OBJECTIVE:To determine whether logopenic features of phonologic loop dysfunction reflect Alzheimer disease (AD) neuropathology in primary progressive aphasia (PPA).
METHODS:We performed a ...retrospective case-control study of 34 patients with PPA with available autopsy tissue. We compared baseline and longitudinal clinical features in patients with primary AD neuropathology to those with primary non-AD pathologies. We analyzed regional neuroanatomic disease burden in pathology-defined groups using postmortem neuropathologic data.
RESULTS:A total of 19/34 patients had primary AD pathology and 15/34 had non-AD pathology (13 frontotemporal lobar degeneration, 2 Lewy body disease). A total of 16/19 (84%) patients with AD had a logopenic spectrum phenotype; 5 met published criteria for the logopenic variant (lvPPA), 8 had additional grammatical or semantic deficits (lvPPA+), and 3 had relatively preserved sentence repetition (lvPPA−). Sentence repetition was impaired in 68% of patients with PPA with AD pathology; forward digit span (DF) was impaired in 90%, substantially higher than in non-AD PPA (33%, p < 0.01). Lexical retrieval difficulty was common in all patients with PPA and did not discriminate between groups. Compared to non-AD, PPA with AD pathology had elevated microscopic neurodegenerative pathology in the superior/midtemporal gyrus, angular gyrus, and midfrontal cortex (p < 0.01). Low DF scores correlated with high microscopic pathologic burden in superior/midtemporal and angular gyri (p ≤ 0.03).
CONCLUSIONS:Phonologic loop dysfunction is a central feature of AD-associated PPA and specifically correlates with temporoparietal neurodegeneration. Quantitative measures of phonologic loop function, combined with modified clinical lvPPA criteria, may help discriminate AD-associated PPA.
The microtubule-binding protein, tau, is the major component of neurofibrillary inclusions characteristic of Alzheimer's disease and related neurodegenerative tauopathies. When tau fibrillizes, it ...undergoes abnormal post-translational modifications resulting in decreased solubility and altered microtubule-stabilizing properties. Recently, we reported that the abnormal acetylation of tau at lysine residue 280 is a novel, pathological post-translational modification. Here, we performed detailed immunohistochemistry to further examine acetylated-tau expression in Alzheimer's disease and other major tauopathies. Immunohistochemistry using a polyclonal antibody specific for acetylated-tau at lysine 280 was conducted on 30 post-mortem central nervous system regions from patients with Alzheimer's disease (10 patients), corticobasal degeneration (5 patients), and progressive supranuclear palsy (5 patients). Acetylated-tau pathology was compared with the sequential emergence of other tau modifications in the Alzheimer's disease hippocampus using monoclonal antibodies to multiple well-characterized tau epitopes. All cases studied showed significant acetylated-tau pathology in a distribution pattern similar to hyperphosphorylated-tau. Acetylated-tau pathology was largely in intracellular, thioflavin-S-positive tau inclusions in Alzheimer's disease, and also thioflavin-S-negative pathology in corticobasal degeneration and progressive supranuclear palsy. Acetylated-tau was present throughout all stages of Alzheimer's disease pathology, but was more prominently associated with pathological tau epitopes in moderate to severe-stage cases. These temporal and morphological immunohistochemical features suggest acetylation of tau at this epitope is preceded by early modifications, including phosphorylation, and followed by later truncation events and cell death in Alzheimer's disease. Acetylation of tau at lysine 280 is a pathological modification that may contribute to tau-mediated neurodegeneration by both augmenting losses of normal tau properties (reduced solubility and microtubule assembly) as well as toxic gains of function (increased tau fibrillization). Thus, inhibiting tau acetylation could be a disease-modifying target for drug discovery target in tauopathies.
Abstract Background Transcranial direct current stimulation (tDCS) is a brain stimulation technique used to examine causal relationships between brain regions and cognitive functions. The effects ...from tDCS are complex, and the extent to which stimulation reliably affects different cognitive domains is not fully understood and continues to be debated. Objective/hypothesis To conduct a meta-analysis of studies examining the effects of single-session anodal tDCS on language. Methods The meta-analysis examined the behavioral results from eleven experiments of single-session anodal tDCS and language processing in healthy adults. The means and standard deviations of the outcome measures were extracted from each experiment and entered into the meta-analyses. In the first analysis, we examined the effects of single-session tDCS across all language studies. Next, a series of sub-analyses examined the effects of tDCS on specific tasks and stimulation protocols. Results There was a significant effect from anodal single-session tDCS in healthy adults compared to sham ( P = 0.001) across all language measures. Next, we found significant effects on specific stimulation protocols (e.g., offline measures, P = 0.002), as well as specific tasks and electrode montages (e.g., verbal fluency measures and left prefrontal cortex, P = 0.035). Conclusions The results indicate that single-session tDCS produces significant and reliable effects on language measures in healthy adults.
Cortical thickness is an important biomarker for image-based studies of the brain. A diffeomorphic registration based cortical thickness (DiReCT) measure is introduced where a continuous one-to-one ...correspondence between the gray matter–white matter interface and the estimated gray matter–cerebrospinal fluid interface is given by a diffeomorphic mapping in the image space. Thickness is then defined in terms of a distance measure between the interfaces of this sheet like structure. This technique also provides a natural way to compute continuous estimates of thickness within buried sulci by preventing opposing gray matter banks from intersecting. In addition, the proposed method incorporates neuroanatomical constraints on thickness values as part of the mapping process. Evaluation of this method is presented on synthetic images. As an application to brain images, a longitudinal study of thickness change in frontotemporal dementia (FTD) spectrum disorder is reported.
Objective
To use digital histology in a large autopsy cohort of Lewy body disorder (LBD) patients with dementia to test the hypotheses that co‐occurring Alzheimer disease (AD) pathology impacts the ...anatomic distribution of α‐synuclein (SYN) pathology and that co‐occurring neocortical tau pathology in LBDs associates with worse cognitive performance and occurs in a pattern differing from AD.
Methods
Fifty‐five autopsy‐confirmed LBD (Parkinson disease with dementia, n = 36; dementia with Lewy bodies, n = 19) patients and 25 AD patients were studied. LBD patients were categorized as having moderate/severe AD copathology (SYN + AD = 20) or little/no AD copathology (SYN−AD = 35). Digital measures of tau, β‐amyloid (Aβ), and SYN histopathology in neocortical and subcortical/limbic regions were compared between groups and related to antemortem cognitive testing.
Results
SYN burden was higher in SYN + AD than SYN−AD in each neocortical region (F1, 54 = 5.6–6.0, p < 0.02) but was equivalent in entorhinal cortex and putamen (F1, 43–49 = 0.7–1.7, p > 0.2). SYN + AD performed worse than SYN−AD on a temporal lobe–mediated naming task (t27 = 2.1, p = 0.04). Antemortem cognitive test scores inversely correlated with tau burden (r = −0.39 to −0.68, p < 0.05). AD had higher tau than SYN + AD in all regions (F1, 43 = 12.8–97.2, p < 0.001); however, SYN + AD had a greater proportion of tau in the temporal neocortex than AD (t41 = 2.0, p < 0.05), whereas AD had a greater proportion of tau in the frontal neocortex than SYN + AD (t41 = 3.3, p < 0.002). SYN + AD had similar severity and distribution of neocortical Aβ compared to AD (F1, 40–43 = 1.6–2.0, p > 0.1).
Interpretation
LBD patients with AD copathology harbor greater neocortical SYN pathology. Regional tau pathology relates to cognitive performance in LBD dementia, and its distribution may diverge from pure AD. Tau copathology contributes uniquely to the heterogeneity of cognitive impairment in LBD. Ann Neurol 2018; 1–13 ANN NEUROL 2019;85:259–271.
Frontotemporal dementia: a review Grossman, Murray
Journal of the International Neuropsychological Society,
05/2002, Letnik:
8, Številka:
4
Journal Article
Recenzirano
This review summarizes the clinical, imaging, and pathological features of frontotemporal dementia (FTD). Clinicians have become increasingly sensitive to FTD in the differential diagnosis of ...Alzheimer's disease. Clinical subgroups of FTD patients have been recognized, including patients with progressive non-fluent aphasia, semantic dementia, and behavioral disorder with executive difficulty. The clinical, neuroimaging and neuropathological profiles associated with these clinically defined subgroups are examined.
Ubiquitin-positive, tau- and α-synuclein-negative inclusions are hallmarks of frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. Although the ...identity of the ubiquitinated protein specific to either disorder was unknown, we showed that TDP-43 is the major disease protein in both disorders. Pathologic TDP-43 was hyper-phosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected central nervous system regions, including hippocampus, neocortex, and spinal cord. TDP-43 represents the common pathologic substrate linking these neurodegenerative disorders.
Objective
Common variants near TMEM106B associate with risk of developing frontotemporal dementia (FTD). Emerging evidence suggests a role for TMEM106B in neurodegenerative processes beyond FTD. We ...evaluate the effect of TMEM106B genotype on cognitive decline across multiple neurogenerative diseases.
Methods
We longitudinally followed 870 subjects with diagnoses of Parkinson disease (PD; n = 179), FTD (n = 179), Alzheimer disease (AD; n = 300), memory‐predominant mild cognitive impairment (MCI; n = 75), or neurologically normal control subjects (NC; n = 137) at the University of Pennsylvania (UPenn). All participants had annual Mini‐Mental State Examination (MMSE; median follow‐up duration = 3.0 years) and were genotyped at TMEM106B index single nucleotide polymorphism rs1990622. Genotype effects on cognition were confirmed by extending analyses to additional cognitive instruments (Mattis Dementia Rating Scale‐2 DRS‐2 and Montreal Cognitive Assessment MoCA) and to an international validation cohort (Parkinson's Progression Markers Initiative PPMI, N = 371).
Results
The TMEM106B rs1990622T allele, linked to increased risk of FTD, associated with greater MMSE decline over time in PD subjects but not in AD or MCI subjects. For FTD subjects, rs1990622T associated with more rapid decrease in MMSE only under the minor‐allele, rs1990622C, dominant model. Among PD patients, rs1990622T carriers from the UPenn cohort demonstrated more rapid longitudinal decline in DRS‐2 scores. Finally, in the PPMI cohort, TMEM106B risk allele carriers demonstrated more rapid longitudinal decline in MoCA scores.
Interpretation
Irrespective of cognitive instrument or cohort assessed, TMEM106B acts as a genetic modifier for cognitive trajectory in PD. Our results implicate lysosomal dysfunction in the pathogenesis of cognitive decline in 2 different proteinopathies. ANN NEUROL 2019;85:801–811.
Accumulation of paired helical filament tau contributes to neurodegeneration in Alzheimer's disease (AD).
F-flortaucipir is a positron emission tomography (PET) radioligand sensitive to tau in AD, ...but its clinical utility will depend in part on its ability to predict cognitive symptoms in diverse dementia phenotypes associated with selective, regional uptake. We examined associations between
F-flortaucipir and cognition in 14 mildly-impaired patients (12 with cerebrospinal fluid analytes consistent with AD pathology) who had amnestic (n = 5) and non-amnestic AD syndromes, including posterior cortical atrophy (PCA, n = 5) and logopenic-variant primary progressive aphasia (lvPPA, n = 4). Amnestic AD patients had deficits in memory; lvPPA in language; and both amnestic AD and PCA patients in visuospatial function. Associations with cognition were tested using sparse regression and compared to associations in anatomical regions-of-interest (ROIs).
F-flortaucipir uptake was expected to show regionally-specific correlations with each domain. In multivariate analyses, uptake was elevated in neocortical areas specifically associated with amnestic and non-amnestic syndromes. Uptake in left anterior superior temporal gyrus accounted for 67% of the variance in language performance. Uptake in right lingual gyrus predicted 85% of the variance in visuospatial performance. Memory was predicted by uptake in right fusiform gyrus and cuneus as well as a cluster comprising right anterior hippocampus and amygdala; this eigenvector explained 57% of the variance in patients' scores. These results provide converging evidence for associations between
F-flortaucipir uptake, tau pathology, and patients' cognitive symptoms.
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