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2006; 16 (7): 916 - 28. 16 Radakovic R, Abrahams S. Developing a new apathy measurement scale: Dimensional Apathy Scale, Psychiatry Res. 2014; 219 (3): 658 - 63. 17 Huynh W, Ahmed R, Mahoney CJ, et al. Measurement of Social Cognition in Amyotrophic Lateral Sclerosis: A Population Based Study. 7 Girardi A, MacPherson SE, Abrahams S, Deficits in emotional and social cognition in amyotrophic lateral sclerosis, Neuropsychology. [Extracted from the article]

Background: Neuroanatomical staging of sporadic amyotrophic lateral sclerosis (ALS) indicates that neurodegeneration may spread corticofugally., Methods: We conducted an observational study to define the initial sites of disease onset and the clinical progression ('spreading patterns') of motor deficits in a cohort of 910 ALS patients in Germany., Results: Mean age of ALS onset was 59.0 ± 12.6 years for males and 61.2 ± 10.5 years for females, the mean ALSFRS-R was 35.1 ± 9.2, and 7.7% of the cohort reported a family history. Onset of motor symptoms was bulbar/upper limb in 26.8%/35.9%, the right arm initially being slightly more often affected than the left (18.5% vs.16.3%). Testing on concordance of handedness and onset in the dominant arm did not reach significance. Lower limb onset was observed in 37.3%. Unilateral limb onset patients reported horizontal spreading about three times more often than vertical spreading. 71/244 bulbar onset patients reported spreading pattern to the legs, and 17/339 lumbar onset patients reported spreading secondarily to the bulbar region., Discussion: Our results indicate that, although the phenotype of so-called 'spinal' or 'intraspinal' spreading predominated, we also observed an additional clinical spreading pattern: 29.1% of patients with bulbar onset experienced spreading clinically to the legs (vice versa in 5.0% of lumbar onset patients). For obvious neuroanatomical reasons, this pattern hardly can be explained solely by a 'spinal' or an 'intraspinal' pattern of spreading. Instead, these findings complement insights from previous clinical and clinicopathological studies supporting a cortical initiation of ALS., (© 2024. The Author(s).)

We quantified and determined for the first time the distribution pattern of the neuropeptide NPFF in the human cerebral cortex and subjacent white matter. To do so, we studied n = 9 cases without neurological disorders and n = 22 cases with neurodegenerative diseases, including sporadic amyotrophic lateral sclerosis (ALS, n = 8), Alzheimer's disease (AD, n = 8), Pick's disease (PiD, n = 3), and schizophrenia (n = 3). NPFF-immunopositive cells were located chiefly, but not exclusively, in the superficial white matter and constituted there a subpopulation of white matter interstitial cells (WMIC): Pyramidal-like and multipolar somata predominated in the gyral crowns, whereas bipolar and ovoid somata predominated in the cortex surrounding the sulci. Their sparsely ramified axons were unmyelinated and exhibited NPFF-positive bead-like varicosities. We found significantly fewer NPFF-immunopositive cells in the gray matter of the frontal, cingulate, and superior temporal gyri of both sporadic ALS and late-stage AD patients than in controls, and significantly fewer NPFF-positive cells in the subjacent as well as deep white matter of the frontal gyrus of these patients compared to controls. Notably, the number of NPFF-positive cells was also significantly lower in the hippocampal formation in AD compared to controls. In PiD, NPFF-positive cells were present in significantly lower numbers in the gray and white matter of the cingulate and frontal gyrii in comparison to controls. In schizophrenic patients, lower wNPFF cell counts in the neocortex were significant and global (cingulate, frontal, superior temporal gyrus, medial, and inferior gyri). The precise functions of NPFF-positive cells and their relationship to the superficial corticocortical white matter U-fibers are currently unknown. Here, NPFF immunohistochemistry and expression characterize a previously unrecognized population of cells in the human brain, thereby providing a new entry-point for investigating their physiological and pathophysiological roles., (© 2024. The Author(s).)

Background: Neuropathologic studies of brains from autopsy series show tau inclusions (pretangles, neuropils threads, neurofibrillary tangles) are detectable more than a decade before amyloid-β (Aβ) deposition in Alzheimer's disease (AD) and develop in a characteristic manner that forms the basis for AD staging. An alternative position views pathological tau without Aβ deposition as a 'primary age-related tauopathy' (PART) rather than prodromal AD. Recently, an early focus of tau inclusions in the Ammon's horn second sector (CA2) with relative sparing of CA1 that occurs before tau inclusions develop in the entorhinal cortex (EC) was proposed as an additional feature of PART., Objective: To test the 'definite PART' hypothesis., Methods: We used AT8-immunohistochemistry in 100μm sections to examine the EC, transentorhinal cortex (TRE), and Ammon's horn in 325 brains with tau inclusions lacking Aβ deposits (average age at death 66.7 years for females, 66.4 years for males)., Results: 100% of cases displayed tau inclusions in the TRE. In 89% of cases, the CA1 tau rating was greater than or equal to that in CA2. In 25%, CA2 was devoid of tau inclusions. Only 4% displayed a higher tau score in CA2 than in the TRE, EC, and CA1. The perforant path also displayed early tau changes. APOE genotyping was available for 199/325 individuals. Of these, 44% had an ɛ4 allele that placed them at greater risk for developing later NFT stages and, therefore, clinical AD., Conclusions: Our new findings call into question the PART hypothesis and are consistent with the idea that our cases represent prodromal AD.

Amyotrophic Lateral Sclerosis (ALS) is mainly characterized by the degeneration of corticospinal neurons and spinal α-motoneurons; vulnerable cells display prominent pTDP-43 inclusions. Evidence gathered from genetics, murine models, and iPSC-derived neurons point to the early involvement of synapses in the disease course and their crucial role in the pathogenic cascade. However, pathology studies, with specimens from large post-mortem cohorts, mapping the pattern of synaptic disturbances over clinical and neuropathological hallmarks of disease progression, are currently not available. Thus, the appearance and progression of synaptic degeneration in human ALS patients are currently not known, preventing a full validation of the murine and in vitro models. Here, we investigated the loss of synaptophysin-positive terminals in cervical, thoracic, and lumbar spinal cord samples from a retrospective cohort of n = 33 ALS patients and n = 8 healthy controls, and we correlated the loss of synapses against clinicodemographic features and neuropathological ALS stage. We found that, although dorsal and intermediate spinal cord laminae do not lose synapses, ALS patients displayed a substantial but variable loss of synapses in the ventral horn of lumbar and cervical spinal cord. The amount of synaptic loss was predicted by disease duration, by the clinical site of onset, and by the loss of α-motoneurons, although not by the fraction of pTDP-43-immunopositive α-motoneurons. Taken together, our findings validate the synaptic pathology observed in other models and suggest that pathogenic pathways unfolding in the spinal microenvironment are critical to the progressive disassembly of local synaptic connectivity., (© 2023. The Author(s).)

Background: Post mortem human brain tissue is an essential resource to study cell types, connectivity as well as subcellular structures down to the molecular setup of the central nervous system especially with respect to the plethora of brain diseases. A key method is immunostaining with fluorescent dyes, which allows high-resolution imaging in three dimensions of multiple structures simultaneously. Although there are large collections of formalin-fixed brains, research is often limited because several conditions arise that complicate the use of human brain tissue for high-resolution fluorescence microscopy., Results: In this study, we developed a clearing approach for immunofluorescence-based analysis of perfusion- and immersion-fixed post mortem human brain tissue, termed human Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging / Immunostaining / In situ hybridization-compatible Tissue-hYdrogel (hCLARITY). hCLARITY is optimized for specificity by reducing off-target labeling and yields very sensitive stainings in human brain sections allowing for super-resolution microscopy with unprecedented imaging of pre- and postsynaptic compartments. Moreover, hallmarks of Alzheimer's disease were preserved with hCLARITY, and importantly classical 3,3'-diaminobenzidine (DAB) or Nissl stainings are compatible with this protocol. hCLARITY is very versatile as demonstrated by the use of more than 30 well performing antibodies and allows for de- and subsequent re-staining of the same tissue section, which is important for multi-labeling approaches, e.g., in super-resolution microscopy., Conclusions: Taken together, hCLARITY enables research of the human brain with high sensitivity and down to sub-diffraction resolution. It therefore has enormous potential for the investigation of local morphological changes, e.g., in neurodegenerative diseases., (© 2023. The Author(s).)

Here, we studied the neuroinflammation- and ischemia-related glial markers chitotriosidase 1 (CHIT1) and chitinase-3-like protein 1 (CHI3L1, alias YKL-40) in the human striate cortex and cerebellum at different time points after global hypoxic-ischemic brain injury (HIBI). Both regions differ considerably in their glial cell population but are supplied by the posterior circulation. CHIT1 and CHI3L1 expression was compared to changes in microglial (IBA1, CD68), astrocytic (GFAP, S100β), and neuronal markers (H&E, neurofilament heavy chain, NfH; calretinin, CALR) using immunohistochemistry and multiple-label immunofluorescence. Initial striatal cortical and cerebellar Purkinje cell damage, detectable already 1/2 d after HIBI, led to delayed neuronal death, whereas loss of cerebellar NfH-positive stellate and CALR-positive granule cells was variable. During the first week post-HIBI, a transient reduction of IBA1-positive microglia was observed in both regions, and fragmented/clasmatodendritic cerebellar Bergmann glia appeared. In long-term survivors, both brain regions displayed high densities of activated IBA1-positive cells and CD68-positive macrophages, which showed CHIT1 co-localization in the striate cortex. Furthermore, enlarged GFAP- and S100β-positive astroglia emerged in both regions around 9-10 d post-HIBI, i.e., along with clearance of dead neurons from the neuropil, although GFAP-/S100β-positive gemistocytic astrocytes that co-expressed CHI3L1 were found only in the striate cortex. Thus, only GFAP-/S100β-positive astrocytes in the striate cortex, but not cerebellar Bergmann glia, differentiated into CHI3L1-positive gemistocytes. CHIT1 was co-expressed almost entirely in macrophages in the striate cortex and not cerebellum of long-term survivors, thereby indicating that CHIT1 and CHI3L1 could be valuable biomarkers for monitoring the outcome of global HIBI., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose of Review: Intracellular inclusions consisting of the abnormal TDP-43 protein and its nucleocytoplasmic mislocalization in selected cell types are hallmark pathological features of sALS. Descriptive (histological, morphological), anatomical, and molecular studies all have improved our understanding of the neuropathology of sporadic amyotrophic lateral sclerosis (sALS). This review highlights some of the latest developments in the field., Recent Findings: Increasing evidence exists from experimental models for the prion-like nature of abnormal TDP-43, including a strain-effect, and with the help of neuroimaging-based studies, for spreading of disease along corticofugal connectivities in sALS. Progress has also been made with respect to finding and establishing reliable biomarkers (neurofilament levels, diffusor tensor imaging)., Summary: The latest findings may help to elucidate the preclinical phase of sALS and to define possible mechanisms for delaying or halting disease development and progression., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The underlying neuropathological process of amyotrophic lateral sclerosis (ALS) can be classified in a four-stage sequential pTDP-43 cerebral propagation scheme. Using diffusion tensor imaging (DTI), in vivo imaging of these stages has already been shown to be feasible for the specific corticoefferent tract systems. Because both cognitive and oculomotor dysfunctions are associated with microstructural changes at the brain level in ALS, a cognitive and an oculomotor staging classification were developed, respectively. The association of these different in vivo staging schemes has not been attempted to date., Methods: A total of 245 patients with ALS underwent DTI, video-oculography, and cognitive testing using Edinburgh Cognitive and Behavioral ALS Screen (ECAS). A set of tract-related diffusion metrics, cognitive, and oculomotor parameters was selected for further analysis. Hierarchical and k-means clustering algorithms were used to obtain an optimal cluster solution., Results: According to cluster analysis, differentiation of patients with ALS into four clusters resulted: Cluster A showed the highest fractional anisotropy (FA) values and thereby the best performances in executive oculomotor tasks and cognitive tests, whereas cluster D showed the lowest FA values, the lowest ECAS scores, and the worst executive oculomotor performance across all clusters. Clusters B and C showed intermediate results regarding parameter values., Discussion: In a multimodal dataset of technical assessments of brain structure and function in ALS, an artificial intelligence-based cluster analysis showed high congruence of DTI, executive oculomotor function, and neuropsychological performance for mapping in vivo correlates of neuropathological spreading., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Flail arm syndrome is a restricted phenotype of motor neuron disease that is characterized by progressive, predominantly proximal weakness and atrophy of the upper limbs., Objective: The study was designed to investigate specific white matter alterations in diffusion tensor imaging (DTI) data from flail arm syndrome patients using a hypothesis-guided tract-of-interest-based approach to identify in vivo microstructural changes according to a neuropathologically defined amyotrophic lateral sclerosis (ALS)-related pathology of the cortico-efferent tracts., Methods: DTI-based white matter mapping was performed both by an unbiased voxel-wise statistical comparison and by a hypothesis-guided tract-wise analysis of fractional anisotropy (FA) maps according to the neuropathological ALS-propagation pattern for 43 flail arm syndrome patients vs 43 'classical' ALS patients vs 40 matched controls., Results: The analysis of white matter integrity demonstrated regional FA reductions for the flail arm syndrome group predominantly along the CST. In the tract-specific analysis according to the proposed sequential cerebral pathology pattern of ALS, the flail arm syndrome patients showed significant alterations of the specific tract systems that were identical to 'classical' ALS if compared to controls., Conclusions: The DTI study including the tract-of-interest-based analysis showed a microstructural involvement pattern in the brains of flail arm syndrome patients, supporting the hypothesis that flail arm syndrome is a phenotypical variant of ALS., (© 2021. The Author(s).)

The entorhinal cortex (EC) is the main interface between the sensory association areas of the neocortex and the hippocampus. It is crucial for the evaluation and processing of sensory data for long-term memory consolidation and shows damage in many brain diseases, for example, neurodegenerative diseases, such as Alzheimer's disease and developmental disorders. The pre-alpha layer of the EC in humans (layer II) displays a remarkable distribution of neurons in islands. These cellular islands give rise to a portion of the perforant path-the major reciprocal data stream for neocortical information into the hippocampal formation. However, the functional relevance of the morphological appearance of the pre-alpha layer in cellular islands and the precise timing of their initial appearance during primate evolution are largely unknown. Here, we conducted a comparative study of the EC from 38 nonhuman primates and Homo sapiens and found a strong relationship between gyrification index (GI) and the presence of the pre-alpha cellular islands. The formation of cellular islands also correlated with brain and body weight as well as neopallial volume. In the two human lissencephalic cases, the cellular islands in the pre-alpha layer were lacking. These findings emphasize the relationship between cortical folding and island formation in the EC from an evolutionary perspective and suggest a role in the pathomechanism of developmental brain disorders., (© 2021 The Authors. The Journal of Comparative Neurology published by Wiley Periodicals LLC.)

Objective: ALS primarily affects motor functions, but cognitive functions, including social understanding, may also be impaired. Von Economo neurons (VENs) are part of the neuronal substrate of social understanding and these cells are histopathologically altered in ALS. We investigated whether activity in areas including VENs is associated with an impairment of cognitive tasks that mirror social functioning., Methods: In this observational prospective study, ALS patients (N = 26) were tested for cognitive behavioural function, encompassing different aspects of empathetic understanding (interpersonal reactivity index, IRI), social behaviour (ultimatum game), recognition of faux-pas situations, and general cognitive functioning (Edinburgh Cognitive and Behavioural ALS Screen, ECAS). For in vivo pathological staging according to Braak, DTI-MRI was performed to determine those ALS patients with expected pathological involvement of VENs (B ALS stages 3 + 4) compared to those without (B ALS stages 1 + 2). Expected hypometabolism of cerebral areas was determined with 18 F-FDG PET in N = 20 ALS patients and compared to N = 20 matched healthy controls. Volume of interest analysis was performed in the anterior cingulate cortex (ACC) and the anterior insular cortex (AIC), which contain high numbers of VENs., Results: Compared to those without expected pathological involvement of VENs (B/B ALS stages 1 + 2), ALS patients with anticipated pathological involvement of VENs (B/B ALS stages 3 + 4) presented with significantly reduced fantasy to understand the mindset of others (IRI) and, social behaviour was more selfish (ultimatum game) despite the fact that cognitive understanding of socially inappropriate behaviour of others (faux-pas) was unimpaired. 18 F-FDG-PET showed hypometabolism in ACC and AIC in ALS patients with anticipated pathological involvement of VENs compared to those without and this was significantly correlated to cognitive-behavioral functions in certain tasks., Conclusion: Here, we present evidence of altered social behaviour in ALS patients associated with regional 18 FDG-PET hypometabolism in areas with a high density of VENs, thereby suggesting a possible causal association., Competing Interests: Declaration of competing interest None of the authors have any disclosures with reference to this work., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Tauopathies are heterogeneous neurodegenerative diseases defined by progressive brain accumulation of tau aggregates. The most common tauopathy, sporadic Alzheimer's disease (AD), involves progressive tau deposition that can be divided into specific stages of neurofibrillary tangle pathology. This classification is consistent with experimental data which suggests that network-based propagation is mediated by cell-cell transfer of tau "seeds", or assemblies, that serve as templates for their own replication. Until now, seeding assays of AD brain have largely been limited to areas previously defined by NFT pathology. We now expand this work to additional regions. We selected 20 individuals with AD pathology of NFT stages I, III, and V. We stained and classified 25 brain regions in each using the anti-phospho-tau monoclonal antibody AT8. We measured tau seeding in each of the 500 samples using a cell-based tau "biosensor" assay in which induction of intracellular tau aggregation is mediated by exogenous tau assemblies. We observed a progressive increase in tau seeding according to NFT stage. Seeding frequently preceded NFT pathology, e.g., in the basolateral subnucleus of the amygdala and the substantia nigra, pars compacta. We observed seeding in brain regions not previously known to develop tau pathology, e.g., the globus pallidus and internal capsule, where AT8 staining revealed mainly axonal accumulation of tau. AT8 staining in brain regions identified because of tau seeding also revealed pathology in a previously undescribed cell type: Bergmann glia of the cerebellar cortex. We also detected tau seeding in brain regions not previously examined, e.g., the intermediate reticular zone, dorsal raphe nucleus, amygdala, basal nucleus of Meynert, and olfactory bulb. In conclusion, tau histopathology and seeding are complementary analytical tools. Tau seeding assays reveal pathology in the absence of AT8 signal in some instances, and previously unrecognized sites of tau deposition. The variation in sites of seeding between individuals could underlie differences in the clinical presentation and course of AD., (© 2021. The Author(s).)