The Role of Steroidomics in the Diagnosis of Alzheimer's Disease and Type 2 Diabetes Mellitus.

Epidemiological studies suggest an association between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). This study aimed to investigate the pathophysiological markers of AD vs. T2DM for each sex separately and propose models that would distinguish control, AD, T2DM, and AD-T2DM comorbidity groups. AD and T2DM differed in levels of some circulating steroids (measured mostly by GC-MS) and in other observed characteristics, such as markers of obesity, glucose metabolism, and liver function tests. Regarding steroid metabolism, AD patients (both sexes) had significantly higher sex hormone binding globulin (SHBG), cortisol, and 17-hydroxy progesterone, and lower estradiol and 5α-androstane-3α,17ß-diol, compared to T2DM patients. However, compared to healthy controls, changes in the steroid spectrum (especially increases in levels of steroids from the C21 group, including their 5α/ß-reduced forms, androstenedione, etc.) were similar in patients with AD and patients with T2DM, though more expressed in diabetics. It can be assumed that many of these steroids are involved in counter-regulatory protective mechanisms that mitigate the development and progression of AD and T2DM. In conclusion, our results demonstrated the ability to effectively differentiate AD, T2DM, and controls in both men and women, distinguish the two pathologies from each other, and differentiate patients with AD and T2DM comorbidities.

Comorbid Neurodegeneration in Primary Progressive Aphasia: Clinicopathological Correlations in a Single-Center Study.

Introduction: Primary progressive aphasia (PPA) is a clinically variable syndrome manifesting as slow progressive loss of speech and language with multiple underlying neurodegenerative pathologies. Materials and Methods: We included data from nine PPA patients with available autopsies. We then retrospectively reviewed all available medical records, neuropsychology, and MRI results to confirm the corresponding subtypes of PPA and compared them with postmortem neuropathological results. Results: Clinical presentations corresponded to the nonfluent/agrammatic variant in six cases, the semantic variant in one case, the logopenic variant in one case, and the mixed variant (concomitant nonfluent/agrammatic plus semantic variant) in one case. Patients with a broader clinical presentation, i.e., combining manifestations of one PPA subtype and symptoms of another PPA variant, had autopsy comorbidities showing multiple neurodegenerative disorders. Of the nine subjects enrolled in the study, Alzheimer's disease (AD) was found in eight cases; however, in only one case, AD was detected as an isolated neuropathological substrate of PPA. In eight brain samples, different comorbid neuropathologies were detected: three cases with comorbid AD and dementia with Lewy bodies, two cases with comorbid AD and TDP-43 pathology, one case with comorbid AD and complex tauopathies, and one case with comorbid AD with both tau and TDP-43 deposits. Finally, one case had comorbid tau and TDP-43 pathology but without comorbid AD pathology. Conclusions: Our observation suggests that PPA cases could be more heterogeneous in their etiology than previously thought and underlying neurodegenerative comorbidities should be considered in routine practice, especially if the clinical presentation of PPA is atypical.

Biomarkers Analysis and Clinical Manifestations in Comorbid Creutzfeldt-Jakob Disease: A Retrospective Study in 215 Autopsy Cases.

Creutzfeldt-Jakob disease (CJD), the most common human prion disorder, may occur as "pure" neurodegeneration with isolated prion deposits in the brain tissue; however, comorbid cases with different concomitant neurodegenerative diseases have been reported. This retrospective study examined correlations of clinical, neuropathological, molecular-genetic, immunological, and neuroimaging biomarkers in pure and comorbid CJD. A total of 215 patients have been diagnosed with CJD during the last ten years by the Czech National Center for Prion Disorder Surveillance. Data were collected from all patients with respect to diagnostic criteria for probable CJD, including clinical description, EEG, MRI, and CSF findings. A detailed neuropathological analysis uncovered that only 11.16% were "pure" CJD, while 62.79% had comorbid tauopathy, 20.47% had Alzheimer's disease, 3.26% had frontotemporal lobar degeneration, and 2.33% had synucleinopathy. The comorbid subgroup analysis revealed that tauopathy was linked to putaminal hyperintensity on MRIs, and AD mainly impacted the age of onset, hippocampal atrophy on MRIs, and beta-amyloid levels in the CSF. The retrospective data analysis found a surprisingly high proportion of comorbid neuropathologies; only 11% of cases were verified as "pure" CJD, i.e., lacking hallmarks of other neurodegenerations. Comorbid neuropathologies can impact disease manifestation and can complicate the clinical diagnosis of CJD.

Corpus callosum hypersignals and focal atrophy: Neuroimaging findings in globular glial tauopathy type I.

BACKGROUND AND PURPOSE: Globular glial tauopathies (GGTs) have heterogeneous presentations; little evidence regarding typical clinical and magnetic resonance imaging (MRI) presentations are available. METHODS: We retrospectively assessed MRIs from three postmortem-confirmed GGT cases, in two patients with atypical progressive aphasia and one with corticobasal syndrome. RESULTS: We suggest that four principal concomitant MRI findings characterize GGT type I: a sagittal callosal hyperintense band, marked focal callosal atrophy suggesting white matter degeneration originating in cortical areas responsible for symptoms (anterior atrophy in predominantly language manifestations and posterior atrophy in predominantly apraxia), periventricular white matter lesions, and mild-to-moderate brain stem atrophy. CONCLUSIONS: We observed four concomitant MRI abnormalities in patients with atypical dementia, parkinsonism, and late incomplete supranuclear gaze palsy. Two patients had atypical progressive aphasia and one had corticobasal syndrome.

Human Prion Disorders: Review of the Current Literature and a Twenty-Year Experience of the National Surveillance Center in the Czech Republic.

Human prion disorders (transmissible spongiform encephalopathies, TSEs) are unique, progressive, and fatal neurodegenerative diseases caused by aggregation of misfolded prion protein in neuronal tissue. Due to the potential transmission, human TSEs are under active surveillance in a majority of countries; in the Czech Republic data are centralized at the National surveillance center (NRL) which has a clinical and a neuropathological subdivision. The aim of our article is to review current knowledge about human TSEs and summarize the experience of active surveillance of human prion diseases in the Czech Republic during the last 20 years. Possible or probable TSEs undergo a mandatory autopsy using a standardized protocol. From 2001 to 2020, 305 cases of sporadic and genetic TSEs including 8 rare cases of Gerstmann-Sträussler-Scheinker syndrome (GSS) were confirmed. Additionally, in the Czech Republic, brain samples from all corneal donors have been tested by the NRL immunology laboratory to increase the safety of corneal transplants since January 2007. All tested 6590 corneal donor brain tissue samples were negative for prion protein deposits. Moreover, the routine use of diagnostic criteria including biomarkers are robust enough, and not even the COVID-19 pandemic has negatively impacted TSEs surveillance in the Czech Republic.

Autopsy-diagnosed neurodegenerative dementia cases support the use of cerebrospinal fluid protein biomarkers in the diagnostic work-up.

Various proteins play a decisive role in the pathology of different neurodegenerative diseases. Nonetheless, most of these proteins can only be detected during a neuropathological assessment, although some non-specific biomarkers are routinely tested for in the cerebrospinal fluid (CSF) as a part of the differential diagnosis of dementia. In antemortem CSF samples from 117 patients with different types of neuropathologically confirmed neurodegenerative disease with dementia, we assessed total-tau (t-tau), phosphorylated-tau (181P) (p-tau), amyloid-beta (1-42) (Aß42), TAR DNA binding protein (TDP)-43, progranulin (PGRN), and neurofilament light (NfL) chain levels, and positivity of protein 14-3-3. We found t-tau levels and the t-tau/p-tau ratios were significantly higher in prion diseases compared to the other neurodegenerative diseases. Statistically significant differences in the t-tau/Aß42 ratio predominantly corresponded to t-tau levels in prion diseases and Aß42 levels in AD. TDP-43 levels were significantly lower in prion diseases. Additionally, the TDP-43/Aß42 ratio was better able to distinguish Alzheimer's disease from other neurodegenerative diseases compared to using Aß42 alone. In frontotemporal lobar degeneration, PRGN levels were significantly higher in comparison to other neurodegenerative diseases. There is an increasing need for biomarkers suitable for diagnostic workups for neurodegenerative diseases. It appears that adding TDP-43 and PGRN to the testing panel for neurodegenerative diseases could improve the resolution of differential diagnoses.

Cognitive and Behavioral Manifestations in ALS: Beyond Motor System Involvement.

Amyotrophic lateral sclerosis (ALS) has long been considered to be a purely motor disorder. However, it has become apparent that many ALS patients develop cognitive and behavioral manifestations similar to frontotemporal dementia and the term amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTSD) is now used in these circumstances. This review is intended to be an overview of the cognitive and behavioral manifestations commonly encountered in ALS patients with the goal of improving case-oriented management in clinical practice. We introduce the principal ALS-FTSD subtypes and comment on their principal clinical manifestations, neuroimaging findings, neuropathological and genetic background, and summarize available therapeutic options. Diagnostic criteria for ALS-FTSD create distinct categories based on the type of neuropsychological manifestations, i.e., changes in behavior, impaired social cognition, executive dysfunction, and language or memory impairment. Cognitive impairment is found in up to 65%, while frank dementia affects about 15% of ALS patients. ALS motor and cognitive manifestations can worsen in parallel, becoming more pronounced when bulbar functions (affecting speech, swallowing, and salivation) are involved. Dementia can precede or develop after the appearance of motor symptoms. ALS-FTSD patients have a worse prognosis and shorter survival rates than patients with ALS or frontotemporal dementia alone. Important negative prognostic factors are behavioral and personality changes. From the clinician's perspective, there are five major distinguishable ALS-FTSD subtypes: ALS with cognitive impairment, ALS with behavioral impairment, ALS with combined cognitive and behavioral impairment, fully developed frontotemporal dementia in combination with ALS, and comorbid ALS and Alzheimer's disease. Although the most consistent ALS and ALS-FTSD pathology is a disturbance in transactive response DNA binding protein 43 kDa (TDP-43) metabolism, alterations in microtubule-associated tau protein metabolism have also been observed in ALS-FTSD. Early detection and careful monitoring of cognitive deficits in ALS are crucial for patient and caregiver support and enable personalized management of individual patient needs.

Regulated upon activation, normal T cell expressed and secreted (RANTES) levels in the peripheral blood of patients with Alzheimer's disease.

Alzheimer's disease (AD) is the most common type of dementia, but it is very difficult to diagnose with certainty, so many AD studies have attempted to find early and relevant diagnostic markers. Regulated upon activation, normal T cell expressed and secreted (RANTES, also known as C-C chemokine ligand) is a chemokine involved in the migration of T cells and other lymphoid cells. Changes in RANTES levels and its expression in blood or in cerebrospinal fluid have been reported in some neurodegenerative diseases, such as Parkinson's disease and multiple sclerosis, but also in metabolic diseases in which inflammation plays a role. The aim of this observational study was to assess RANTES levels in peripheral blood as clinical indicators of AD. Plasma levels of RANTES were investigated in 85 AD patients in a relatively early phase of AD (median 8.5 months after diagnosis; 39 men and 46 women; average age 75.7 years), and in 78 control subjects (24 men and 54 women; average age 66 years). We found much higher plasma levels of RANTES in AD patients compared to controls. A negative correlation of RANTES levels with age, disease duration, Fazekas scale score, and the medial temporal lobe atrophy (MTA) score (Scheltens's scale) was found in AD patients, i.e., the higher levels corresponded to earlier stages of the disease. Plasma RANTES levels were not correlated with cognitive scores. In AD patients, RANTES levels were positively correlated with the levels of pro-inflammatory cytokines interleukin-6 and tumor necrosis factor-α, which is consistent with the well-known fact that AD is associated with inflammatory processes. RANTES levels were also positively correlated with insulin levels in AD patients, with insulin resistance (HOMA-R) and pancreatic beta cell function (HOMA-F). This study evaluated several clinical and metabolic factors that may affect plasma levels of RANTES, but these factors could not explain the increases in RANTES levels observed in AD patients. Plasma levels of RANTES appear to be an interesting peripheral marker for early stages of AD. The study was approved by the Ethics Committee of Institute of Endocrinology, Prague, Czech Republic on July 22, 2011.

Sporadic Creutzfeldt-Jakob Disease and Other Proteinopathies in Comorbidity.

Background: Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common type of a group of transmissible spongiform encephalopathies (prion diseases). The etiology of the sporadic form of CJD is still unclear. sCJD can occur in combination with other neurodegenerative diseases, which further complicates the diagnosis. Alzheimer's disease (AD), e.g., is often seen in conjunction with sCJD. Method: In this study, we performed a systematic analysis of 15 genes related to the most important neurodegenerative diseases - AD, frontotemporal dementia, amyotrophic lateral sclerosis, prion disease, and Parkinson's disease - in a cohort of sCJD and sCJD in comorbidity with AD and primary age-related proteinopathy (PART). A total of 30 neuropathologically verified cases of sCJD with and without additional proteinopathies were included in the study. In addition, we compared microtubule-associated protein tau (MAPT) haplotypes between sCJD patients and patients with sCJD and PART or sCJD and AD. Then we studied the interaction between the Apolipoprotein E gene (APOE) and PRNP in sCJD patients. Results: We did not find any causal mutations in the neurodegenerative disease genes. We did detect a p.E318G missense variant of uncertain significance (VUS) in PSEN1 in three patients. In PRNP, we also found a previously described non-pathogenic insertion (p.P84_Q91Q). Conclusion: Our pilot study failed to find any critical differences between pure sCJD and sCJD in conjunction with other comorbid neurodegenerative diseases. Further investigations are needed to better understand this phenomenon.

Alzheimer's disease and other neurodegenerative dementias in comorbidity: A clinical and neuropathological overview.

Neuropathological diagnostic criteria of neurodegenerative disorders are based on the presence of specific inclusions in a specific area of brain tissue that correlate with clinical manifestations. Concomitant neurodegenerative disorders correspond to a combination of two (or more) different fully developed diseases in the same patient. Concomitant neurodegenerative pathology represents the presence of definite neurodegeneration and deposits of pathological proteins specific for another disease, which is not, however, fully developed. Very frequent overlaps include Alzheimer's disease and alpha-synuclein inclusions. Nevertheless, careful neuropathological investigations reveal an increasing frequency of different co-pathologies in examined brains. In Alzheimer's disease, protein TDP-43 may co-aggregate, but it is not clear whether this is atypical isolated Alzheimer's disease or overlap of Alzheimer's disease with early frontotemporal lobar degeneration. Comorbidities of Alzheimer's disease and tauopathies are relatively rare. A combination of vascular pathology with primary neurodegeneration (mostly Alzheimer's disease or dementia with Lewy bodies) is historically called mixed dementia. Overlap of different neuropathologically confirmed neurodegenerations could lead to atypical and unusual clinical presentations and may be responsible for faster disease progression. Several CSF biomarkers have been evaluated for their utility in diagnostic processes in different neurodegenerative dementias; however, evidence regarding their role in neurodegenerative overlaps is still limited.

Clinical Variability in P102L Gerstmann-Sträussler-Scheinker Syndrome.

Gerstmann-Sträussler-Scheinker syndrome (GSS) with the P102L mutation is a rare genetic prion disease caused by a pathogenic mutation at codon 102 in the prion protein gene. Cluster analysis encompassing data from 7 Czech patients and 87 published cases suggests the existence of 4 clinical phenotypes (typical GSS, GSS with areflexia and paresthesia, pure dementia GSS, and Creutzfeldt-Jakob disease-like GSS); GSS may be more common than previously estimated. In making a clinical diagnosis or progression estimates of GSS, magnetic resonance imaging and real-time quaking-induced conversion may be helpful, but the results should be evaluated with respect to the overall clinical context. ANN NEUROL 2019;86:643-652.

Megalencephalic leukoencephalopathy with subcortical cysts without macrocephaly: A case study of comorbid Turner's syndrome.

We present a case of megalencephalic leukoencephalopathy with subcortical cysts without macrocephaly and who initially presented with severe psychiatric symptoms. The patient presented with presented with late-onset secondary generalized focal motor seizures, gait ataxia and mild spasticity with hyperreflexia. MRI showed diffuse white matter hyperintensities and bilateral anterotemporal cysts. Genetic analysis confirmed the causal MLC1 mutation and Turner's syndrome. Surprisingly, our patient had no macrocephaly, which is a typical finding in MCL1 mutations; we emphasize that comorbid unrelated Turner's syndrome could explain the absence of macrocephaly: although short stature is typical, microcephaly is not associated with Turner's syndrome. Our observation thus argues for detailed investigations in cases presenting with an atypical clinical picture.

Pyramidal system involvement in progressive supranuclear palsy - a clinicopathological correlation.

BACKGROUND: We aimed to produce a detailed neuropathological analysis of pyramidal motor system pathology and provide its clinical pathological correlation in cases with definite progressive supranuclear palsy (PSP). METHODS: Pyramidal motor system pathologies were analyzed in 18 cases with neuropathologically confirmed PSP. Based on a retrospective clinical analysis, cases were subtyped according to Movement Disorder Society criteria for clinical diagnosis of PSP as probable, possible or suggestive of PSP with Richardson's syndrome (n = 10), PSP with predominant corticobasal syndrome (n = 3), PSP with predominant parkinsonism (n = 3), PSP with predominant speech/language disorder (n = 1), and PSP with progressive gait freezing (n = 1). Clinical manifestations of motor neuron involvement (pseudobulbar or bulbar signs and spasticity) were retrospectively assessed semiquantitatively. Neuropathologically, hyperphosphorylated tau-related pyramidal motor system neuronal, neuritic, and glial pathology using anti-tau AT8 clone immunohistochemistry, was also evaluated. RESULTS: Clinical manifestations of pyramidal motor system involvement were found in patients with different PSP subtypes. A statistically significant higher load of tau pathology was found in the pyramidal system in PSP-Richardson's syndrome compared to other PSP subtypes (p = 0.016); however, there was no significant correlation between pyramidal system tau pathology and related motor clinical symptoms. CONCLUSIONS: Tau pathology in the spinal cord and pyramidal motor system structures is very common in progressive supranuclear palsy and may neuropathologically supplement the distinction between classic Richardson's syndrome from other progressive supranuclear palsy subtypes.

Globular Glial Tauopathy Type I Presenting as Atypical Progressive Aphasia, With Comorbid Limbic-Predominant Age-Related TDP-43 Encephalopathy.

Globular glial tauopathies (GGTs) have heterogeneous presentations with little available information regarding typical clinical manifestations. We report on a case of atypical primary progressive aphasia (PPA) due to comorbid GGT and limbic transactive response DNA binding protein of 43 kDa (TDP-43) proteinopathy. The initial clinical phenotype was compatible with the nonfluent-agrammatical variant of PPA and early hippocampal amnesia. Progressively, parkinsonism and supranuclear oculomotor impairment occurred, and finally, late mutism with frontal-type dementia, impaired comprehension, and behavioral manifestations developed. The neuropathology was characteristic of GGT type I with vascular changes and comorbid limbic-predominant age-related TDP-43 encephalopathy (LATE). Our findings expand the clinical spectrum of GGTs to include a complex progressive aphasia syndrome. The extraordinary feature, in this case, was the combination of two progressive aphasia subtypes, that is, the early nonfluent-agrammatical variant and the late semantic variant. Our findings also expand the spectrum of neuropathological comorbidities in GGT.

Cognitive impairment in cerebellar lesions: a logit model based on neuropsychological testing.

BACKGROUND: Damage to the cerebellum may lead to motor dysfunctions, but also to the neuropsychological deficits that comprise the Cerebellar Cognitive Affective Syndrome (CCAS). It can affect executive functions, attention, memory, visuospatial functions, language, and emotions. Our goal was to determine which neuropsychological tests could be effectively used to identify this syndrome during a short examination. METHODS: Twenty-five patients with an isolated cerebellar lesion and 25 matched healthy controls were examined using an extensive neuropsychological battery. RESULTS: Logistic regression models and sub-models were computed for individual tests, as well as for the full battery. The best results were produced by a model combining patient education level, the number of errors on the California Verbal Learning Test, and time on Prague Stroop Test (Dots). CONCLUSIONS: Based on the results, we suggest that a condensed battery of neuropsychological tests can be used to detect CCAS. The tests are easy to administer and could be helpful in both research and clinical settings.

Genetic Alzheimer Disease and Sporadic Dementia With Lewy Bodies: A Comorbidity Presenting as Primary Progressive Aphasia.

We report a 44-year-old woman, with a family history of early-onset dementia, presenting with primary progressive aphasia. This clinically variable syndrome has multiple underlying pathologies, and correlations between clinical manifestations and postmortem neuropathologic findings are controversial. Our patient suffered worsening language impairment with major word-finding difficulties but preserved comprehension. She also developed episodic memory impairment. Her condition progressed to dementia with behavioral changes. Magnetic resonance imaging showed early left perisylvian and bitemporal atrophy. The patient died shortly afterward from colon cancer. Neuropathologic examination revealed advanced early-onset Alzheimer and Lewy body disease, plus a clinically nonrelevant metastasis of her colon cancer in her left parietal lobe. Genetic examination revealed a p.Glu184Asp mutation in the presenilin1 gene. Our findings confirm the importance of a thorough appreciation for the clinical and neuropathologic correlations in patients with atypical neurodegenerative dementias.