Search

Background: Approximately 90% of individuals diagnosed with the clinical syndrome of semantic variant of primary progressive aphasia (PPA‐S) will present at autopsy with the TDP‐43 type C pathologic form of frontotemporal lobar degeneration (FTLD‐TDP‐C). FTLD‐TDP‐C is primarily characterized by the presence of TDP‐43‐immunoreactive long, thick dystrophic neurites (DNs), which tend to be found in superficial cortical layers, perpendicular to the cortical surface. The cellular identity of long DNs is not yet known. This study aims to understand the neuronal origin of DNs via colocalization of pathologic TDP with axonal and dendritic markers. Method: Two right‐handed cases with FTLD‐TDP‐C as the sole pathologic diagnosis and a clinical diagnosis of PPA‐S were identified from the Northwestern University Alzheimer's Disease Research Center (NU‐ADRC) brain bank. Participants were co‐enrolled in the NU PPA program, a longitudinal study of individuals with this dementia syndrome. Paraffin‐embedded sections of right inferior frontal gyrus (IFG) were fluorescently double‐stained immunohistochemically with an antibody to TDP‐43 phosphorylated at Ser 409 / 410 (pTDP) and antibodies to either phosphorylated neurofilament (pNFH) or non‐phosphorylated neurofilament (npNFH) to visualize axons or proximal dendrites, respectively. A digital image of each slide was obtained at 20X magnification using the Olympus VS200 Slide Scanner and analyzed using QuPath software (v.0.4.3). Result: In both cases, staining revealed that a small amount (∼2%) of total DNs per section colocalize with npNFH (see Figure 1). Both long and short DNs, the latter of which are commonly apparent in other pathologic TDP subtypes (e.g., type A), demonstrated colocalization. By observation, half of colocalized DNs were oriented vertically. No DNs were found to colocalize with pNFH. Conclusion: Preliminary findings suggest that DNs in FTLD‐TDP‐C may be remnants of dystrophic dendrites. The vertical orientation of colocalized DNs could reflect the orientation of apical dendrites in superficial layers of cortex. It is possible that DNs that did not colocalize with dendritic or axonal protein may be of distal dendritic origin or may reflect loss of dendritic protein in affected neurons. While it is difficult to determine the pathogenic history of DNs, these observations are promising and warrant future in‐depth investigation. [ABSTRACT FROM AUTHOR]

Background: Persons with dementia syndromes such as primary progressive aphasia (PPA) and behavioral variant frontotemporal dementia (bvFTD) often develop neuropsychiatric symptoms (NPS). Various neurodegenerative diseases may cause PPA or bvFTD, including frontotemporal lobar degeneration (FTLD) with 3‐repeat tau pathology (Pick disease, "PiD"). Limbic regions implicated in mood and behavior, such as the amygdala, are highly impacted in FTLD with PiD. This study quantified Pick bodies and activated microglia in the amygdala of individuals with antemortem diagnosis of PPA or bvFTD and postmortem PiD neuropathology and examined associations with initial NPS. Method: We identified 16 right‐handed cases from the Northwestern University Alzheimer's Disease Research Center brain bank with bvFTD (N = 8) or PPA (N = 8) due to PiD with unilateral amygdala tissue (basolateral region) available. Fifteen cases had data on 12 NPS assessed via the Neuropsychiatric Inventory‐Questionnaire (NPI‐Q) from their earliest visit. We performed AT‐8 or HLA‐DR immunohistochemistry on amygdala sections to visualize Pick bodies or HLA‐DR+ activated microglia, respectively. We quantified the density of Pick bodies per mm3 via modified unbiased stereology and used HALO software (Indica Labs) to quantify percent area of HLA‐DR immunopositivity. We assessed differences between clinical groups via Welch's t‐test (Pick bodies) or repeated‐measures two‐way ANOVA (HLA‐DR). Pearson clinicopathologic correlations were examined between Pick bodies or HLA‐DR immunopositivity and initial endorsement of total (out of 12) or behavioral/comportmental (apathy, disinhibition, motor stereotypies, or appetite disturbance) NPI‐Q symptoms. Result: Amygdalar Pick body densities were similar between PPA (M = 28,822/mm3) and bvFTD (M = 29,114/mm3) cases. Compared to bvFTD, PPA cases trended towards a lower percent area of HLA‐DR immunopositivity (5.54% vs. 2.39%, p<0.10). There was no significant relationship between Pick Body density and initial NPIQ symptoms endorsed across all cases. However, area of HLA‐DR immunopositivity was positively correlated with initial endorsement of total (r = 0.47, p<0.10) and behavioral/comportmental (r = 0.54, p<0.05) NPI‐Q symptoms. Conclusion: Our findings suggest that microglial pathology in the amygdala contributes to early neuropsychiatric presentations in PiD, particularly symptoms reflective of behavioral/comportmental disturbance. Future study will investigate the impact of neuronal size and density in the amygdala on NPS in these dementia syndromes due to PiD. [ABSTRACT FROM AUTHOR]

Background: Primary Progressive Aphasia (PPA) is a dementia syndrome characterized by isolated and progressive impairment of language and focal atrophy of left‐hemispheric cortical regions. PPA presents with various underlying FTLD‐tauopathies such as Pick's disease (PiD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP). This study investigated clinicopathologic concordance between the aphasic phenotype of PPA and regional distributions of PSP markers quantified in language‐related cortical areas and the dentate gyrus (DG) of the hippocampus—an area of interest due to intact memory exhibited in PPA. Another goal was to compare regional distributions of tau‐positive markers in PSP compared to CBD and PiD to identify differential susceptibility patterns across FTLD‐tauopathies. Method: Paraffin‐embedded sections were stained immunohistochemically with AT‐8 to visualize neuronal tau inclusions and astrocytes containing phosphorylated tau in 8 right‐handed cases with PPA and autopsy‐confirmed PSP. Modified unbiased stereology was performed in bilateral middle frontal gyrus (MFG) and inferior parietal lobule (IPL), and left DG. A secondary analysis compared distributions of tau markers in cases with PiD (N = 6; tau‐positive inclusions) and CBD (N = 4; tau‐positive inclusions + astrocytic plaques). One‐way ANOVAs and students' t‐tests were used to analyze distributions. Result: Within the PSP group, there was significant left‐sided asymmetric predominance of tau‐positive neuronal inclusions and astrocytic tau in cortical areas; left MFG showed over double the total marker density vs right (3,490 vs 1,549 counts/mm3, respectively; p<0.05). In PSP, there was significantly less tau‐positive inclusions and astrocytes in the DG relative to cortical regions, where the ratio of left‐sided dentate‐to‐cortical inclusions was ∼1:2. This was remarkably lower than dentate‐to‐cortical ratios of ∼2:1 in CBD and ∼3:1 in PiD (p<0.01). Finally, PSP cases showed significantly greater astrocytic tau in cortical regions compared to CBD, by ∼100 fold in the left hemisphere (p<0.01). Conclusion: Findings from this stereological study of PPA with FTLD‐PSP show leftward cortical predominance of pathology concordant with the salience of the aphasic phenotype. Dentate predominance of pathology in PPA due to FTLD‐tau remains a mystery. The relative distribution of dentate‐to‐cortical tau pathology is different across FTLD‐tau species, offering insights into the selective vulnerability of distinct neuronal populations in neurodegenerative dementias. [ABSTRACT FROM AUTHOR]

Background: Inclusions containing phosphorylated transactive response DNA‐binding protein 43 (TDP‐43) aggregates have been shown to coexist in ∼60% of cases with postmortem Alzheimer's disease (AD) pathology, typically confined to mediotemporal brain regions. Together, these comorbid proteinopathies (TDP/AD) can lead to an amnestic dementia syndrome. The goal of this study was to identify, at early symptom onset, the shared versus distinct clinical, neuropsychological, and psychiatric features of cases with amnestic dementia and comorbid TDP/AD compared to those with AD as the primary neuropathologic diagnosis. Method: Twenty‐six individuals with amnestic impairment (Memory CDR=0.5 or 1) were identified from the Northwestern Alzheimer's Disease Research Center and stratified by the presence of either postmortem AD pathology (N=13) or comorbid TDP/AD (N=13). Neuropsychological scores from tests of attention, language, executive functioning, visuoconstructional abilities, and mood/neuropsychiatric symptoms were analyzed from the NIA's Uniform Data Set, version 2.0 or 3.0. Verbal (narrative and list‐learning) encoding and recall, and visual recall were included in memory assessment. In a subset of cases, a "visual‐to‐verbal" recall score was computed to determine the relative strength of visual memory compared to verbal. Student t‐tests with Welch's correction were used to determine differences between groups. Result: There were no differences in age at onset or death, frequency of APOE‐4 allele, or years of education between clinical groups. Preliminary findings showed no differences in attentional, executive, language, or visuoconstructional abilities. However, at disease onset, the TDP/AD group showed substantially higher frequency and severity of neuropsychiatric symptoms, including depression (p<0.005). Memory testing showed no group differences at the levels of learning/encoding verbal information; however, the TDP/AD group performed significantly worse in long‐term recall for narrative information (p<0.05). Qualitatively, the TDP/AD group showed stronger visual recall abilities (relative to verbal), whereas the AD group showed comparable performances in recall of material‐specific information. Conclusion: Preliminary findings suggest that comorbid TDP/AD underlying amnestic impairments demonstrate a distinct cognitive and neuropsychiatric phenotype at disease onset. These findings help lay the groundwork for future in‐depth clinicopathologic studies and can help guide proper diagnosis of multiple etiology amnestic dementia. [ABSTRACT FROM AUTHOR]