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

OBJECTIVE: 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). METHODS: 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. RESULTS: 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. INTERPRETATION: 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.

Temporopolar regions of the human brain.

Following prolonged neglect during the formative decades of behavioural neurology, the temporopolar region has become a site of vibrant research on the neurobiology of cognition and conduct. This turnaround can be attributed to increasing recognition of neurodegenerative diseases that target temporopolar regions for peak destruction. The resultant syndromes include behavioural dementia, associative agnosia, semantic forms of primary progressive aphasia and semantic dementia. Clinicopathological correlations show that object naming and word comprehension are critically dependent on the language-dominant (usually left) temporopolar region, whereas behavioural control and non-verbal object recognition display a more bilateral representation with a rightward bias. Neuroanatomical experiments in macaques and neuroimaging in humans show that the temporoparietal region sits at the confluence of auditory, visual and limbic streams of processing at the downstream (deep) pole of the 'what' pathway. The functional neuroanatomy of this region revolves around three axes, an anterograde horizontal axis from unimodal to heteromodal and paralimbic cortex; a radial axis where visual (ventral), auditory (dorsal) and paralimbic (medial) territories encircle temporopolar cortex and display hemispheric asymmetry; and a vertical depth-of-processing axis for the associative elaboration of words, objects and interoceptive states. One function of this neural matrix is to support the transformation of object and word representations from unimodal percepts to multimodal concepts. The underlying process is likely to start at canonical gateways that successively lead to generic (superordinate), specific (basic) and unique levels of recognition. A first sign of left temporopolar dysfunction takes the form of taxonomic blurring where boundaries among categories are preserved but not boundaries among exemplars of a category. Semantic paraphasias and coordinate errors in word-picture verification tests are consequences of this phenomenon. Eventually, boundaries among categories are also blurred and comprehension impairments become more profound. The medial temporopolar region belongs to the amygdalocentric component of the limbic system and stands to integrate exteroceptive information with interoceptive states underlying social interactions. Review of the pertinent literature shows that word comprehension and conduct impairments caused by temporopolar strokes and temporal lobectomy are far less severe than those seen in temporopolar atrophies. One explanation for this unexpected discrepancy invokes the miswiring of residual temporopolar neurons during the many years of indolently progressive neurodegeneration. According to this hypothesis, the temporopolar regions become not only dysfunctional but also sources of aberrant outputs that interfere with the function of areas elsewhere in the language and paralimbic networks, a juxtaposition not seen in lobectomy or stroke.

The production of adjectives in narratives by individuals with primary progressive aphasia.

Adjectives (e.g., hungry) are an important part of language, but have been little studied in individuals with impaired language. Adjectives are used in two different ways in English: attributively, to modify a noun (the hungry dog); or predicatively, after a verb (the dog is hungry). Attributive adjectives have a more complex grammatical structure than predicative adjectives, and may therefore be particularly prone to disruption in individuals with grammatical impairments. We investigated adjective production in three subtypes of primary progressive aphasia (PPA: agrammatic, semantic, logopenic), as well as in agrammatic stroke aphasia and a group of healthy control participants. Participants produced narratives based on picture books, and we coded every adjective they produced for its syntactic structure. Compared to healthy controls, the two agrammatic groups, but not the other two patient groups, produced significantly fewer attributive adjectives per sentence. All four patient groups were similar to controls for their rate of predicative adjective production. In addition, we found a significant correlation in the agrammatic PPA participants between their rate of producing attributive adjective and impaired production of sentences with complex syntactic structure (subject cleft sentences like It was the boy that chased the girl); no such correlation was found for predicative adjectives. Irrespective of structure, we examined the lexical characteristics of the adjectives that were produced, including length, frequency, semantic diversity and neighborhood density. Overall, the lexical characteristics of the produced adjectives were largely consistent with the language profile of each group. In sum, the results suggest that attributive adjectives present a particular challenge for individuals with agrammatic language production, and add a new dimension to the description of agrammatism. Our results further suggest that attributive adjectives may be a fruitful target for improved treatment and recovery of agrammatic language.

Integrity of Neuronal Size in the Entorhinal Cortex Is a Biological Substrate of Exceptional Cognitive Aging.

Average aging is associated with a gradual decline of memory capacity. SuperAgers are humans ≥80 years of age who show exceptional episodic memory at least as good as individuals 20-30 years their junior. This study investigated whether neuronal integrity in the entorhinal cortex (ERC), an area critical for memory and selectively vulnerable to neurofibrillary degeneration, differentiated SuperAgers from cognitively healthy younger individuals, cognitively average peers ("Normal Elderly"), and individuals with amnestic mild cognitive impairment. Postmortem sections of the ERC were stained with cresyl violet to visualize neurons and immunostained with mouse monoclonal antibody PHF-1 to visualize neurofibrillary tangles. The cross-sectional area (i.e., size) of layer II and layer III/V ERC neurons were quantified. Two-thirds of total participants were female. Unbiased stereology was used to quantitate tangles in a subgroup of SuperAgers and Normal Elderly. Linear mixed-effect models were used to determine differences across groups. Quantitative measurements found that the soma size of layer II ERC neurons in postmortem brain specimens were significantly larger in SuperAgers compared with all groups (p < 0.05)-including younger individuals 20-30 years their junior (p < 0.005). SuperAgers had significantly fewer stereologically quantified Alzheimer's disease-related neurofibrillary tangles in layer II ERC than Normal Elderly (p < 0.05). This difference in tangle burden in layer II between SuperAgers and Normal Elderly suggests that tangle-bearing neurons may be prone to shrinkage during aging. The finding that SuperAgers show ERC layer II neurons that are substantially larger even compared with individuals 20-30 years younger is remarkable, suggesting that layer II ERC integrity is a biological substrate of exceptional memory in old age.SIGNIFICANCE STATEMENT Average aging is associated with a gradual decline of memory. Previous research shows that an area critical for memory, the entorhinal cortex (ERC), is susceptible to the early formation of Alzheimer's disease neuropathology, even during average (or typical) trajectories of aging. The Northwestern University SuperAging Research Program studies unique individuals known as SuperAgers, individuals ≥80 years old who show exceptional memory that is at least as good as individuals 20-30 years their junior. In this study, we show that SuperAgers harbor larger, healthier neurons in the ERC compared with their cognitively average same-aged peers, those with amnestic mild cognitive impairment, and - remarkably - even compared with individuals 20-30 years younger. We conclude that larger ERC neurons are a biological signature of the SuperAging trajectory.

NIH Toolbox® Episodic Memory Measure Differentiates Older Adults with Exceptional Memory Capacity from those with Average-for-Age Cognition.

OBJECTIVE: Older adults with exceptional memory function, designated "SuperAgers," include individuals over age 80, with episodic memory at least as good as individuals ages 50s-60s. The Northwestern University SuperAging cohort is defined by performance on an established test of verbal memory. The purpose of this study was to determine if superior verbal memory extends to nonverbal memory in SuperAgers by examining differences in the National Institutes of Health Toolbox® (NIHTB) between older adults with exceptional memory and those with average-for-age cognition. METHOD: SuperAgers (n = 46) and cognitively average-for-age older adults (n = 31) completed a comprehensive neuropsychological battery and the NIHTB Cognition module. Multiple linear regressions were used to examine differences on subtests between groups. RESULTS: There was a significant effect of group on the Picture Sequence Memory score, (p = .007), such that SuperAgers had higher scores than cognitively average-for-age older adults. There were no other group effects across other non-episodic memory NIHTB Cognition measures. CONCLUSIONS: Findings from this study demonstrated stronger performance on the memory measure of the NIHTB in SuperAgers compared to cognitively average-for-age older adults demonstrating superior memory in not only verbal but also nonverbal episodic memory in this group. Additionally, this study adds to the literature validating the NIHTB in older adults, particularly in a novel population of adults over age 80 with exceptional memory.

Neuropathological fingerprints of survival, atrophy and language in primary progressive aphasia.

Primary progressive aphasia is a neurodegenerative disease that selectively impairs language without equivalent impairment of speech, memory or comportment. In 118 consecutive autopsies on patients with primary progressive aphasia, primary diagnosis was Alzheimer's disease neuropathological changes (ADNC) in 42%, corticobasal degeneration or progressive supranuclear palsy neuropathology in 24%, Pick's disease neuropathology in 10%, transactive response DNA binding proteinopathy type A [TDP(A)] in 10%, TDP(C) in 11% and infrequent entities in 3%. Survival was longest in TDP(C) (13.2 ± 2.6 years) and shortest in TDP(A) (7.1 ± 2.4 years). A subset of 68 right-handed participants entered longitudinal investigations. They were classified as logopenic, agrammatic/non-fluent or semantic by quantitative algorithms. Each variant had a preferred but not invariant neuropathological correlate. Seventy-seven per cent of logopenics had ADNC, 56% of agrammatics had corticobasal degeneration/progressive supranuclear palsy or Pick's disease and 89% of semantics had TDP(C). Word comprehension impairments had strong predictive power for determining underlying neuropathology positively for TDP(C) and negatively for ADNC. Cortical atrophy was smallest in corticobasal degeneration/progressive supranuclear palsy and largest in TDP(A). Atrophy encompassed posterior frontal but not temporoparietal cortex in corticobasal degeneration/progressive supranuclear palsy, anterior temporal but not frontoparietal cortex in TDP(C), temporofrontal but not parietal cortex in Pick's disease and all three lobes with ADNC or TDP(A). There were individual deviations from these group patterns, accounting for less frequent clinicopathologic associations. The one common denominator was progressive asymmetric atrophy overwhelmingly favouring the left hemisphere language network. Comparisons of ADNC in typical amnestic versus atypical aphasic dementia and of TDP in type A versus type C revealed fundamental biological and clinical differences, suggesting that members of each pair may constitute distinct clinicopathologic entities despite identical downstream proteinopathies. Individual TDP(C) participants with unilateral left temporal atrophy displayed word comprehension impairments without additional object recognition deficits, helping to dissociate semantic primary progressive aphasia from semantic dementia. When common and uncommon associations were considered in the set of 68 participants, one neuropathology was found to cause multiple clinical subtypes, and one subtype of primary progressive aphasia to be caused by multiple neuropathologies, but with different probabilities. Occasionally, expected clinical manifestations of atrophy sites were absent, probably reflecting individual peculiarities of language organization. The hemispheric asymmetry of neurodegeneration and resultant language impairment in primary progressive aphasia reflect complex interactions among the cellular affinities of the degenerative disease, the constitutive biology of language cortex, familial or developmental vulnerabilities of this network and potential idiosyncrasies of functional anatomy in the affected individual.

Cortical and subcortical pathological burden and neuronal loss in an autopsy series of FTLD-TDP-type C.

The TDP-43 type C pathological form of frontotemporal lobar degeneration is characterized by the presence of immunoreactive TDP-43 short and long dystrophic neurites, neuronal cytoplasmic inclusions, neuronal loss and gliosis and the absence of neuronal intranuclear inclusions. Frontotemporal lobar degeneration-TDP-type C cases are commonly associated with the semantic variant of primary progressive aphasia or behavioural variant frontotemporal dementia. Here, we provide detailed characterization of regional distributions of pathological TDP-43 and neuronal loss and gliosis in cortical and subcortical regions in 10 TDP-type C cases and investigate the relationship between inclusions and neuronal loss and gliosis. Specimens were obtained from the first 10 TDP-type C cases accessioned from the Northwestern Alzheimer's Disease Research Center (semantic variant of primary progressive aphasia, n = 7; behavioural variant frontotemporal dementia, n = 3). A total of 42 cortical (majority bilateral) and subcortical regions were immunostained with a phosphorylated TDP-43 antibody and/or stained with haematoxylin-eosin. Regions were evaluated for atrophy, and for long dystrophic neurites, short dystrophic neurites, neuronal cytoplasmic inclusions, and neuronal loss and gliosis using a semiquantitative 5-point scale. We calculated a 'neuron-to-inclusion' score (TDP-type C mean score - neuronal loss and gliosis mean score) for each region per case to assess the relationship between TDP-type C inclusions and neuronal loss and gliosis. Primary progressive aphasia cases demonstrated leftward asymmetry of cortical atrophy consistent with the aphasic phenotype. We also observed abundant inclusions and neurodegeneration in both cortical and subcortical regions, with certain subcortical regions emerging as particularly vulnerable to dystrophic neurites (e.g. amygdala, caudate and putamen). Interestingly, linear mixed models showed that regions with lowest TDP-type C pathology had high neuronal dropout, and conversely, regions with abundant pathology displayed relatively preserved neuronal densities (P < 0.05). This inverse relationship between the extent of TDP-positive inclusions and neuronal loss may reflect a process whereby inclusions disappear as their associated neurons are lost. Together, these findings offer insight into the putative substrates of neurodegeneration in unique dementia syndromes.

Evaluating the association between genetically proxied ACE inhibition and dementias.

INTRODUCTION: Angiotensin-converting enzyme (ACE) has been implicated in the metabolism of amyloid beta; however, the causal effect of ACE inhibition on risk of Alzheimer's disease (AD) dementia and other common dementias is largely unknown. METHODS: We examined the causal association of genetically proxied ACE inhibition with four types of dementias using a two-sample Mendelian randomization (MR) approach. RESULTS: Genetically proxied ACE inhibition was associated with increased risk of AD dementia (odds ratio per one standard deviation reduction in serum ACE [95% confidence interval]; 1.07 [1.04-1.10], P = 5 × 10-07 ) and frontotemporal dementia (1.16 [1.04-1.29], P = 0.01) but not with Lewy body dementia or vascular dementia (P > 0.05). These findings were independently replicated and remained consistent in sensitivity analyses. DISCUSSION: This comprehensive MR study provided genetic evidence for an association between ACE inhibition and the risk for AD and frontotemporal dementias. These results should encourage further studies of the neurocognitive effects of ACE inhibition. HIGHLIGHTS: This study evaluated genetically proxied angiotensin-converting enzyme (ACE) inhibition association with dementias. The results suggest an association between ACE inhibition and Alzheimer's disease. The results suggest an association between ACE inhibition and frontotemporal dementia. Those associations can be interpreted as potentially causal.

Genome-wide association study and functional validation implicates JADE1 in tauopathy.

Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-ß (Aß) plaques. The pathogenesis of PART is not known, but evidence suggests an association with genes that promote tau pathology and others that protect from Aß toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n = 647) using Braak neurofibrillary tangle stage as a quantitative trait. We found some significant associations with candidate loci associated with AD (SLC24A4, MS4A6A, HS3ST1) and progressive supranuclear palsy (MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brains with four microtubule-binding domain repeats (4R) isoforms and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation in post-mortem human PART brain tissue revealed a specific binding of JADE1 protein to four repeat tau lacking N-terminal inserts (0N4R). Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model, as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration.

Neuropsychological Profiles of Older Adults with Superior versus Average Episodic Memory: The Northwestern "SuperAger" Cohort.

OBJECTIVE: SuperAgers are adults over the age of 80 with superior episodic memory performance and at least average-for-age performance in non-episodic memory domains. This study further characterized the neuropsychological profile of SuperAgers compared to average-for-age episodic memory peers to determine potential cognitive mechanisms contributing to their superior episodic memory performance. METHOD: Retrospective analysis of neuropsychological test data from 56 SuperAgers and 23 similar-age peers with average episodic memory was conducted. Independent sample t-tests evaluated between-group differences in neuropsychological scores. Multiple linear regression determined the influence of non-episodic memory function on episodic memory scores across participants. RESULTS: As a group, SuperAgers had better scores than their average memory peers on measures of attention, working memory, naming, and speeded set shifting. Scores on tests of processing speed, visuospatial function, verbal fluency, response inhibition, and abstract reasoning did not differ. On an individual level, there was variability among SuperAgers with regard to non-episodic memory performance, with some performing above average-for-age across cognitive domains while others performed in the average-for-age range on non-memory tests. Across all participants, attention and executive function scores explained 20.4% of the variance in episodic memory scores. CONCLUSIONS: As a group, SuperAgers outperformed their average memory peers in multiple cognitive domains, however, there was considerable intragroup variability suggesting that SuperAgers' episodic memory strength is not simply related to globally superior cognitive functioning. Attention and executive function performance explained approximately one-fifth of the variance in episodic memory and maybe areas to target with cognitive interventions.

Paucity of Entorhinal Cortex Pathology of the Alzheimer's Type in SuperAgers with Superior Memory Performance.

Advancing age is typically associated with declining memory capacity and increased risk of Alzheimer's disease (AD). Markers of AD such as amyloid plaques (AP) and neurofibrillary tangles (NFTs) are commonly found in the brains of cognitively average elderly but in more limited distribution than in those at the mild cognitive impairment and dementia stages of AD. Cognitive SuperAgers are individuals over age 80 who show superior memory capacity, at a level consistent with individuals 20-30 years their junior. Using a stereological approach, the current study quantitated the presence of AD markers in the memory-associated entorhinal cortex (ERC) of seven SuperAgers compared with six age-matched cognitively average normal control individuals. Amyloid plaques and NFTs were visualized using Thioflavin-S histofluorescence, 6E10, and PHF-1 immunohistochemistry. Unbiased stereological analysis revealed significantly more NFTs in ERC in cognitively average normal controls compared with SuperAgers (P < 0.05) by a difference of ~3-fold. There were no significant differences in plaque density. To highlight relative magnitude, cases with typical amnestic dementia of AD showed nearly 100 times more entorhinal NFTs than SuperAgers. The results suggest that resistance to age-related neurofibrillary degeneration in the ERC may be one factor contributing to preserved memory in SuperAgers.

Taxonomic Interference Associated with Phonemic Paraphasias in Agrammatic Primary Progressive Aphasia.

Phonemic paraphasias are thought to reflect phonological (post-semantic) deficits in language production. Here we present evidence that phonemic paraphasias in non-semantic primary progressive aphasia (PPA) may be associated with taxonomic interference. Agrammatic and logopenic PPA patients and control participants performed a word-to-picture visual search task where they matched a stimulus noun to 1 of 16 object pictures as their eye movements were recorded. Participants were subsequently asked to name the same items. We measured taxonomic interference (ratio of time spent viewing related vs. unrelated foils) during the search task for each item. Target items that elicited a phonemic paraphasia during object naming elicited increased taxonomic interference during the search task in agrammatic but not logopenic PPA patients. These results could reflect either very subtle sub-clinical semantic distortions of word representations or partial degradation of specific phonological word forms in agrammatic PPA during both word-to-picture matching (input stage) and picture naming (output stage). The mechanism for phonemic paraphasias in logopenic patients seems to be different and to be operative at the pre-articulatory stage of phonological retrieval. Glucose metabolic imaging suggests that degeneration in the left posterior frontal lobe and left temporo-parietal junction, respectively, might underlie these different patterns of phonemic paraphasia.

Nosology of Primary Progressive Aphasia and the Neuropathology of Language.

Primary progressive aphasia (PPA) is a dementia syndrome associated with several neuropathologic entities, including Alzheimer's disease (AD) and all major forms of frontotemporal lobar degeneration (FTLD). It is classified into subtypes defined by the nature of the language domain that is most impaired. The asymmetric neurodegeneration of the hemisphere dominant for language (usually left) is one consistent feature of all PPA variants. This feature offers unique opportunities for exploring mechanisms of selective vulnerability in neurodegenerative diseases and the neuroanatomy of language. This chapter reviews some of the current trends in PPA research as well as the challenges that remain to be addressed on the nosology, clinicopathologic correlations, and therapy of this syndrome.

Relationships among tau burden, atrophy, age, and naming in the aphasic variant of Alzheimer's disease.

INTRODUCTION: Examination of pathologic, anatomic, and cognitive relationships has been limited in primary progressive aphasia (PPA) with underlying Alzheimer's disease (AD) neuropathology. METHODS: Spatial relationships between tau positron emission tomography (PET), cortical thickness, age, and naming on the Boston Naming Test (BNT) in PPA with biomarker evidence of AD (PPA-AD) were examined. RESULTS: Higher tau PET burden was associated with atrophy and younger age. There was a significant left-lateralized relationship between lower BNT and more atrophy, and between lower BNT and increased tau burden. Variance in naming was primarily shared between tau and atrophy (51%), but naming was uniquely explained more by atrophy (32%) than tau (16%). Higher left anterior temporal tau burden was associated with greater 1-year rate of decline in naming. DISCUSSION: PPA-AD has a similar relationship between abnormal biomarkers as first described in amnestic AD, with differing spatial extent, reflecting the left-lateralized nature of the language network.

Functional decline in the aphasic variant of Alzheimer's disease.

INTRODUCTION: Primary progressive aphasia (PPA) is a clinical dementia syndrome associated with frontotemporal lobar degeneration (FTLD) or Alzheimer's disease (AD). Impairment in activities of daily living is essential for dementia diagnosis, yet less is known about the neuropathologic impact on functional decline in PPA, especially over time. METHODS: Activities of Daily Living Questionnaire (ADLQ) ratings were compared by suspected underlying pathology between 17 PPAAß+ and 11 PPAAß- participants at 6-month intervals for 2 years using a linear mixed-effects model. A general linear model examined associations between functional decline and cortical thickness at baseline. RESULTS: Groups did not differ in demographics or aphasia severity at baseline, yet overall and subdomain scores of the ADLQ were significantly worse for PPAAß+ compared to PPAAß- (P = .015) at each interval across 18 months. DISCUSSION: Functional decline appears more pronounced and disrupts more aspects of life activities for individuals with non-semantic PPA with suspected AD versus non-AD neuropathology.

Differential Neurotoxicity Related to Tetracycline Transactivator and TDP-43 Expression in Conditional TDP-43 Mouse Model of Frontotemporal Lobar Degeneration.

Frontotemporal lobar degeneration (FTLD) is among the most prevalent dementias of early-onset. Pathologically, FTLD presents with tauopathy or TAR DNA-binding protein 43 (TDP-43) proteinopathy. A biallelic mouse model of FTLD was produced on a mix FVB/129SVE background overexpressing wild-type human TDP-43 (hTDP-43) using tetracycline transactivator (tTA), a system widely used in mouse models of neurological disorders. tTA activates hTDP-43, which is placed downstream of the tetracycline response element. The original study on this transgenic mouse found hippocampal degeneration following hTDP-43 expression, but did not account for independent effects of tTA protein. Here, we initially analyzed the neurotoxic effects of tTA in postweaning age mice of either sex using immunostaining and area measurements of select brain regions. We observed tTA-dependent toxicity selectively in the hippocampus affecting the dentate gyrus significantly more than CA fields, whereas hTDP-43-dependent toxicity in bigenic mice occurred in most other cortical regions. Atrophy was associated with inflammation, activation of caspase-3, and loss of neurons. The atrophy associated with tTA expression was rescuable by the tetracycline analog, doxycycline, in the diet. MRI studies corroborated the patterns of atrophy. tTA-induced degeneration was strain-dependent and was rescued by moving the transgene onto a congenic C57BL/6 background. Despite significant hippocampal atrophy, behavioral tests in bigenic mice revealed no hippocampally mediated memory impairment. Significant atrophy in most cortical areas due solely to TDP-43 expression indicates that this mouse model remains useful for providing critical insight into co-occurrence of TDP-43 pathology, neurodegeneration, and behavioral deficits in FTLD.SIGNIFICANCE STATEMENT The tTA expression system has been widely used in mice to model neurological disorders. The technique allows investigators to reversibly turn on or off disease causing genes. Here, we report on a mouse model that overexpresses human TDP-43 using tTA and attempt to recapitulate features of TDP-43 pathology present in human FTLD. The tTA expression system is problematic, resulting in dramatic degeneration of the hippocampus. Thus, our study adds a note of caution for the use of the tTA system. However, because FTLD is primarily characterized by cortical degeneration and our mouse model shows significant atrophy in most cortical areas due to human TDP-43 overexpression, our animal model remains useful for providing critical insight on this human disease.

Cognitive trajectories and spectrum of neuropathology in SuperAgers: The first 10 cases.

On average, memory capacity is significantly higher in populations of 50-60 year olds than in populations of 80 year olds. We define SuperAgers as individuals 80 or older whose episodic memory capacity is at least as good as that of cognitively average individuals in their 50s and 60s. SuperAgers therefore have memory capacity that is superior for age. Previous work showed that SuperAgers have greater cortical volumes and greater resistance to age-related cortical atrophy than "cognitively average" individuals of the same age. Here we report on the cognitive, personality, and neuropathologic characteristics of the first 10 autopsy cases in the Northwestern SuperAging Program. During the follow-up period, seven SuperAgers maintained episodic memory performance within or above the average range for 50-65 year-old norms and all 10 SuperAgers maintained episodic memory scores within normal limits for their own age. Extraversion scores tended to be high on the NEO-PI-R measure of personality. The 10 autopsy specimens showed variable findings within the spectrum of Alzheimer pathology. The hippocampus and entorhinal cortex contained neurofibrillary degeneration mostly in the Braak II-III stages. However, even these limbic areas contained many healthy appearing neurons and the neocortex was generally free of neurofibrillary degeneration. In contrast, neocortical areas in at least five of the cases contained moderate to high densities of neuritic plaques. These findings need to be placed in context by comparing them to the neuropathology of cognitively average individuals of the same age. Future research on SuperAgers is likely to offer insights into factors that either prevent the emergence of involutional changes in the brain or that makes cognitive function more resistant to their consequences.

Prominent microglial activation in cortical white matter is selectively associated with cortical atrophy in primary progressive aphasia.

AIMS: Primary progressive aphasia (PPA) is a clinical syndrome characterized by selective language impairments associated with focal cortical atrophy favouring the language dominant hemisphere. PPA is associated with Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) and significant accumulation of activated microglia. Activated microglia can initiate an inflammatory cascade that may contribute to neurodegeneration, but their quantitative distribution in cortical white matter and their relationship with cortical atrophy remain unknown. We investigated white matter activated microglia and their association with grey matter atrophy in 10 PPA cases with either AD or FTLD-TDP pathology. METHODS: Activated microglia were quantified with optical density measures of HLA-DR immunoreactivity in two regions with peak cortical atrophy, and one nonatrophied region within the language dominant hemisphere of each PPA case. Nonatrophied contralateral homologues of the language dominant regions were examined for hemispheric asymmetry. RESULTS: Qualitatively, greater densities of activated microglia were observed in cortical white matter when compared to grey matter. Quantitative analyses revealed significantly greater densities of activated microglia in the white matter of atrophied regions compared to nonatrophied regions in the language dominant hemisphere (P < 0.05). Atrophied regions of the language dominant hemisphere also showed significantly more activated microglia compared to contralateral homologues (P < 0.05). CONCLUSIONS: White matter activated microglia accumulate more in atrophied regions in the language dominant hemisphere of PPA. While microglial activation may constitute a response to neurodegenerative processes in white matter, the resultant inflammatory processes may also exacerbate disease progression and contribute to cortical atrophy.

Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD.

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole-genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (p value = 4.82e - 08, OR = 2.12), and two known loci: UNC13A, led by rs1297319 (p value = 1.27e - 08, OR = 1.50) and HLA-DQA2 led by rs17219281 (p value = 3.22e - 08, OR = 1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole-genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n ≥ 3) as compared to controls (n = 0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g., DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis.

The cholinergic system in the pathophysiology and treatment of Alzheimer's disease.

Cholinergic synapses are ubiquitous in the human central nervous system. Their high density in the thalamus, striatum, limbic system, and neocortex suggest that cholinergic transmission is likely to be critically important for memory, learning, attention and other higher brain functions. Several lines of research suggest additional roles for cholinergic systems in overall brain homeostasis and plasticity. As such, the brain's cholinergic system occupies a central role in ongoing research related to normal cognition and age-related cognitive decline, including dementias such as Alzheimer's disease. The cholinergic hypothesis of Alzheimer's disease centres on the progressive loss of limbic and neocortical cholinergic innervation. Neurofibrillary degeneration in the basal forebrain is believed to be the primary cause for the dysfunction and death of forebrain cholinergic neurons, giving rise to a widespread presynaptic cholinergic denervation. Cholinesterase inhibitors increase the availability of acetylcholine at synapses in the brain and are one of the few drug therapies that have been proven clinically useful in the treatment of Alzheimer's disease dementia, thus validating the cholinergic system as an important therapeutic target in the disease. This review includes an overview of the role of the cholinergic system in cognition and an updated understanding of how cholinergic deficits in Alzheimer's disease interact with other aspects of disease pathophysiology, including plaques composed of amyloid-ß proteins. This review also documents the benefits of cholinergic therapies at various stages of Alzheimer's disease and during long-term follow-up as visualized in novel imaging studies. The weight of the evidence supports the continued value of cholinergic drugs as a standard, cornerstone pharmacological approach in Alzheimer's disease, particularly as we look ahead to future combination therapies that address symptoms as well as disease progression.