy older control (n = 15) participants. Behaviourally, the two bvFTD groups displayed comparable episodic memory profiles, irrespective of task administered, with prominent impairments evident relative to Controls. Whole-brain voxel-based morphometry analyses revealed distinct neural correlates of episodic memory dysfunction in each patient group. Widespread atrophy in medial prefrontal, medial and lateral temporal cortices correlated robustly with episodic memory dysfunction in sporadic bvFTD cases. In contrast, atrophy in a distributed set of regions in the frontal, temporal, and parietal lobes including the posterior cingulate cortex, was implicated in episodic memory dysfunction in C9ORF72 cases. Our results demonstrate that while episodic memory is disrupted to the same extent irrespective of genetic predisposition in bvFTD, distinct neural changes specific to each patient group are evident. The involvement of medial and lateral parietal regions in episodic memory dysfunction in C9ORF72 cases is of particular significance and represents an avenue of considerable interest for future studies.

Retrosplenial Cortex (BA 29) Volumes in Behavioral Variant Frontotemporal Dementia and Alzheimer’s Disease

Background: The retrosplenial cortex (RSC) is a crucial transit region between the hippocampus and cingulate cortex and has been implicated in spatial navigation and memory. Importantly, RSC atrophy is a predilection site of Alzheimer’s (AD) pathology, but there have been no studies assessing structural changes in the RSC in behavioral variant frontotemporal dementia (bvFTD). Methods: A manual tracing method was used to calculate regional RSC volume in MRI scans from patients with bvFTD (n = 15) and AD (n = 15), as well as age- and sex-matched controls (n = 15). Results: RSC volumes were significantly reduced in the AD (p < 0.001), but not the bvFTD cohort (p > 0.1) compared to age-matched controls. RSC volumes discriminated bvFTD from AD in over 90% of the cases. Conclusion: These findings provide further evidence that RSC atrophy is specific to AD, which might explain the commonly observed spatial disorientation in this patient group.

Comparison of Prefrontal Atrophy and Episodic Memory Performance in Dysexecutive Alzheimer’s Disease and Behavioral-Variant Frontotemporal Dementia

Alzheimers disease (AD) sometimes presents with prominent executive dysfunction and associated prefrontal cortex atrophy. The impact of such executive deficits on episodic memory performance as well as their neural correlates in AD, however, remains unclear. The aim of the current study was to investigate episodic memory and brain atrophy in AD patients with relatively spared executive functioning (SEF-AD; n = 12) and AD patients with relatively impaired executive functioning (IEF-AD; n = 23). We also compared the AD subgroups with a group of behavioral-variant frontotemporal dementia patients (bvFTD; n = 22), who typically exhibit significant executive deficits, and age-matched healthy controls (n = 38). On cognitive testing, the three patient groups showed comparable memory profiles on standard episodic memory tests, with significant impairment relative to controls. Voxel-based morphometry analyses revealed extensive prefrontal and medial temporal lobe atrophy in IEF-AD and bvFTD, whereas this was limited to the middle frontal gyrus and hippocampus in SEF-AD. Moreover, the additional prefrontal atrophy in IEF-AD and bvFTD correlated with memory performance, whereas this was not the case for SEF-AD. These findings indicate that IEF-AD patients show prefrontal atrophy in regions similar to bvFTD, and suggest that this contributes to episodic memory performance. This has implications for the differential diagnosis of bvFTD and subtypes of AD.

False Recognition in Behavioral Variant Frontotemporal Dementia and Alzheimer's Disease-Disinhibition or Amnesia?

Episodic memory recall processes in Alzheimers disease (AD) and behavioral variant frontotemporal dementia (bvFTD) can be similarly impaired, whereas recognition performance is more variable. A potential reason for this variability could be false-positive errors made on recognition trials and whether these errors are due to amnesia per se or a general over-endorsement of recognition items regardless of memory. The current study addressed this issue by analysing recognition performance on the Rey Auditory Verbal Learning Test (RAVLT) in 39 bvFTD, 77 AD and 61 control participants from two centers (India, Australia), as well as disinhibition assessed using the Hayling test. Whereas both AD and bvFTD patients were comparably impaired on delayed recall, bvFTD patients showed intact recognition performance in terms of the number of correct hits. However, both patient groups endorsed significantly more false-positives than controls, and bvFTD and AD patients scored equally poorly on a sensitivity index (correct hits—false-positives). Furthermore, measures of disinhibition were significantly associated with false positives in both groups, with a stronger relationship with false-positives in bvFTD. Voxel-based morphometry analyses revealed similar neural correlates of false positive endorsement across bvFTD and AD, with both patient groups showing involvement of prefrontal and Papez circuitry regions, such as medial temporal and thalamic regions, and a DTI analysis detected an emerging but non-significant trend between false positives and decreased fornix integrity in bvFTD only. These findings suggest that false-positive errors on recognition tests relate to similar mechanisms in bvFTD and AD, reflecting deficits in episodic memory processes and disinhibition. These findings highlight that current memory tests are not sufficient to accurately distinguish between bvFTD and AD patients.

The pathogenesis of cingulate atrophy in behavioral variant frontotemporal dementia and Alzheimer’s disease

BackgroundEarly atrophy of the cingulate cortex is a feature of both behavioral variant frontotemporal dementia (bvFTD) and Alzheimer’s disease (AD), with degeneration of the anterior cingulate region increasingly recognized as a strong predictor of bvFTD. The total number of neurons in this region, rather than the density of neurons, is associated with mood disturbance in other dementias, although there are no data on the extent and magnitude of neuronal loss in patients with bvFTD. While the density of small populations of neurons in this region has been assessed, it is unlikely that the degree of atrophy of the cingulate cortex seen in bvFTD can be explained by the loss of these subpopulations. This suggests that there is more generalized degeneration of neurons in this region in bvFTD.The present study assesses total neuronal number, as well as characteristic pathologies, in the anterior and posterior cingulate cortices of pathologically confirmed bvFTD (N = 11) and AD (N = 9) patients compared with age-matched controls (N = 14). The bvFTD cohort comprised 5 cases with tau pathology (Pick’s disease), and 6 with TDP-43 pathology.ResultsAt postmortem, atrophy was detected in the anterior and posterior cingulate cortices of bvFTD cases, but only in the posterior cingulate cortex of AD cases. As predicted, there was a significant reduction in both the density and total number of neurons in the anterior but not the posterior cingulate cortex of bvFTD cases with the opposite observed for the AD cases. Importantly, neuronal loss in the anterior cingulate cortex was only observed in cases with tau pathology.ConclusionsThis study confirms significant neuronal loss in the posterior but not anterior cingulate cortex in AD, and demonstrates that significant neuron loss in bvFTD occurs only in the anterior cingulate cortex but only in cases with tau pathology compared with cases with TDP pathology. We propose that significant neurodegeneration in the anterior cingulate cortex may be useful in differentiating the pathological subtypes in vivo.