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1. Distinct Patterns of Hippocampal Pathology in Alzheimer's Disease with Transactive Response DNA‐binding Protein 43

   https://doi.org/10.1002/ana.26762  

   Minogue, Grace ; Kawles, Allegra ; Zouridakis, Antonia ; Keszycki, Rachel ; Macomber, Alyssa ; Lubbat, Vivienne ; Gill, Nathan ; Mao, Qinwen ; Flanagan, Margaret E. ; Zhang, Hui ; et al ( September 2023 , Annals of Neurology)

   Age‐related dementia syndromes are often not related to a single pathophysiological process, leading to multiple neuropathologies found at autopsy. An amnestic dementia syndrome can be associated with Alzheimer's disease (AD) with comorbid transactive response DNA‐binding protein 43 (TDP‐43) pathology (AD/TDP). Here, we investigated neuronal integrity and pathological burden of TDP‐43 and tau, along the well‐charted trisynaptic hippocampal circuit (dentate gyrus [DG], CA3, and CA1) in participants with amnestic dementia due to AD/TDP, amnestic dementia due to AD alone, or non‐amnestic dementia due to TDP‐43 proteinopathy associated with frontotemporal lobar degeneration (FTLD‐TDP).

   A total of 48 extensively characterized cases (14 AD, 16 AD/TDP, 18 FTLD‐TDP) were analyzed using digital HALO software (Indica Labs, Albuquerque, NM, USA) to quantify pathological burden and neuronal loss.

   In AD/TDP and FTLD‐TDP, TDP‐43 immunoreactivity was greatest in the DG. Tau immunoreactivity was significantly greater in DG and CA3 in AD/TDP compared with pure AD. All clinical groups showed the highest amounts of neurons in DG, followed by CA3, then CA1. The AD and AD/TDP groups showed lower neuronal counts compared with the FTLD‐TDP group across all hippocampal subregions consistent with the salience of the amnestic phenotype.

   We conclude that AD/TDP can be distinguished from AD and FTLD‐TDP based on differential regional distributions of hippocampal tau and TDP‐43. Findings suggest that tau aggregation in AD/TDP might be enhanced by TDP‐43. ANN NEUROL 2023;94:1036–1047

    

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2. Stereological Changes in Microvascular Parameters in Hippocampus of a Transgenic Rat Model of Alzheimer’s Disease

   https://doi.org/10.3233/JAD-210738  

   Kolinko, Yaroslav ; Marsalova, Lucie ; Proskauer Pena, Stephanie ; Kralickova, Milena ; Mouton, Peter R. ( October 2021 , Journal of Alzheimer's Disease)

   de la Torre, Jack (Ed.)

   Background: Microcirculatory factors play an important role in amyloid-β (Aβ)-related neuropathology in Alzheimer’s disease (AD). Transgenic (Tg) rat models of mutant Aβ deposition can enhance our understanding of this microvascular pathology. Objective: Here we report stereology-based quantification and comparisons (between- and within-group) of microvessel length and number and associated parameters in hippocampal subregions in Tg model of AD in Fischer 344 rats and non-Tg littermates. Methods: Systematic-random samples of tissue sections were processed and laminin immunostained to visualize microvessels through the entire hippocampus in Tg and non-Tg rats. A computer-assisted stereology system was used to quantify microvessel parameters including total number, total length, and associated densities in dentate gyrus (DG) and cornu ammonis (CA) subregions. Results: Thin hair-like capillaries are common near Aβ plaques in hippocampal subregions of Tg rats. There are a 53% significant increase in average length per capillary across entire hippocampus (p≤0.04) in Tg compared to non-Tg rats; 49% reduction in capillary length in DG (p≤0.02); and, higher microvessel density in principal cell layers (p≤0.03). Furthermore, within-group comparisons confirm Tg but not non-Tg rats have significant increase in number density (p≤0.01) and potential diffusion distance (p≤0.04) of microvessels in principal cell layers of hippocampal subregions. Conclusion: We show the Tg deposition of human Aβ mutations in rats disrupts the wild-type microanatomy of hippocampal microvessels. Stereology-based microvascular parameters could promote the development of novel strategies for protection and the therapeutic management of AD. 

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3. Proportional loss of parvalbumin‐immunoreactive synaptic boutons and granule cells from the hippocampus of sea lions with temporal lobe epilepsy

   https://doi.org/10.1002/cne.24680  

   Cameron, Starr ; Lopez, Ariana ; Glabman, Raisa ; Abrams, Emily ; Johnson, Shawn ; Field, Cara ; Gulland, Frances M. D. ; Buckmaster, Paul S. ( March 2019 , Journal of Comparative Neurology)

   One in 26 people develop epilepsy and in these temporal lobe epilepsy (TLE) is common. Many patients display a pattern of neuron loss called hippocampal sclerosis. Seizures usually start in the hippocampus but underlying mechanisms remain unclear. One possibility is insufficient inhibition of dentate granule cells. Normally parvalbumin‐immunoreactive (PV) interneurons strongly inhibit granule cells. Humans with TLE display loss of PV interneurons in the dentate gyrus but questions persist. To address this, we evaluated PV interneuron and bouton numbers in California sea lions (Zalophus californianus) that naturally develop TLE after exposure to domoic acid, a neurotoxin that enters the marine food chain during harmful algal blooms. Sclerotic hippocampi were identified by the loss of Nissl‐stained hilar neurons. Stereological methods were used to estimate the number of granule cells and PV interneurons per dentate gyrus. Sclerotic hippocampi contained fewer granule cells, fewer PV interneurons, and fewer PV synaptic boutons, and the ratio of granule cells to PV interneurons was higher than in controls. To test whether fewer boutons was attributable to loss versus reduced immunoreactivity, expression of synaptotagmin‐2 (syt2) was evaluated. Syt2 is also expressed in boutons of PV interneurons. Sclerotic hippocampi displayed proportional losses of syt2‐immunoreactive boutons, PV boutons, and granule cells. There was no significant difference in the average numbers of PV‐ or syt2‐positive boutons per granule cell between control and sclerotic hippocampi. These findings do not address functionality of surviving synapses but suggest reduced granule cell inhibition in TLE is not attributable to anatomical loss of PV boutons.

    

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4. Classifying Non-Dementia and Alzheimer’s Disease/Vascular Dementia Patients Using Kinematic, Time-Based, and Visuospatial Parameters: The Digital Clock Drawing Test

   https://doi.org/10.3233/JAD-201129  

   Davoudi, Anis ; Dion, Catherine ; Amini, Shawna ; Tighe, Patrick J. ; Price, Catherine C. ; Libon, David J. ; Rashidi, Parisa ( June 2021 , Journal of Alzheimer's Disease)

   Bondi, Mark (Ed.)

   Background: Advantages of digital clock drawing metrics for dementia subtype classification needs examination. Objective: To assess how well kinematic, time-based, and visuospatial features extracted from the digital Clock Drawing Test (dCDT) can classify a combined group of Alzheimer’s disease/Vascular Dementia patients versus healthy controls (HC), and classify dementia patients with Alzheimer’s disease (AD) versus vascular dementia (VaD). Methods: Healthy, community-dwelling control participants (n = 175), patients diagnosed clinically with Alzheimer’s disease (n = 29), and vascular dementia (n = 27) completed the dCDT to command and copy clock drawing conditions. Thirty-seven dCDT command and 37 copy dCDT features were extracted and used with Random Forest classification models. Results: When HC participants were compared to participants with dementia, optimal area under the curve was achieved using models that combined both command and copy dCDT features (AUC = 91.52%). Similarly, when AD versus VaD participants were compared, optimal area under the curve was, achieved with models that combined both command and copy features (AUC = 76.94%). Subsequent follow-up analyses of a corpus of 10 variables of interest determined using a Gini Index found that groups could be dissociated based on kinematic, time-based, and visuospatial features. Conclusion: The dCDT is able to operationally define graphomotor output that cannot be measured using traditional paper and pencil test administration in older health controls and participants with dementia. These data suggest that kinematic, time-based, and visuospatial behavior obtained using the dCDT may provide additional neurocognitive biomarkers that may be able to identify and tract dementia syndromes. 

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5. Transcriptomic profiling of sporadic Alzheimer’s disease patients

   https://doi.org/10.1186/s13041-022-00963-2  

   Caldwell, Andrew B. ; Anantharaman, Balaji G. ; Ramachandran, Srinivasan ; Nguyen, Phuong ; Liu, Qing ; Trinh, Ivy ; Galasko, Douglas R. ; Desplats, Paula A. ; Wagner, Steven L. ; Subramaniam, Shankar ( October 2022 , Molecular Brain)

   Alzheimer’s disease (AD) manifested before age 65 is commonly referred to as early-onset AD (EOAD) (Reitz et al. Neurol Genet. 2020;6:e512). While the majority (> 90%) of EOAD cases are not caused by autosomal-dominant mutations inPSEN1,PSEN2, andAPP, they do have a higher heritability (92–100%) than sporadic late-onset AD (LOAD, 70%) (Wingo et al. Arch Neurol. 2012;69:59–64, Fulton-Howard et al. Neurobiol Aging. 2021;99:101.e1–101.e9). Although the endpoint clinicopathological changes, i.e., Aβ plaques, tau tangles, and cognitive decline, are common across EOAD and LOAD, the disease progression is highly heterogeneous (Neff et al. Sci Adv Am Assoc Adv Sci. 2021;7:eabb5398). This heterogeneity, leading to temporally distinct age at onset (AAO) and stages of cognitive decline, may be caused by myriad combinations of distinct disease-associated molecular mechanisms. We and others have used transcriptome profiling in AD patient-derived neuron models of autosomal-dominant EOAD and sporadic LOAD to identify disease endotypes (Caldwell et al. Sci Adv Am Assoc Adv Sci. 2020;6:eaba5933, Mertens et al. Cell Stem Cell. 2021;28:1533–1548.e6, Caldwell et al. Alzheimers Demen. 2022). Further, analyses of large postmortem brain cohorts demonstrate that only one-third of AD patients show hallmark disease endotypes like increased inflammation and decreased synaptic signaling (Neff et al. Sci Adv Am Assoc Adv Sci. 2021;7:eabb5398). Areas of the brain less affected by AD pathology at early disease stages—such as the primary visual cortex—exhibit similar transcriptomic dysregulation as those regions traditionally affected and, therefore, may offer a view into the molecular mechanisms of AD without the associated inflammatory changes and gliosis induced by pathology (Haroutunian et al. Neurobiol Aging. 2009;30:561–73). To this end, we analyzed AD patient samples from the primary visual cortex (19 EOAD, 20 LOAD) using transcriptomic signatures to identify patient clusters and disease endotypes. Interestingly, although the clusters showed distinct combinations and severity of endotypes, each patient cluster contained both EOAD and LOAD cases, suggesting that AAO may not directly correlate with the identity and severity of AD endotypes.

    

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