Objective To characterize sequential patterns of regional neuropathology and clinical symptoms in a well-characterized cohort of 21 patients with autopsy-confirmed Pick’s disease. Methods Detailed neuropathological examination using 70 μm and traditional 6 μm sections was performed using Thioflavin-S staining and immunohistochemistry for phosphorylated-tau, 3R and 4R tau isoforms, ubiquitin, and C-terminally truncated tau. Patterns of regional tau deposition were correlated with clinical data. In a subset of cases (n=5) converging evidence was obtained using antemortem neuroimaging measures of grey and white matter integrity. Results Four sequential patterns of pathological tau deposition were identified starting in frontotemporal limbic/paralimbic and neocortical regions (Phase I). Sequential involvement was seen in subcortical structures, including basal ganglia, locus coeruleus and raphe nuclei (Phase II), followed by primary motor cortex and pre-cerebellar nuclei (Phase III) and finally visual cortex in the most severe (Phase IV) cases. Behavioral variant frontotemporal dementia was the predominant clinical phenotype (18/21) but all patients eventually developed a social comportment disorder. Pathological tau phases reflected the evolution of clinical symptoms and degeneration on serial antemortem neuroimaging, directly correlated with disease-duration and inversely correlated with brain-weight at autopsy. The majority of neuronal and glial tau inclusions were 3R tau-positive and 4R tau-negative in sporadic cases. There was a relative abundance of mature tau pathology markers in frontotemporal limbic/paralimbic regions compared to neocortical regions. Interpretation Pick’s disease tau neuropathology may originate in limbic/paralimbic cortices. The patterns of tau pathology observed here provide novel insights into the natural history and biology of tau-mediated neurodegeneration.

We remember a considerable number of personal experiences because we are frequently reminded of them, a process known as memory reactivation. Although memory reactivation helps to stabilize and update memories, reactivation may also introduce distortions if novel information becomes incorporated with memory. Here we used functional magnetic resonance imaging (fMRI) to investigate the neural mechanisms mediating reactivationinduced updating in memory for events experienced during a museum tour. During scanning, participants were shown target photographs to reactivate memories from the museum tour followed by a novel lure photograph from an alternate tour. Later, participants were presented with target and lure photographs and asked to determine whether the photographs showed a stop they visited during the tour. We used a subsequent memory analysis to examine neural recruitment during reactivation that was associated with later true and false memories. We predicted that the quality of reactivation, as determined by online ratings of subjective recollection, would increase subsequent true memories but also facilitate incorporation of the lure photograph, thereby increasing subsequent false memories. The fMRI results revealed that the quality of reactivation modulated subsequent true and false memories via recruitment of left posterior parahippocampal, bilateral retrosplenial, and bilateral posterior inferior parietal cortices. However, the timing of neural recruitment and the way in which memories were reactivated contributed to differences in whether memory reactivation led to distortions or not. These data reveal the neural mechanisms recruited during memory reactivation that modify how memories will be subsequently retrieved, supporting the flexible and dynamic aspects of memory.autobiographical memory | false memory | episodic memory R esearch in psychology and neuroscience supports the idea that memory is not an exact reproduction of past experiences, but is instead a constructive process subject to a variety of errors and distortions (1-8). Both in the laboratory and everyday life, much evidence shows that people sometimes remember events differently from the way they actually unfolded and under some conditions remember events that never happened (9-12). Memory distortions can have serious consequences in everyday life, as illustrated by the frequent involvement of eyewitness memory errors (13) in wrongful convictions of individuals who were eventually exonerated on the basis of DNA evidence (14).Memory distortions are often viewed as flaws in the memory system or as evidence of impairment, and there is evidence consistent with this view: increased susceptibility to memory distortions has been linked with such phenomena as low intelligence (15), frontal-lobe damage (16-18), and symptoms of posttraumatic stress disorder (19). An alternative approach characterizes memory distortions as byproducts of otherwise adaptive features of memory. An early example of this approach comes from Bartlett (7), who theorized t...

Importance Grammatical comprehension difficulty is an essential supporting feature of the non-fluent/agrammatic variant of primary progressive aphasia (naPPA), but well-controlled clinical measures of grammatical comprehension are unavailable. Objective To develop a measure of grammatical comprehension and examine this comparatively in PPA variants and behavioural-variant frontotemporal degeneration (bvFTD) and to assess the neuroanatomic basis for these deficits with volumetric grey matter atrophy and whole-brain fractional anisotropy (FA) in white matter tracts. Design Case–control study. Setting Academic medical centre. Participants 39 patients with variants of PPA (naPPA=12, lvPPA=15 and svPPA=12), 27 bvFTD patients without aphasia and 12 healthy controls. Main outcome measure Grammatical comprehension accuracy. Results Patients with naPPA had selective difficulty understanding cleft sentence structures, while all PPA variants and patients with bvFTD were impaired with sentences containing a centre-embedded subordinate clause. Patients with bvFTD were also impaired understanding sentences involving short-term memory. Linear regressions related grammatical comprehension difficulty in naPPA to left anterior-superior temporal atrophy and reduced FA in corpus callosum and inferior frontal-occipital fasciculus. Difficulty with centre-embedded sentences in other PPA variants was related to other brain regions. Conclusions and relevance These findings emphasise a distinct grammatical comprehension deficit in naPPA and associate this with interruption of a frontal-temporal neural network.

Genome-wide association studies have identified SNPs that are sensitive for tau or TDP-43 pathology in frontotemporal lobar degeneration (FTLD). Neuroimaging analyses have revealed distinct distributions of disease in FTLD patients with genetic mutations. However, genetic influences on neuroanatomical structure in sporadic FTLD have not been assessed. In this report we use novel multivariate tools, eigenanatomy and sparse canonical correlation analysis (SCCAN), to identify associations between SNPs and neuroanatomical structure in sporadic FTLD. MRI analyses revealed that rs8070723 (MAPT) was associated with grey matter variance in the temporal cortex. DTI analyses revealed that rs1768208 (MOBP), rs646776 (near SORT1) and rs5848 (PGRN) were associated with white matter variance in the midbrain and superior longitudinal fasciculus. In an independent autopsy series we observed that rs8070723 and rs1768208 conferred significant risk of tau pathology relative to TDP-43, and rs646776 conferred increased risk of TDP-43 pathology relative to tau. Identified brain regions and SNPs may help provide an in vivo screen for underlying pathology in FTLD and contribute to our understanding of sporadic FTLD.

Objective: We examined narrative discourse in amyotrophic lateral sclerosis (ALS) to assess the role of executive functioning in support of language and the neuroanatomical basis for such support.Methods: We analyzed a semistructured speech sample in 26 patients with ALS and 19 healthy seniors for narrative discourse features of coherence. Regression analyses related a measure of discourse coherence ("local connectedness") to gray matter atrophy and reduced white matter fractional anisotropy.Results: Patients with ALS were impaired relative to controls on measures of discourse adequacy, including local connectedness and maintenance of the theme. These discourse measures were related to measures of executive functioning but not to motor functioning. Regressions related local connectedness to gray matter atrophy in ventral and dorsal prefrontal regions and to reduced fractional anisotropy in white matter tracts mediating projections between prefrontal regions. Conclusion:Patients with ALS exhibit deficits in their ability to organize narrative discourse.These deficits appear to be related in part to executive limitations. Consistent with the hypothesis that ALS is a multisystem disorder, this deficit is related to disease in prefrontal regions. Amyotrophic lateral sclerosis (ALS) is typically viewed as a motor system disorder, but cognitive impairments in ALS are increasingly recognized.1,2 Language impairments in ALS may result in part from deficits in executive functioning, 3-5 but they have also been shown to be at least in part independent of executive dysfunction.6-8 Most reports of language performance in ALS have focused on the comprehension or production of single words. 1,7,9,10 There are few studies of spontaneous, continuous speech-referred to as "connected speech"-in these patients, despite the importance of connected speech in everyday life. In this study, we elicited a semistructured speech sample in the form of a narrative of sufficient length to allow subjects to demonstrate the full range of their linguistic capabilities. We examined the discourse structure of the narratives to determine whether executive impairments were associated with difficulty in telling the story, and we assessed the contribution of motor weakness to narrative production.MRI studies of ALS have demonstrated gray matter (GM) atrophy and white matter (WM) reduced fractional anisotropy (FA) in prefrontal regions, 11,12 consistent with the claim that ALS is a multisystem disorder. 13,14 To elucidate the neuroanatomical basis of narrative discourse deficits in ALS, we related performance to high-resolution GM and WM structural imaging in a subset of patients. Based on previous fMRI work in healthy adults and nonaphasic patients with