Limbic-predominant age-related TDP-43 encephalopathy in the oldest old: a population-based study.

Population-based cohort studies are essential for understanding the pathological basis of dementia in older populations. Previous studies have shown that limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) increases with age, but there have been only a few studies, which have investigated this entity in a population-based setting. Here we studied the frequency of LATE-NC and its associations with other brain pathologies and cognition in a population aged ≥ 85 years. The population-based Vantaa 85+ study cohort includes all 601 individuals aged ≥ 85 years who were living in Vantaa, Finland in 1991. A neuropathological examination was performed on 304 subjects (50.5%) and LATE-NC staging was possible in 295 of those. Dementia status and Mini-Mental State Examination (MMSE) scores were defined in the baseline study and 3 follow-ups (1994-99). The LATE-NC stages were determined based on TDP-43 immunohistochemistry, according to recently updated recommendations. Arteriolosclerosis was digitally assessed by calculating the average sclerotic index of five random small arterioles in amygdala and hippocampal regions, and frontal white matter. The association of LATE-NC with arteriolosclerosis and previously determined neuropathological variables including Alzheimer's disease neuropathological change (ADNC), Lewy-related pathology (LRP), hippocampal sclerosis (HS), and cerebral amyloid angiopathy (CAA), and cognitive variables were analysed by Fisher's exact test, linear and logistic regression (univariate and multivariate) models. LATE-NC was found in 189 of 295 subjects (64.1%). Stage 2 was the most common (28.5%) and stage 3 the second most common (12.9%), whereas stages 1a, 1b and 1c were less common (9.5%, 5.1% and 8.1%, respectively). Stages 1a (P < 0.01), 2 (P < 0.001) and 3 (P < 0.001) were significantly associated with dementia and lower MMSE scores. LATE-NC was associated with ADNC (P < 0.001), HS (P < 0.001), diffuse neocortical LRP (P < 0.002), and arteriolosclerosis in amygdala (P < 0.02). In most cases LATE-NC occurred in combination alongside other neuropathological changes. There were only six subjects with dementia who had LATE-NC without high levels of ADNC or LRP (2% of the cohort, 3% of the cases with dementia), and five of these had HS. In all multivariate models, LATE-NC was among the strongest independent predictors of dementia. When LATE-NC and ADNC were assessed in a multivariate model without other dementia-associated pathologies, the attributable risk was higher for LATE-NC than ADNC (24.2% vs. 18.6%). This population-based study provides evidence that LATE-NC is very common and one of the most significant determinants of dementia in the general late-life aged population.

Glycosylation spectral signatures for glioma grade discrimination using Raman spectroscopy.

BACKGROUND: Gliomas are the most common brain tumours with the high-grade glioblastoma representing the most aggressive and lethal form. Currently, there is a lack of specific glioma biomarkers that would aid tumour subtyping and minimally invasive early diagnosis. Aberrant glycosylation is an important post-translational modification in cancer and is implicated in glioma progression. Raman spectroscopy (RS), a vibrational spectroscopic label-free technique, has already shown promise in cancer diagnostics. METHODS: RS was combined with machine learning to discriminate glioma grades. Raman spectral signatures of glycosylation patterns were used in serum samples and fixed tissue biopsy samples, as well as in single cells and spheroids. RESULTS: Glioma grades in fixed tissue patient samples and serum were discriminated with high accuracy. Discrimination between higher malignant glioma grades (III and IV) was achieved with high accuracy in tissue, serum, and cellular models using single cells and spheroids. Biomolecular changes were assigned to alterations in glycosylation corroborated by analysing glycan standards and other changes such as carotenoid antioxidant content. CONCLUSION: RS combined with machine learning could pave the way for more objective and less invasive grading of glioma patients, serving as a useful tool to facilitate glioma diagnosis and delineate biomolecular glioma progression changes.

Distribution of Lewy-related pathology in the brain, spinal cord, and periphery: the population-based Vantaa 85 + study.

Evolving evidence has supported the existence of two anatomically distinct Lewy-related pathology (LRP) types. Investigation of spinal cord and peripheral LRP can elucidate mechanisms of Lewy body disorders and origins of synuclein accumulation. Still, very few unselected studies have focused on LRP in these regions. Here we analysed LRP in spinal cord, dorsal root ganglion, and adrenal gland in the population-based Vantaa 85 + study, including every ≥ 85 years old citizen living in the city of Vantaa in 1991 (n = 601). Samples from spinal cord (C6-7, TH3-4, L3-4, S1-2) were available from 303, lumbar dorsal root ganglion from 219, and adrenal gland from 164 subjects. Semiquantitative scores of LRP were determined from immunohistochemically stained sections (anti-alpha-synuclein antibody 5G4). LRP in the ventral and dorsal horns of spinal cord, thoracic intermediolateral column, dorsal root ganglion and adrenal gland were compared with brain LRP, previously determined according to DLB Consortium criteria and by caudo-rostral versus amygdala-based LRP classification. Spinal LRP was found in 28% of the total population and in 61% of those who had LRP in the brain. Spinal cord LRP was found only in those subjects with LRP in the brain, and the quantity of spinal cord LRP was associated with the severity of brain LRP (p < 0.001). Unsupervised K-means analysis identified two cluster types of spinal and brain LRP corresponding to caudo-rostral and amygdala-based LRP types. The caudo-rostral LRP type exhibited more frequent and severe pathology in spinal cord, dorsal root ganglion and adrenal gland than the amygdala-based LRP type. Analysis of specific spinal cord regions showed that thoracic intermediolateral column and sacral dorsal horn were the most frequently affected regions in both LRP types. This population-based study on brain, spinal and peripheral LRP provides support to the concept of at least two distinct LRP types.

The diagnostic and prognostic potential of the EGFR/MUC4/MMP9 axis in glioma patients.

Glioblastoma is the most aggressive form of brain cancer, presenting poor prognosis despite current advances in treatment. There is therefore an urgent need for novel biomarkers and therapeutic targets. Interactions between mucin 4 (MUC4) and the epidermal growth factor receptor (EGFR) are involved in carcinogenesis, and may lead to matrix metalloproteinase-9 (MMP9) overexpression, exacerbating cancer cell invasiveness. In this study, the role of MUC4, MMP9, and EGFR in the progression and clinical outcome of glioma patients was investigated. Immunohistochemistry (IHC) and immunofluorescence (IF) in fixed tissue samples of glioma patients were used to evaluate the expression and localization of EGFR, MMP9, and MUC4. Kaplan-Meier survival analysis was also performed to test the prognostic utility of the proteins for glioma patients. The protein levels were assessed with enzyme-linked immunosorbent assay (ELISA) in serum of glioma patients, to further investigate their potential as non-invasive serum biomarkers. We demonstrated that MUC4 and MMP9 are both significantly upregulated during glioma progression. Moreover, MUC4 is co-expressed with MMP9 and EGFR in the proliferative microvasculature of glioblastoma, suggesting a potential role for MUC4 in microvascular proliferation and angiogenesis. The combined high expression of MUC4/MMP9, and MUC4/MMP9/EGFR was associated with poor overall survival (OS). Finally, MMP9 mean protein level was significantly higher in the serum of glioblastoma compared with grade III glioma patients, whereas MUC4 mean protein level was minimally elevated in higher glioma grades (III and IV) compared with control. Our results suggest that MUC4, along with MMP9, might account for glioblastoma progression, representing potential therapeutic targets, and suggesting the 'MUC4/MMP9/EGFR axis' may play a vital role in glioblastoma diagnostics.

Frequency of LATE neuropathologic change across the spectrum of Alzheimer's disease neuropathology: combined data from 13 community-based or population-based autopsy cohorts.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and Alzheimer's disease neuropathologic change (ADNC) are each associated with substantial cognitive impairment in aging populations. However, the prevalence of LATE-NC across the full range of ADNC remains uncertain. To address this knowledge gap, neuropathologic, genetic, and clinical data were compiled from 13 high-quality community- and population-based longitudinal studies. Participants were recruited from United States (8 cohorts, including one focusing on Japanese-American men), United Kingdom (2 cohorts), Brazil, Austria, and Finland. The total number of participants included was 6196, and the average age of death was 88.1 years. Not all data were available on each individual and there were differences between the cohorts in study designs and the amount of missing data. Among those with known cognitive status before death (n = 5665), 43.0% were cognitively normal, 14.9% had MCI, and 42.4% had dementia-broadly consistent with epidemiologic data in this age group. Approximately 99% of participants (n = 6125) had available CERAD neuritic amyloid plaque score data. In this subsample, 39.4% had autopsy-confirmed LATE-NC of any stage. Among brains with "frequent" neuritic amyloid plaques, 54.9% had comorbid LATE-NC, whereas in brains with no detected neuritic amyloid plaques, 27.0% had LATE-NC. Data on LATE-NC stages were available for 3803 participants, of which 25% had LATE-NC stage > 1 (associated with cognitive impairment). In the subset of individuals with Thal Aß phase = 0 (lacking detectable Aß plaques), the brains with LATE-NC had relatively more severe primary age-related tauopathy (PART). A total of 3267 participants had available clinical data relevant to frontotemporal dementia (FTD), and none were given the clinical diagnosis of definite FTD nor the pathological diagnosis of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). In the 10 cohorts with detailed neurocognitive assessments proximal to death, cognition tended to be worse with LATE-NC across the full spectrum of ADNC severity. This study provided a credible estimate of the current prevalence of LATE-NC in advanced age. LATE-NC was seen in almost 40% of participants and often, but not always, coexisted with Alzheimer's disease neuropathology.

Primary age-related tauopathy in a Finnish population-based study of the oldest old (Vantaa 85+).

AIMS: Few studies have investigated primary age-related tauopathy (PART) in a population-based setting. Here, we assessed its prevalence, genetic background, comorbidities and features of cognitive decline in an unselected elderly population. METHODS: The population-based Vantaa 85+ study includes all 601 inhabitants of Vantaa aged ≥ 85 years in 1991. Neuropathological assessment was possible in 301. Dementia (DSM IIIR criteria) and Mini-Mental State Examination (MMSE) scores were assessed at the baseline of the study and follow-ups. PART subjects were identified according to the criteria by Crary et al and were compared with subjects with mild and severe Alzheimer's disease (AD) neuropathological changes. The effects of other neuropathologies were taken into account using multivariate and sensitivity assays. Genetic analyses included APOE genotypes and 29 polymorphisms of the MAPT 3' untranslated region (3'UTR region). RESULTS: The frequency of PART was 20% (n = 61/301, definite PART 5%). When PART subjects were compared with those with severe AD pathology, dementia was less common, its age at onset was higher and duration shorter. No such differences were seen when compared with those with milder AD pathology. However, both AD groups showed a steeper decline in MMSE scores in follow-ups compared with PART. APOE ε4 frequency was lower, and APOE ε2 frequency higher in the PART group compared with each AD group. The detected nominally significant associations between PART and two MAPT 3'UTR polymorphisms and haplotypes did not survive Bonferroni correction. CONCLUSIONS: PART is common among very elderly. PART subjects differ from individuals with AD-type changes in the pattern of cognitive decline, associated genetic and neuropathological features.

Forecasting stroke-like episodes and outcomes in mitochondrial disease.

In this retrospective, multicentre, observational cohort study, we sought to determine the clinical, radiological, EEG, genetics and neuropathological characteristics of mitochondrial stroke-like episodes and to identify associated risk predictors. Between January 1998 and June 2018, we identified 111 patients with genetically determined mitochondrial disease who developed stroke-like episodes. Post-mortem cases of mitochondrial disease (n = 26) were identified from Newcastle Brain Tissue Resource. The primary outcome was to interrogate the clinico-radiopathological correlates and prognostic indicators of stroke-like episode in patients with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome (MELAS). The secondary objective was to develop a multivariable prediction model to forecast stroke-like episode risk. The most common genetic cause of stroke-like episodes was the m.3243A>G variant in MT-TL1 (n = 66), followed by recessive pathogenic POLG variants (n = 22), and 11 other rarer pathogenic mitochondrial DNA variants (n = 23). The age of first stroke-like episode was available for 105 patients [mean (SD) age: 31.8 (16.1)]; a total of 35 patients (32%) presented with their first stroke-like episode ≥40 years of age. The median interval (interquartile range) between first and second stroke-like episodes was 1.33 (2.86) years; 43% of patients developed recurrent stroke-like episodes within 12 months. Clinico-radiological, electrophysiological and neuropathological findings of stroke-like episodes were consistent with the hallmarks of medically refractory epilepsy. Patients with POLG-related stroke-like episodes demonstrated more fulminant disease trajectories than cases of m.3243A>G and other mitochondrial DNA pathogenic variants, in terms of the frequency of refractory status epilepticus, rapidity of progression and overall mortality. In multivariate analysis, baseline factors of body mass index, age-adjusted blood m.3243A>G heteroplasmy, sensorineural hearing loss and serum lactate were significantly associated with risk of stroke-like episodes in patients with the m.3243A>G variant. These factors informed the development of a prediction model to assess the risk of developing stroke-like episodes that demonstrated good overall discrimination (area under the curve = 0.87, 95% CI 0.82-0.93; c-statistic = 0.89). Significant radiological and pathological features of neurodegeneration were more evident in patients harbouring pathogenic mtDNA variants compared with POLG: brain atrophy on cranial MRI (90% versus 44%, P < 0.001) and reduced mean brain weight (SD) [1044 g (148) versus 1304 g (142), P = 0.005]. Our findings highlight the often idiosyncratic clinical, radiological and EEG characteristics of mitochondrial stroke-like episodes. Early recognition of seizures and aggressive instigation of treatment may help circumvent or slow neuronal loss and abate increasing disease burden. The risk-prediction model for the m.3243A>G variant can help inform more tailored genetic counselling and prognostication in routine clinical practice.

Loss with ageing but preservation of frontal cortical capillary pericytes in post-stroke dementia, vascular dementia and Alzheimer's disease.

Cerebral pericytes are an integral component of the neurovascular unit, which governs the blood-brain barrier. There is paucity of knowledge on cortical pericytes across different dementias. We quantified cortical pericytes in capillaries in 124 post-mortem brains from subjects with post-stroke dementia (PSD), vascular dementia (VaD), Alzheimer's disease (AD) and AD-VaD (Mixed) and, post-stroke non-demented (PSND) stroke survivors as well as normal ageing controls. Collagen 4 (COL4)-positive nucleated pericyte soma were identified as protrusions on capillaries of the frontal cortex. The COL4-positive somata or nodule-like cell bodies were also verified by platelet derived growth factor receptor-ß (PDGFR-ß) immunohistochemistry. The mean (± SEM) pericyte somata in frontal cortical capillaries in normal young controls (46-65 years of age) was estimated as 5.2 ± 0.2 per mm capillary length. This number was reduced by 45% in older controls (> 78 years) to 2.9 ± 0.1 per mm capillary length (P < 0.001). We further found that the numbers of pericyte cell bodies per COL4 mm2 area or per mm capillary length were not decreased but rather preserved or increased in PSD, AD and Mixed dementia groups compared to similar age older controls (P < 0.01). Consistent with this, we noted that capillary length densities identified by the endothelial marker glucose transporter 1 or COL4 were not different across the dementias compared to older controls. There was a negative correlation with age (P < 0.001) suggesting fewer pericyte somata in older age, although the % COL4 immunoreactive capillary area was increased in older controls compared to young controls. Using a proven reliable method to quantify COL4-positive nucleated pericytes, our observations demonstrate ageing related loss but mostly preserved pericytes in the frontal cortex of vascular and AD dementias. We suggest there is differential regulation of capillary pericytes in the frontal lobe between the cortex and white matter in ageing-related dementias.

Developmental Consequences of Defective ATG7-Mediated Autophagy in Humans.

BACKGROUND: Autophagy is the major intracellular degradation route in mammalian cells. Systemic ablation of core autophagy-related (ATG) genes in mice leads to embryonic or perinatal lethality, and conditional models show neurodegeneration. Impaired autophagy has been associated with a range of complex human diseases, yet congenital autophagy disorders are rare. METHODS: We performed a genetic, clinical, and neuroimaging analysis involving five families. Mechanistic investigations were conducted with the use of patient-derived fibroblasts, skeletal muscle-biopsy specimens, mouse embryonic fibroblasts, and yeast. RESULTS: We found deleterious, recessive variants in human ATG7, a core autophagy-related gene encoding a protein that is indispensable to classical degradative autophagy. Twelve patients from five families with distinct ATG7 variants had complex neurodevelopmental disorders with brain, muscle, and endocrine involvement. Patients had abnormalities of the cerebellum and corpus callosum and various degrees of facial dysmorphism. These patients have survived with impaired autophagic flux arising from a diminishment or absence of ATG7 protein. Although autophagic sequestration was markedly reduced, evidence of basal autophagy was readily identified in fibroblasts and skeletal muscle with loss of ATG7. Complementation of different model systems by deleterious ATG7 variants resulted in poor or absent autophagic function as compared with the reintroduction of wild-type ATG7. CONCLUSIONS: We identified several patients with a neurodevelopmental disorder who have survived with a severe loss or complete absence of ATG7, an essential effector enzyme for autophagy without a known functional paralogue. (Funded by the Wellcome Centre for Mitochondrial Research and others.).

A cryptic intronic LAMA2 insertion in a boy with mild congenital muscular dystrophy type 1A.

Recessive mutations in the LAMA2 gene lead to congenital muscular dystrophy type 1A and limb girdle muscular dystrophy R23 with complete or partial laminin α2 chain deficiency. Complete laminin α2 chain deficiency presents with early onset of severe hypotonia and generalized weakness, whereas partial deficiency shows a milder and more variable course with limb girdle weakness. Here, we report a child with mildly delayed motor development, elevated serum creatine kinase levels (>1000 U/l) and brain white matter hypointensity, indicative of laminin α2 chain deficiency. In addition to a stop gain variant in exon 39, the patient was found to carry an intronic insertion of 72 bp in intron 38 of the LAMA2 gene in trans. RNA analysis revealed that this insertion results in abnormally spliced as well as wild type transcript, which explains the partial laminin α2 chain deficiency observed in the muscle biopsy.

Neuropathological consensus criteria for the evaluation of Lewy pathology in post-mortem brains: a multi-centre study.

Currently, the neuropathological diagnosis of Lewy body disease (LBD) may be stated according to several staging systems, which include the Braak Lewy body stages (Braak), the consensus criteria by McKeith and colleagues (McKeith), the modified McKeith system by Leverenz and colleagues (Leverenz), and the Unified Staging System by Beach and colleagues (Beach). All of these systems use semi-quantitative scoring (4- or 5-tier scales) of Lewy pathology (LP; i.e., Lewy bodies and Lewy neurites) in defined cortical and subcortical areas. While these systems are widely used, some suffer from low inter-rater reliability and/or an inability to unequivocally classify all cases with LP. To address these limitations, we devised a new system, the LP consensus criteria (LPC), which is based on the McKeith system, but applies a dichotomous approach for the scoring of LP (i.e., "absent" vs. "present") and includes amygdala-predominant and olfactory-only stages. α-Synuclein-stained slides from brainstem, limbic system, neocortex, and olfactory bulb from a total of 34 cases with LP provided by the Newcastle Brain Tissue Resource (NBTR) and the University of Pennsylvania brain bank (UPBB) were scanned and assessed by 16 raters, who provided diagnostic categories for each case according to Braak, McKeith, Leverenz, Beach, and LPC systems. In addition, using LP scores available from neuropathological reports of LP cases from UPBB (n = 202) and NBTR (n = 134), JT (UPBB) and JA (NBTR) assigned categories according to all staging systems to these cases. McKeith, Leverenz, and LPC systems reached good (Krippendorff's α ≈ 0.6), while both Braak and Beach systems had lower (Krippendorff's α ≈ 0.4) inter-rater reliability, respectively. Using the LPC system, all cases could be unequivocally classified by the majority of raters, which was also seen for 97.1% when the Beach system was used. However, a considerable proportion of cases could not be classified when using Leverenz (11.8%), McKeith (26.5%), or Braak (29.4%) systems. The category of neocortical LP according to the LPC system was associated with a 5.9 OR (p < 0.0001) of dementia in the 134 NBTR cases and a 3.14 OR (p = 0.0001) in the 202 UPBB cases. We established that the LPC system has good reproducibility and allows classification of all cases into distinct categories. We expect that it will be reliable and useful in routine diagnostic practice and, therefore, suggest that it should be the standard future approach for the basic post-mortem evaluation of LP.

TDP-43 proteinopathies: a new wave of neurodegenerative diseases.

Inclusions of pathogenic deposits containing TAR DNA-binding protein 43 (TDP-43) are evident in the brain and spinal cord of patients that present across a spectrum of neurodegenerative diseases. For instance, the majority of patients with sporadic amyotrophic lateral sclerosis (up to 97%) and a substantial proportion of patients with frontotemporal lobar degeneration (~45%) exhibit TDP-43 positive neuronal inclusions, suggesting a role for this protein in disease pathogenesis. In addition, TDP-43 inclusions are evident in familial ALS phenotypes linked to multiple gene mutations including the TDP-43 gene coding (TARDBP) and unrelated genes (eg, C9orf72). While TDP-43 is an essential RNA/DNA binding protein critical for RNA-related metabolism, determining the pathophysiological mechanisms through which TDP-43 mediates neurodegeneration appears complex, and unravelling these molecular processes seems critical for the development of effective therapies. This review highlights the key physiological functions of the TDP-43 protein, while considering an expanding spectrum of neurodegenerative diseases associated with pathogenic TDP-43 deposition, and dissecting key molecular pathways through which TDP-43 may mediate neurodegeneration.

Loss of capillary pericytes and the blood-brain barrier in white matter in poststroke and vascular dementias and Alzheimer's disease.

White matter (WM) disease is associated with disruption of the gliovascular unit, which involves breach of the blood-brain barrier (BBB). We quantified pericytes as components of the gliovascular unit and assessed their status in vascular and other common dementias. Immunohistochemical and immunofluorescent methods were developed to assess the distribution and quantification of pericytes connected to the frontal lobe WM capillaries. Pericytes with a nucleus were identified by collagen 4 (COL4) and platelet-derived growth factor receptor-ß (PDGFR-ß) antibodies with further verification using PDGFR-ß-specific ELISA. We evaluated a total of 124 post-mortem brains from subjects with post-stroke dementia (PSD), vascular dementia (VaD), Alzheimer's disease (AD), AD-VaD (Mixed) and post-stroke non-demented (PSND) stroke survivors as well as normal aging controls. COL4 and PDGFR-ß reactive pericytes adopted the characteristic "crescent" or nodule-like shapes around capillary walls. We estimated densities of pericyte somata to be 225 ±38 and 200 ±13 (SEM) per COL4 mm2 area or 2.0 ± 0.1 and 1.7 ± 0.1 per mm capillary length in young and older aging controls. Remarkably, WM pericytes were reduced by ~35%-45% in the frontal lobe of PSD, VaD, Mixed and AD subjects compared to PSND and controls subjects (P < 0.001). We also found pericyte numbers were correlated with PDGFR-ß reactivity in the WM. Our results first demonstrate a reliable method to quantify COL4-positive pericytes and then, indicate that deep WM pericytes are decreased across different dementias including PSD, VaD, Mixed and AD. Our findings suggest that downregulation of pericytes is associated with the disruption of the BBB in the deep WM in several aging-related dementias.

TDP-43 Related Neuropathologies and Phosphorylation State: Associations with Age and Clinical Dementia in the Cambridge City over-75s Cohort.

Pathologies associated with the Tar-DNA binding protein 43 KDa (TDP-43) are associated with neurodegenerative diseases and aging. Phosphorylation of cellular proteins is a well-accepted mechanism of biological control and can be associated with disease pathways. Phosphorylation state associated with TDP-43 associated pathology has not been investigated with respect to dementia status in a population representative sample. TDP-43 immunohistochemistry directed toward phosphorylated (TDP-43P) and unphosphorylated (TDP-43U) was assessed in sections of hippocampus and temporal cortex from 222 brains donated to the population representative Cambridge City over-75s Cohort. Relationships between dementia status and age at death for TDP-43 immunoreactive pathologies by phosphorylation state were investigated. TDP-43 pathologies are common in the oldest old in the population and often do not conform to MacKenzie classification. Increasing age is associated with glial (TDP-43P) and neuronal inclusions (TDP-43P and TDP-43U), neurites, and granulovacuolar degeneration (GVD). Dementia status is associated with GVD and glial (TDP-43 P) and neural inclusions (TDP-43 P and U). Dementia severity was associated with glial (TDP-43P) and neuronal inclusions (TDP-43U and TDP-43P), GVD, and neurites. The associations between dementia severity and both glial cytoplasmic inclusions and GVD were independent from other pathologies and TDP-43 neuronal cytoplasmic inclusions. TDP-43 pathology contributes to dementia status and progression in a variety of ways in different phosphorylation states involving both neurons and glia, independently from age and from classic Alzheimer-related pathologies. TDP-43 pathologies as cytoplasmic inclusions in neurons or glia or as GVD contribute independently to dementia.

Small vessel disease pathological changes in neurodegenerative and vascular dementias concomitant with autonomic dysfunction.

We performed a clinicopathological study to assess the burden of small vessel disease (SVD) type of pathological changes in elderly demented subjects, who had clinical evidence of autonomic dysfunction, either carotid sinus hypersensitivity or orthostatic hypotension or both or had exhibited unexpected repeated falls. Clinical and neuropathological diagnoses in 112 demented subjects comprised dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD), Alzheimer's disease (AD), Mixed dementia (mostly AD-DLB) and vascular dementia (VaD). Of these, 12 DLB subjects had no recorded unexpected falls in life and therefore no evidence of concomitant autonomic dysfunction. A further 17 subjects were assessed as aging controls without significant pathology or signs of autonomic dysfunction. We quantified brain vascular pathological changes and determined severities of neurodegenerative lesions including α-synuclein pathology. We found moderate-severe vascular changes and high-vascular pathology scores (P < 0.01) in all neurodegenerative dementias and as expected in VaD compared to similar age controls. Arteriolosclerosis, perivascular spacing and microinfarcts were frequent in the basal ganglia and frontal white matter (WM) across all dementias, whereas small infarcts (<5 mm) were restricted to VaD. In a sub-set of demented subjects, we found that vascular pathology scores were correlated with WM hyperintensity volumes determined by MRI in life (P < 0.02). Sclerotic index values were increased by ~50% in both the WM and neocortex in all dementias compared to similar age controls. We found no evidence for increased α-synuclein deposition in subjects with autonomic dysfunction. Our findings suggest greater SVD pathological changes occur in the elderly diagnosed with neurodegenerative dementias including DLB and who develop autonomic dysfunction. SVD changes may not necessarily manifest in clinically overt symptoms but they likely confound motor or cognitive dysfunction. We propose dysautonomia promotes chronic cerebral hypoperfusion to impact upon aging-related neurodegenerative disorders and characterize their end-stage clinical syndromes.

Putative risk alleles for LATE-NC with hippocampal sclerosis in population-representative autopsy cohorts.

Limbic-predominant age-related TAR-DNA-binding protein-43 (TDP-43) encephalopathy with hippocampal sclerosis pathology (LATE-NC + HS) is a neurodegenerative disorder characterized by severe hippocampal CA1 neuron loss and TDP-43-pathology, leading to cognitive dysfunction and dementia. Polymorphisms in GRN, TMEM106B and ABCC9 are proposed as LATE-NC + HS risk factors in brain bank collections. To replicate these results in independent population-representative cohorts, hippocampal sections from brains donated to three such studies (Cambridge City over 75-Cohort [CC75C], Cognitive Function and Ageing Study [CFAS], and Vantaa 85+ Study) were stained with hematoxylin-eosin (n = 744) and anti-pTDP-43 (n = 713), and evaluated for LATE-NC + HS and TDP-43 pathology. Single nucleotide polymorphism genotypes in GRN rs5848, TMEM106B rs1990622 and ABCC9 rs704178 were determined. LATE-NC + HS (n = 58) was significantly associated with the GRN rs5848 genotype (χ2 (2) = 20.61, P < 0.001) and T-allele (χ2 (1) = 21.04, P < 0.001), and TMEM106B rs1990622 genotype (Fisher's exact test, P < 0.001) and A-allele (χ2 (1) = 25.75, P < 0.001). No differences in ABCC9 rs704178 genotype or allele frequency were found between LATE-NC + HS and non-LATE-NC + HS neuropathology cases. Dentate gyrus TDP-43 pathology associated with GRN and TMEM106B variations, but the association with TMEM106B nullified when LATE-NC + HS cases were excluded. Our results indicate that GRN and TMEM106B are associated with severe loss of CA1 neurons in the aging brain, while ABCC9 was not confirmed as a genetic risk factor for LATE-NC + HS. The association between TMEM106B and LATE-NC + HS may be independent of dentate TDP-43 pathology.

Lewy-related pathology exhibits two anatomically and genetically distinct progression patterns: a population-based study of Finns aged 85.

According to a generally accepted concept Lewy-related pathology (LRP) follows hierarchical caudo-rostral progression. LRP is also frequently present concomitantly with Alzheimer's disease (AD), and it has been hypothesized that AD-associated LRP forms a distinct type of α-synucleinopathy, where LRP originates in the amygdala. The frequency of distinct forms of LRP progression types has not been studied in a population-based setting. We investigated the distribution and progression of LRP and its relation to AD pathology and apolipoprotein (APOE) ε4 in a population-based sample of Finns aged over 85 years (N = 304). Samples from spinal cord to neocortical areas representing 11 anatomical sites without any hierarchical selection were analyzed immunohistochemically (α-synuclein antibody clone 5G4). LRP was present in 124 individuals (41%) and according to DLB Consortium guidelines 19 of them were categorized as brainstem, 10 amygdala-predominant, 41 limbic, and 43 diffuse neocortical type, whereas 11 could not be classified. To determine the LRP progression patterns, a systematic anatomical scoring was carried out by taking into account the densities of the semiquantitative LRP scores in each anatomic site. With this scoring 123 (99%) subjects could be classified into two progression pattern types: 67% showed caudo-rostral and 32% amygdala-based progression. The unsupervised statistical K-means cluster analysis was used as a supplementary test and supported the presence of two progression patterns and had a 90% overall concordance with the systematic anatomical scoring method. Severe Braak NFT stage, high CERAD score and APOE ε4 were significantly (all p < 0.00001) associated with amygdala-based, but not with caudo-rostral progression type (all p > 0.2). This population-based study demonstrates two distinct common LRP progression patterns in the very elderly population. The amygdala-based pattern was associated with APOE ε4 and AD pathology. The results confirm the previous progression hypotheses but also widen the concept of the AD-associated LRP.

Prediction models for dementia and neuropathology in the oldest old: the Vantaa 85+ cohort study.

BACKGROUND: We developed multifactorial models for predicting incident dementia and brain pathology in the oldest old using the Vantaa 85+ cohort. METHODS: We included participants without dementia at baseline and at least 2 years of follow-up (N = 245) for dementia prediction or with autopsy data (N = 163) for pathology. A supervised machine learning method was used for model development, considering sociodemographic, cognitive, clinical, vascular, and lifestyle factors, as well as APOE genotype. Neuropathological assessments included ß-amyloid, neurofibrillary tangles and neuritic plaques, cerebral amyloid angiopathy (CAA), macro- and microscopic infarcts, α-synuclein pathology, hippocampal sclerosis, and TDP-43. RESULTS: Prediction model performance was evaluated using AUC for 10 × 10-fold cross-validation. Overall AUCs were 0.73 for dementia, 0.64-0.68 for Alzheimer's disease (AD)- or amyloid-related pathologies, 0.72 for macroinfarcts, and 0.61 for microinfarcts. Predictors for dementia were different from those in previous reports of younger populations; for example, age, sex, and vascular and lifestyle factors were not predictive. Predictors for dementia versus pathology were also different, because cognition and education predicted dementia but not AD- or amyloid-related pathologies. APOE genotype was most consistently present across all models. APOE alleles had a different impact: ε4 did not predict dementia, but it did predict all AD- or amyloid-related pathologies; ε2 predicted dementia, but it was protective against amyloid and neuropathological AD; and ε3ε3 was protective against dementia, neurofibrillary tangles, and CAA. Very few other factors were predictive of pathology. CONCLUSIONS: Differences between predictors for dementia in younger old versus oldest old populations, as well as for dementia versus pathology, should be considered more carefully in future studies.