The basal forebrain cholinergic neurons (BFCN) provide the primary source of cholinergic innervation of the human cerebral cortex. They are involved in the cognitive processes of learning, memory, ...and attention. These neurons are differentially vulnerable in various neuropathologic entities that cause dementia. This review summarizes the relevance to BFCN of neuropathologic markers associated with dementias, including the plaques and tangles of Alzheimer's disease (AD), the Lewy bodies of diffuse Lewy body disease, the tauopathy of frontotemporal lobar degeneration (FTLD‐TAU) and the TDP‐43 proteinopathy of FTLD‐TDP. Each of these proteinopathies has a different relationship to BFCN and their corticofugal axons. Available evidence points to early and substantial degeneration of the BFCN in AD and diffuse Lewy body disease. In AD, the major neurodegenerative correlate is accumulation of phosphotau in neurofibrillary tangles. However, these neurons are less vulnerable to the tauopathy of FTLD. An intriguing finding is that the intracellular tau of AD causes destruction of the BFCN, whereas that of FTLD does not. This observation has profound implications for exploring the impact of different species of tauopathy on neuronal survival. The proteinopathy of FTLD‐TDP shows virtually no abnormal inclusions within the BFCN. Thus, the BFCN are highly vulnerable to the neurodegenerative effects of tauopathy in AD, resilient to the neurodegenerative effect of tauopathy in FTLD and apparently resistant to the emergence of proteinopathy in FTLD‐TDP and perhaps also in Pick's disease. Investigations are beginning to shed light on the potential mechanisms of this differential vulnerability and their implications for therapeutic intervention.
This Review is part of the special issue “Cholinergic Mechanisms” and summarizes the relevance to basal forebrain cholinergic neurons (BFCN) of neuropathologic markers associated with dementias. Available evidence points to early and substantial degeneration of the BFCN in Alzheimer’s disease and diffuse Lewy body disease. BFCN are resilient to the neurodegenerative effect of some tauopathies in frontotemporal lobar degeneration (FTLD), such as that is corticobasal degeneration, and they are apparently resistant to the emergence of proteinopathy in FTLD‐TDP and perhaps also in Pick’s disease. These findings have important implications for selective neuronal vulnerability and cholinergic based therapies in dementias.
The anatomical distribution of most neurodegenerative diseases shows considerable interindividual variations. In contrast, frontotemporal lobar degeneration with transactive response DNA-binding ...protein type C (TDP-C) shows a consistent predilection for the anterior temporal lobe (ATL). The relatively selective atrophy of ATL in TDP-C patients has highlighted the importance of this region for complex cognitive and behavioral functions. This review includes observations on 28 TDP-C patients, 18 with semantic primary progressive aphasia and 10 with other syndromes. Longitudinal imaging allowed the delineation of progression trajectories. At post-mortem examination, the pathognomonic feature of TDP-C consisted of long, thick neurites found predominantly in superficial cortical layers. These neurites may represent dystrophic apical dendrites of layer III and V pyramidal neurons that are known to play pivotal roles in complex cortical computations. Other types of frontotemporal lobar degeneration TDP, such as TDP-A and TDP-B, are not associated with long dystrophic neurites in the cerebral cortex, and do not show similar predilection patterns for ATL. Research is beginning to identify molecular, structural, and immunological differences between pathological TDP-43 in TDP-C versus TDP-A and B. Parallel investigations based on proteomics, somatic mutations, and genome-wide association studies are detecting molecular features that could conceivably mediate the selective vulnerability of ATL to TDP-C. Future work will focus on characterizing the distinctive features of the abnormal TDP-C neurites, the mechanisms of neurotoxicity, initial cellular targets within the ATL, trajectory of spread, and the nature of ATL-specific markers that modulate vulnerability to TDP-C. ANN NEUROL 2023;94:1-12.
Shades of gray in human white matter Zouridakis, Antonia; Ayala, Ivan; Minogue, Grace ...
Journal of comparative neurology (1911),
December 2023, 2023-12-00, 20231201, Letnik:
531, Številka:
18
Journal Article
Recenzirano
Odprti dostop
Anatomists have long expressed interest in neurons of the white matter, which is by definition supposed to be free of neurons. Hypotheses regarding their biochemical signature and physiological ...function are mainly derived from animal models. Here, we investigated 15 whole‐brain human postmortem specimens, including cognitively normal cases and those with pathologic Alzheimer's disease (AD). Quantitative and qualitative methods were used to investigate differences in neuronal size and density, and the relationship between neuronal processes and vasculature. Double staining was used to evaluate colocalization of neurochemicals. Two topographically distinct populations of neurons emerged: one appearing to arise from developmental subplate neurons and the other embedded within deep, subcortical white matter. Both populations appeared to be neurochemically heterogeneous, showing positive reactivity to acetylcholinesterase (AChE) but not choline acetyltransferase (ChAT), neuronal nuclei (NeuN), nicotinamide adenine dinucleotide phosphate‐diaphorase (NADPH‐d), microtubule‐associated protein 2 (MAP–2), somatostatin (SOM), nonphosphorylated neurofilament protein (SMI‐32), and calcium‐binding proteins calbindin‐D28K (CB), calretinin (CRT), and parvalbumin (PV). PV was more richly expressed in superficial as opposed to deep white matter neurons (WMNs); subplate neurons were also significantly larger than their deeper counterparts. NADPH‐d, a surrogate for nitric oxide synthase, allowed for the striking morphological visualization of subcortical WMNs. NADPH‐d‐positive subcortical neurons tended to embrace the outer walls of microvessels, suggesting a functional role in vasodilation. The presence of AChE positivity in these neurons, but not ChAT, suggests that they are cholinoceptive but noncholinergic. WMNs were also significantly smaller in AD compared to control cases. These observations provide a landscape for future systematic investigations.
This graphic illustrates a coronal section of the human brain and highlights key characteristics of white matter neurons (WMNs). Two classes emerged, subplate and subcortical deep WMNs, which appeared to be neurochemically heterogenous; for example, image (a) demonstrates that there was no chemical overlap between NADPH‐d (blue) and MAP‐2 (red) positivity. Inspection of morphological features led to (b) the classification of three groups of NADPH‐d+ WMNs: (1) unipolar, (2) bipolar, and (3) multipolar—the latter of which was most frequently observed. (c) In cognitively normal par, subplate WMNs were found to be significantly larger than subcortical deep WMNs. (d) NADPH‐d+ subcortical neurons also tended to embrace the outer walls of microvessels, suggesting a functional role in vasodilation. Together, these observations provide a landscape for future systematic investigations of this unique cell population. Created with BioRender.com.
A patient with mild cognitive impairment who was treated in the extension phase of a trial of lecanemab, an antiamyloid compound, had multiple cerebral hemorrhages during infusion of t-PA for acute ...stroke.
Microglia maintain homeostasis in the brain, but whether aberrant microglial activation can cause neurodegeneration remains controversial. Here, we use transcriptome profiling to demonstrate that ...deficiency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progressive upregulation of lysosomal and innate immunity genes, increased complement production, and enhanced synaptic pruning in microglia. During aging, Grn−/− mice show profound microglia infiltration and preferential elimination of inhibitory synapses in the ventral thalamus, which lead to hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder (OCD)-like grooming behaviors. Remarkably, deleting C1qa gene significantly reduces synaptic pruning by Grn−/− microglia and mitigates neurodegeneration, behavioral phenotypes, and premature mortality in Grn−/− mice. Together, our results uncover a previously unrecognized role of progranulin in suppressing aberrant microglia activation during aging. These results represent an important conceptual advance that complement activation and microglia-mediated synaptic pruning are major drivers, rather than consequences, of neurodegeneration caused by progranulin deficiency.
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•Progranulin regulates lysosomal function and complements production in microglia•Grn−/− microglia preferentially eliminates inhibitory synapse in ventral thalamus•Grn−/− mice exhibit hyperexcitability in ventral thalamus and OCD-like behaviors•Loss of C1qa mitigates neurodegeneration and improves survival in Grn−/− mice
Loss of progranulin, which occurs in patients with frontotemporal dementia, causes lysosomal defects and excessive complement production, triggering selective synaptic pruning by microglia and behavioral deficits that can be rescued by blocking complement activation.
Objective
To quantitatively determine the density and distribution of activated microglia across cortical regions and hemispheres in the brains of primary progressive aphasia (PPA) participants with ...pathological diagnoses of frontotemporal lobar degeneration with transactive response DNA‐binding protein‐43 (TDP‐43) inclusions and to examine the relationships between microglial densities, patterns of focal atrophy, (TDP‐43) inclusions, and clinical phenotype.
Methods
Activated microglia and TDP‐43 inclusions were visualized in whole‐hemisphere brain sections using immunohistochemical methods from five participants with PPA‐TDP. Unbiased stereology was used to bilaterally quantify human leuckocyte antigen/D related–positive activated microglia and TDP‐43 inclusions across five language‐related regions. Density and distribution of both markers were compared across cortical regions and hemispheres, and their relationships to patterns of focal atrophy and clinical phenotype were determined.
Results
Activated microglia displayed asymmetric distribution favoring the language‐dominant hemisphere, consistent with greater postmortem and/or in vivo atrophy in that hemisphere, in PPA‐TDP. In one participant with no asymmetric atrophy, quantitative distribution of microglia also lacked asymmetry. Patterns of microglial activation also showed variation that favored areas of high atrophy in regions affiliated with language function, demonstrating concordance between patterns of microglial activation, atrophy, and clinical phenotype. TDP‐43 also showed higher inclusion densities in areas of high atrophy than in regions with low atrophy, but no clear relationship with microglia density at a regional level.
Interpretation
The initial activation of microglia is most likely a response to cortical abnormalities in PPA‐TDP, which contribute to atrophy. The patterns of microglial activation, TDP‐43 inclusion deposition, atrophy, and clinical phenotype suggest that activated microglia may make unique contributions to cortical thinning and TDP‐43 inclusion formation. Ann Neurol 2018;83:1096–1104
The Montreal Cognitive Assessment (MoCA) is a popular and simple-to-administer screening instrument to detect cognitive impairment. The MoCA generates a total score and six domain-specific index ...scores: (1) Memory, (2) Executive Functioning, (3) Attention, (4) Language, (5) Visuospatial, and (6) Orientation. It is unclear whether these MoCA scores can differentiate between distinct clinical dementia syndromes. This study compared MoCA Index scores between amnestic dementia of the Alzheimer's type (DAT) and primary progressive aphasia (PPA), a language-based dementia.
Baseline MoCA data were analyzed from 33 DAT, 37 PPA, and 83 cognitively normal individuals enrolled in the Clinical Core of the Northwestern Alzheimer's Disease Center. A one-way analysis of covariance adjusted for age was used to compare MoCA scores among groups. A logistic regression model was implemented to observe individual likelihood of group affiliation based on MoCA Index scores.
The mean MoCA total score was significantly higher in controls compared to both patient groups (p < .001) but did not differ between DAT and PPA groups. However, in accordance with salient clinical features commonly observed in DAT versus PPA, Memory and Orientation Index scores were lowest in the DAT group (p < .001), whereas Language and Attention Index scores were lowest in the PPA group (p < .001). Multivariate logistic regression analysis showed that the individual effects of Memory (p = .001), Language (p = .002), and Orientation (p = .025) Indices were significant.
MoCA Index scores can help differentiate among distinct cognitive syndromes, suggesting it may be a useful brief screening tool to detect domain-specific cognitive impairment.
Studies on the neural bases of sentence production have yielded mixed results, partly due to differences in tasks and participant types. In this study, 101 individuals with primary progressive ...aphasia (PPA) were evaluated using a test that required spoken production following an auditory prime (Northwestern Assessment of Verbs and Sentences-Sentence Production Priming Test, NAVS-SPPT), and one that required building a sentence by ordering word cards (Northwestern Anagram Test, NAT). Voxel-Based Morphometry revealed that gray matter (GM) volume in left inferior/middle frontal gyri (L IFG/MFG) was associated with sentence production accuracy on both tasks, more so for complex sentences, whereas, GM volume in left posterior temporal regions was exclusively associated with NAVS-SPPT performance and predicted by performance on a Digit Span Forward (DSF) task. Verb retrieval deficits partly mediated the relationship between L IFG/MFG and performance on the NAVS-SPPT. These findings underscore the importance of L IFG/MFG for sentence production and suggest that this relationship is partly accounted for by verb retrieval deficits, but not phonological loop integrity. In contrast, it is possible that the posterior temporal cortex is associated with auditory short-term memory ability, to the extent that DSF performance is a valid measure of this in aphasia.
Abstract
Basal forebrain cholinergic neurons (BFCN) display accumulation of neurofibrillary tangles and degeneration in Alzheimer disease and are targets of therapeutic intervention. This study ...determined vulnerability of BFCN to accumulation of TDP-43 in primary progressive aphasia with TDP-43 proteinopathy (PPA-TDP). Brains from 16 PPA participants with pathologically confirmed TDP-43 proteinopathy, with available paraffin-embedded sections (Group 1), or systematically sampled frozen sections (Group 2), were studied. Immunohistochemistry was performed with an antibody against phosphorylated TDP-43. BFCN were identified by their magnocellular appearance in Nissl preparations. Presence of TDP-43 inclusions and preinclusions in BFCN was determined and quantitative analysis was performed in Group 2. In Group 1, BFCN were completely free of inclusions except for occasional dystrophic neurites. Sparse TDP-43 preinclusions with smooth or granular staining in BFCN were detected. In Group 2, extremely rare TDP-43 intranuclear inclusions were detected in 0.1% of BFCN per section, along with occasional dystrophic neurites. Although sparse, significantly more preinclusions (1.4% of BFCN) were present when compared with inclusions. No hemispheric differences were noted. Small neurons near BFCN contained more preinclusions compared with BFCN. Thus, BFCN in PPA-TDP are resistant to TDP-43 proteinopathy and degeneration, suggesting that cholinergic therapy is unlikely to be effective in this disorder.
Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, ...metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD-abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions.
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