Frontotemporal Lobar Degeneration Group Research Articles

Cerebrospinal Fluid Neurofilament Light as a Marker of Neuro-axonal Injury in Normal Pressure Hydrocephalus (P10-6.001)

<h3>Objective:</h3> To compare Cerebrospinal fluid (CSF) Neurofilament-light chain (NfL) and NfL/amyloid beta₄₂ (Abeta42) ratio levels in normal pressure hydrocephalus (NPH) patients with healthy controls (HC), Alzheimer’s disease (AD), and Frontotemporal lobar degeneration (FTLD). <h3>Background:</h3> Levels of CSF NfL have been shown to be a marker of neuro-axonal injury and are elevated in neurodegenerative disease. One putative etiology of NPH involves axonal injury; however, low CSF Abeta42 has been reported in NPH. To control for the higher volume of CSF in NPH, the NfL/Abeta42 ratio was used. <h3>Design/Methods:</h3> 120 patients with CSF analysis: (a) 46 NPH: ventriculomegaly on MRI or CT, negative AD biomarkers, clinical symptoms of NPH, improvement in gait after tap test; (b) 39 FTLD: 5 behavioural-variant frontotemporal dementia, 14 corticobasal syndrome, 4 frontotemporal dementia with motor neuron disease, 12 progressive supranuclear palsy, 2 semantic-variant primary progressive aphasia (PPA), and 2 non-fluent PPA; (c) 29 AD; and (d) 6 HC. Levels of CSF NfL were measured using single molecule array (Simoa) technology while Abeta42 was measured using a sandwich ELISA method (Innotest). All statistical analyses were corrected for multiple comparisons and age. <h3>Results:</h3> Log transformed NfL levels in the NPH group were significantly higher than HC (p &lt; 0.05), but lower than FTLD and AD group (p &lt;0 .001). Log transformed CSF NfL/Abeta42 ratio was significantly higher in the NPH group compared to HC (p&lt;0.05); but no significant difference with FTLD and AD groups. <h3>Conclusions:</h3> Intermediate CSF NfL levels in NPH patients suggest that there is some neuro-axonal injury present - although less than in FTLD and AD. Further investigations are warranted to determine whether the NfL normalizes after shunting or the neuroaxonal injury is irreversible. NfL in NPH may help elucidate the pathophysiology of the disease. <b>Disclosure:</b> Ms. Davenport has nothing to disclose. Dr. Taghdiri has nothing to disclose. Anna Vasilevskaya has nothing to disclose. Ms. Anastassiadis has received research support from Fonds de Recherche du Québec - Santé (FRQS). Dr. Thapa has nothing to disclose. Dr. Dimal has nothing to disclose. Namita Multani, 14039 has nothing to disclose. Dr. Fasano has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Abbott. Dr. Fasano has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Abbvie. Dr. Fasano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ipsen. Dr. Fasano has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Medtronic. Dr. Fasano has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Boston Scientific. Dr. Fasano has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Abbott. Dr. Fasano has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Medtronic. Dr. Fasano has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sunovion. Dr. Fasano has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Ceregate. The institution of Dr. Fasano has received research support from Boston Scientific. The institution of Dr. Fasano has received research support from Medtronic. The institution of Dr. Fasano has received research support from Abbvie. Dr. Fasano has received publishing royalties from a publication relating to health care. Dr. Tang-Wai has nothing to disclose. Dr. Tartaglia has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. The institution of Dr. Tartaglia has received research support from NIH. The institution of Dr. Tartaglia has received research support from University of Toronto.

Neurofilament light as a marker of neuro‐axonal injury and potential biomarker of disease progression in normal pressure hydrocephalus

AbstractBackgroundThe etiology of normal pressure hydrocephalus (NPH) is unknown. Patients worsen but the cause of the progression is unclear. A prognostic biomarker in NPH is required for selecting the best candidates for shunt surgery. Neurofilament‐light chain (NfL) is a marker of neuro‐axonal injury and is elevated in neurodegenerative disease, traumatic brain injury, stroke and encephalitis. The aim of this study was: (1) To compare cerebrospinal fluid (CSF) NfL of NPH patients with healthy controls (HC), and other neurodegenerative diseases: Alzheimer’s disease (AD), and Frontotemporal lobar degeneration (FTLD); and (2) To evaluate CSF NfL levels as a potential biomarker of disease progression in NPH.Method108 patients with CSF analysis: (a) NPH group (39 patients): ventriculomegaly on MRI or CT, negative AD biomarkers, clinical symptoms of NPH, improvement in gait after removal of a large amount of CSF. 14 patients of the unshunted NPH group had a 1‐year follow‐up scan. EVANS index was calculated for these participants; (b) FTLD group (45 patients): 5 behavioural‐variant frontotemporal‐dementia, 19 corticobasal syndrome, 3 frontotemporal dementia with motor neuron disease, 13 progressive supranuclear palsy, 3 semantic‐variant primary progressive aphasia (PPA), and 2 non‐fluent PPA; (c) AD group (19 patients): CSF biomarkers and cognitive symptoms consistent with AD; and (d) HC group (5 participants): cognitively and functionally normal. Levels of NfL in CSF were measured using single molecule array (Simoa) technology. All statistical analyses were corrected for multiple comparisons and age.ResultNfL levels in patients with NPH were significantly higher than HC (1504.7±520 vs 702.5±170pg/ml, p &lt; 0.001), and lower than FTLD group (1504.7±520 vs 3071.7±2830pg/ml, p=0.005). There was a trend for lower NfL in NPH compared to AD, (1504.7±520 vs 2305.4±1179.7pg/ml, p=0.056). There was a significant correlation between baseline NfL levels and increase in EVANS index (r=0.784, p=0.002) in the 14 NPH patients with longitudinal brain imaging.ConclusionCSF NfL levels in NPH patients suggests there is neuro‐axonal injury but is lower than some other neurodegenerative diseases (i.e., FTLD and AD). NfL may be a biomarker for neuro‐axonal injury and disease progression in NPH.

Early-stage differentiation between Alzheimer's disease and frontotemporal lobe degeneration: Clinical, neuropsychology, and neuroimaging features.

Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) are the two most common forms of neurodegenerative dementia. Although both of them have well-established diagnostic criteria, achieving early diagnosis remains challenging. Here, we aimed to make the differential diagnosis of AD and FTLD from clinical, neuropsychological, and neuroimaging features. In this retrospective study, we selected 95 patients with PET-CT defined AD and 106 patients with PET-CT/biomarker-defined FTLD. We performed structured chart examination to collect clinical data and ascertain clinical features. A series of neuropsychological scales were used to assess the neuropsychological characteristics of patients. Automatic tissue segmentation of brain by Dr. Brain tool was used to collect multi-parameter volumetric measurements from different brain areas. All patients' structural neuroimage data were analyzed to obtain brain structure and white matter hyperintensities (WMH) quantitative data. The prevalence of vascular disease associated factors was higher in AD patients than that in FTLD group. 56.84% of patients with AD carried at least one APOE ε4 allele, which is much high than that in FTLD patients. The first symptoms of AD patients were mostly cognitive impairment rather than behavioral abnormalities. In contrast, behavioral abnormalities were the prominent early manifestations of FTLD, and few patients may be accompanied by memory impairment and motor symptoms. In direct comparison, patients with AD had slightly more posterior lesions and less frontal atrophy, whereas patients with FTLD had more frontotemporal atrophy and less posterior lesions. The WMH burden of AD was significantly higher, especially in cortical areas, while the WMH burden of FTLD was higher in periventricular areas. These results indicate that dynamic evaluation of cognitive function, behavioral and psychological symptoms, and multimodal neuroimaging are helpful for the early diagnosis and differentiation between AD and FTLD.

Locus Coeruleus Degeneration Differs Between Frontotemporal Lobar Degeneration Subtypes.

Background:There are few studies on the locus coeruleus (LC) in frontotemporal lobar degeneration (FTLD) and the potential differences in the LC related to the underlying proteinopathy.Objective:The aim of this study was to investigate the LC in FTLD subgroups.Methods:Neuropathological cases diagnosed with FTLD were included. The subgroups consisted of FTLD with tau, transactive response DNA-binding protein 43 (TDP) and fused in sarcoma (FUS). Micro- and macroscopical degeneration of the LC were assessed with respect to the number of neurons and the degree of depigmentation. A group of cognitively healthy subjects and a group with vascular cognitive impairment (VCI) served as comparison groups.Results: A total of 85 FTLD cases were included, of which 44 had FTLD-TDP, 38 had FTLD-tau, and three had FTLD-FUS. The groups were compared with 25 VCI cases and 41 cognitively healthy control cases (N = 151 for the entire study). All FTLD groups had a statistically higher microscopical degeneration of the LC compared to the controls, but the FTLD-tau group had greater micro- and macroscopical degeneration than the FTLD-TDP group. Age correlated positively with the LC score in the FTLD-tau group, but not in the FTLD-TDP group.Conclusion:A greater microscopical degeneration of the LC was observed in all FTLD cases compared to healthy controls and those with VCI. The LC degeneration was more severe in FTLD-tau than in FTLD-TDP. The macroscopically differential degeneration of the LC in FTLD subgroups may facilitate differential diagnostics, potentially with imaging.

Resting state functional brain networks associated with emotion processing in frontotemporal lobar degeneration

This study investigated the relationship between emotion processing and resting-state functional connectivity (rs-FC) of the brain networks in frontotemporal lobar degeneration (FTLD). Eighty FTLD patients (including cases with behavioral variant of frontotemporal dementia, primary progressive aphasia, progressive supranuclear palsy syndrome, motor neuron disease) and 65 healthy controls underwent rs-functional MRI. Emotion processing was tested using the Comprehensive Affect Testing System (CATS). In patients and controls, correlations were investigated between each emotion construct and rs-FC changes within critical networks. Mean rs-FC of the clusters significantly associated with CATS scoring were compared among FTLD groups. FTLD patients had pathological CATS scores compared with controls. In controls, increased rs-FC of the cerebellar and visuo-associative networks correlated with better scores in emotion-matching and discrimination tasks, respectively; while decreased rs-FC of the visuo-spatial network was related with better performance in the affect-matching and naming. In FTLD, the associations between rs-FC and CATS scores involved more brain regions, such as orbitofrontal and middle frontal gyri within anterior networks (i.e., salience and default-mode), parietal and somatosensory regions within visuo-spatial and sensorimotor networks, caudate and thalamus within basal-ganglia network. Rs-FC changes associated with CATS were similar among all FTLD groups. In FTLD compared to controls, the pattern of rs-FC associated with emotional processing involves a larger number of brain regions, likely due to functional specificity loss and compensatory attempts. These associations were similar across all FTLD groups, suggesting a common physiopathological mechanism of emotion processing breakdown, regardless the clinical presentation and pattern of atrophy.

Diminished preparatory physiological responses in frontotemporal lobar degeneration syndromes.

Researchers typically study physiological responses either after stimulus onset or when the emotional valence of an upcoming stimulus is revealed. Yet, participants may also respond when they are told that an emotional stimulus is about to be presented even without knowing its valence. Increased physiological responding during this time may reflect a ‘preparation for action’. The generation of such physiological responses may be supported by frontotemporal regions of the brain that are vulnerable to damage in frontotemporal lobar degeneration. We examined preparatory physiological responses and their structural and functional neural correlate in five frontotemporal lobar degeneration clinical subtypes (behavioural variant frontotemporal dementia, n = 67; semantic variant primary progressive aphasia, n = 35; non-fluent variant primary progressive aphasia, n = 30; corticobasal syndrome, n = 32; progressive supranuclear palsy, n = 30). Comparison groups included patients with Alzheimer’s disease (n = 56) and healthy controls (n = 35). Preparatory responses were quantified as cardiac interbeat interval decreases (i.e. heart rate increases) from baseline to an ‘instruction period’, during which participants were told to watch the upcoming emotional film but not provided the film’s valence. Patients’ behavioural symptoms (apathy and disinhibition) were also evaluated via a caregiver-reported measure. Compared to healthy controls and Alzheimer’s disease, the frontotemporal lobar degeneration group showed significantly smaller preparatory responses. When comparing each frontotemporal lobar degeneration clinical subtype with healthy controls and Alzheimer’s disease, significant group differences emerged for behavioural variant frontotemporal dementia and progressive supranuclear palsy. Behavioural analyses revealed that frontotemporal lobar degeneration patients showed greater disinhibition and apathy compared to Alzheimer’s disease patients. Further, these group differences in disinhibition (but not apathy) were mediated by patients’ smaller preparatory responses. Voxel-based morphometry and resting-state functional MRI analyses revealed that across patients and healthy controls, smaller preparatory responses were associated with smaller volume and lower functional connectivity in a circuit that included the ventromedial prefrontal cortex and cortical and subcortical regions of the salience network. Diminished preparatory physiological responding in frontotemporal lobar degeneration may reflect a lack of preparation for actions that are appropriate for an upcoming situation, such as approaching or withdrawing from emotional stimuli. The ventromedial prefrontal cortex and salience network are critical for evaluating stimuli, thinking about the future, triggering peripheral physiological responses, and processing and interpreting interoceptive signals. Damage to these circuits in frontotemporal lobar degeneration may impair preparatory responses and help explain often-observed clinical symptoms such as disinhibition in these patients.

Signature laminar distributions of pathology in frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD) with either tau (FTLD-tau) or TDP-43 (FTLD-TDP) inclusions are distinct proteinopathies that frequently cause similar frontotemporal dementia (FTD) clinical syndromes. FTD syndromes often display macroscopic signatures of neurodegeneration at the level of regions and networks, but it is unclear if subregional laminar pathology display patterns unique to proteinopathy or clinical syndrome. We hypothesized that FTLD-tau and FTLD-TDP accumulate pathology in relatively distinct cortical layers independent of clinical syndrome, with greater involvement of lower layers in FTLD-tau. The current study examined 170 patients with either FTLD-tau (n = 73) or FTLD-TDP (n = 97) spanning dementia and motor phenotypes in the FTD spectrum. We digitally measured the percent area occupied by tau and TDP-43 pathology in upper layers (I–III), lower layers (IV–VI), and juxtacortical white matter (WM) from isocortical regions in both hemispheres where available. Linear mixed-effects models compared ratios of upper to lower layer pathology between FTLD groups and investigated relationships with regions, WM pathology, and global cognitive impairment while adjusting for demographics. We found lower ratios of layer pathology in FTLD-tau and higher ratios of layer pathology in FTLD-TDP, reflecting lower layer-predominant tau pathology and upper layer-predominant TDP-43 pathology, respectively (p < 0.001). FTLD-tau displayed lower ratios of layer pathology related to greater WM tau pathology (p = 0.002) and to earlier involved/severe pathology regions (p = 0.007). In contrast, FTLD-TDP displayed higher ratios of layer pathology not related to either WM pathology or regional severity. Greater cognitive impairment was associated with higher ratios of layer pathology in FTLD-tau (p = 0.018), but was not related to ratios of layer pathology in FTLD-TDP. Lower layer-predominant tau pathology and upper layer-predominant TDP-43 pathology are proteinopathy-specific, regardless of clinical syndromes or regional networks that define these syndromes. Thus, patterns of laminar change may provide a useful anatomical framework for investigating how degeneration of select cells and corresponding laminar circuits influence large-scale networks and clinical symptomology in FTLD.

Calsyntenin‐1 is a cerebrospinal fluid marker of frontotemporal dementia‐related synapse degeneration

AbstractBackgroundFrontotemporal dementia (FTD) clinical diagnosis is challenged by the variable correspondence between the clinical syndrome and underlying neuropathological changes, the phenotypic overlap with Alzheimer's disease (AD) and the lack of pathophysiologic diagnostic biomarkers. As synapse degeneration is an early event in pathological frontotemporal lobar degeneration (FTLD), a surrogate marker of synapse loss could aid the early diagnosis of FTD. The aim of this study was to evaluate the diagnostic performance of a panel of 9 synaptic proteins in cerebrospinal fluid (CSF) for FTLD in a neuropathological cohort.MethodWe included cognitively normal controls (n=35, 69 years+/‐7) and patients with neuropathological confirmation of FTLD (n=49, mean age‐at‐CSF 67 years+/‐10) or AD (n=25, 73 years+/‐6) from the Penn FTD Center. Subsets of the FTLD group included FTLD‐TDP (n=25) and FTLD‐Tau (n=24) neuropathological subtypes and “pure FTLD” (neurofibrillary tangle score of B0/B1 according to the NIA‐AA classification; n=39). We quantified the synaptic panel by targeted mass spectrometry using isotopically‐labeled proteotypic peptides as internal standards. We used linear regression with Dunnett’s post‐hoc tests to compare group differences, receiver‐operating characteristic curves to assess diagnostic accuracy (AUC) and linear regression adjusting for age‐at‐death and sex to assess the association with tau burden.ResultOf the 9 synaptic proteins, CSF Calsyntenin‐1 showed the strongest association with disease etiology (r2 =.12, p=.0006). Calsyntenin‐1 was lower in FTLD compared to controls (p=.03) and AD (p=.0008), particularly in “pure FTLD” (p=.02 vs controls, p=.0004 vs AD). Calsyntenin‐1 levels were comparable between AD and controls (p=.33) and between neuropathological FTLD subtypes (p=.66). Calsyntenin‐1 did not correlate with age‐at‐CSF analysis in controls (p=.74), FTLD (p=.07) or AD (p=.40). Calsyntenin‐1 showed the best diagnostic accuracy for differentiating FTLD from AD (AUC=73.4%) and showed similar accuracy in “pure FTLD” (AUC=75.7%) and in FTLD‐TDP (AUC=76.0%) and FTLD‐Tau (AUC=70.4%). Calsyntenin‐1 directly correlated with global pathological tau burden in FTLD (r2=.22; p=0.005) and in “pure FTLD” (r2=.17; p=0.02).ConclusionLow CSF levels of the post‐synaptic modulator, Calsyntenin‐1, is specific to FTLD, particularly in cases with little or no tau pathology and could aid the early diagnosis of FTD and the differential diagnosis from AD and other tauopathies.

CSF biomarkers for frontotemporal dementia and its pathological subtypes

AbstractBackgroundFrontotemporal dementia (FTD) is caused by frontotemporal lobar degeneration (FTLD) and is characterized mainly by the presence of aggregates of the proteins tau (FTLD‐Tau) or TDP43 (FTLD‐ TDP) in the brain, which likely require distinct pharmacological therapy. However, the clinical presentation of the pathological subtypes is heterogeneous and overlapping, making this diagnostic subtyping at present virtually impossible. Thus, there is a strong unmet need to identify body‐fluid biomarkers to discriminate FTD and its pathological subtypes. Most biomarker studies performed to date have analyzed pathologically heterogeneous populations. The few studies analyzing antemortem cerebrospinal fluid (CSF) with known underlying neuropathology have revealed several candidate biomarkers (e.g. p/tTau ratio). Despite these promising results, their specificity is still not optimal, most of the identified markers are awaiting further validation and their diagnostic accuracy remains to be evaluated.MethodWe have recently taken advantage of a novel high‐multiplex and sensitive antibody‐based proteomic technology to analyze &gt;600 proteins in a large multicenter cohort providing CSF samples from controls (n=195) and FTD patients (n=199). For a subset of FTD cases, the underlying specific pathology was known (FTLD‐Tau=34: 18 autopsy‐confirmed and 27 MAPT mutation carriers; FTLD‐ FTLD‐TDP=54: 27 autopsy‐confirmed and 18 C9orf72 and 9 GRN mutation carriers). Differences in the protein expression profile were analyzed by GlobalTesting. Generalized linear modeling was used to identified classification protein signatures.ResultWe identified CSF protein biomarker signatures for specific diagnosis of FTD (8‐9 proteins, AUC&gt;0.85). The proteins identified were related to mechanisms involved in immune system, extracellular remodeling and cell killing. There were no between‐group differences in the CSF protein profiles of the FTLD groups. However, differences in the absolute levels of some proteins were detected when autopsy‐confirmed cases and mutation carriers were analyzed separately.ConclusionThe similarity of the CSF profiles between FTLD groups suggests shared pathological mechanisms. Alternatively, each subtype may be heterogeneous, which possibly results from analyzing together familial and autopsy‐confirmed cases. Taken together, the FTLD studies performed to date indicate a highly complex disorder challenging the development of efficient diagnostic and therapeutic markers.

Degeneration of the locus coeruleus is a common feature of tauopathies and distinct from TDP-43 proteinopathies in the frontotemporal lobar degeneration spectrum.

Neurodegeneration of the locus coeruleus (LC) in age-related neurodegenerative diseases such as Alzheimer's disease (AD) is well documented. However, detailed studies of LC neurodegeneration in the full spectrum of frontotemporal lobar degeneration (FTLD) proteinopathies comparing tauopathies (FTLD-tau) to TDP-43 proteinopathies (FTLD-TDP) are lacking. Here, we tested the hypothesis that there is greater LC neuropathology and neurodegeneration in FTLD-tau compared to FTLD-TDP. We examined 280 patients including FTLD-tau (n = 94), FTLD-TDP (n = 135), and two reference groups: clinical/pathological AD (n = 32) and healthy controls (HC, n = 19). Adjacent sections of pons tissue containing the LC were immunostained for phosphorylated TDP-43 (1D3-p409/410), hyperphosphorylated tau (PHF-1), and tyrosine hydroxylase (TH) to examine neuromelanin-containing noradrenergic neurons. Blinded to clinical and pathologic diagnoses, we semi-quantitatively scored inclusions of tau and TDP-43 both inside LC neuronal somas and in surrounding neuropil. We also digitally measured the percent area occupied of neuromelanin inside of TH-positive LC neurons and in surrounding neuropil to calculate a ratio of extracellular-to-intracellular neuromelanin as an objective composite measure of neurodegeneration. We found that LC tau burden in FTLD-tau was greater than LC TDP-43 burden in FTLD-TDP (z = - 11.38, p < 0.0001). Digital measures of LC neurodegeneration in FTLD-tau were comparable to AD (z = - 1.84, p > 0.05) but greater than FTLD-TDP (z = - 3.85, p < 0.0001) and HC (z = - 4.12, p < 0.0001). Both tau burden and neurodegeneration were consistently elevated in the LC across pathologic and clinical subgroups of FTLD-tau compared to FTLD-TDP subgroups. Moreover, LC tau burden positively correlated with neurodegeneration in the total FTLD group (rho = 0.24, p = 0.001), while TDP-43 burden did not correlate with LC neurodegeneration in FTLD-TDP (rho = - 0.01, p = 0.90). These findings suggest that patterns of disease propagation across all tauopathies include prominent LC tau and neurodegeneration that are relatively distinct from the minimal degenerative changes to the LC in FTLD-TDP and HC. Antemortem detection of LC neurodegeneration and/or function could potentially improve antemortem differentiation of underlying FTLD tauopathies from clinically similar FTLD-TDP proteinopathies.

Frontotemporal Dementia: Correlations Between Psychiatric Symptoms and Pathology.

ObjectiveThe pathology of frontotemporal dementia, termed frontotemporal lobar degeneration (FTLD), is characterized by distinct molecular classes of aggregated proteins, the most common being TAR DNA‐binding protein‐43 (TDP‐43), tau, and fused in sarcoma (FUS). With a few exceptions, it is currently not possible to predict the underlying pathology based on the clinical syndrome. In this study, we set out to investigate the relationship between pathological and clinical presentation at single symptom level, including neuropsychiatric features.MethodsThe presence or absence of symptoms from the current clinical guidelines, together with neuropsychiatric features, such as hallucinations and delusions, were scored and compared across pathological groups in a cohort of 150 brain donors.ResultsOur cohort consisted of 68.6% FTLD donors (35.3% TDP‐43, 28% tau, and 5.3% FUS) and 31.3% non‐FTLD donors with a clinical diagnosis of frontotemporal dementia and a different pathological substrate, such as Alzheimer's disease (23%). The presence of hyperorality points to FTLD rather than non‐FTLD pathology (p < 0.001). Within the FTLD group, hallucinations in the initial years of the disease were related to TDP‐43 pathology (p = 0.02), including but not limited to chromosome 9 open reading frame 72 (C9orf72) repeat expansion carriers. The presence of perseverative or compulsive behavior was more common in the TDP‐B and TDP‐C histotypes (p = 0.002).InterpretationOur findings indicate that neuropsychiatric features are common in FTLD and form an important indicator of underlying pathology. In order to allow better inclusion of patients in targeted molecular trials, the routine evaluation of patients with frontotemporal dementia should include the presence and nature of neuropsychiatric symptoms. ANN NEUROL 2020;87:950–961

Serum neurofilament light chain is a discriminative biomarker between frontotemporal lobar degeneration and primary psychiatric disorders

Due to the significant clinical overlap between frontotemporal lobar degeneration (FTLD) spectrum disorders and late-onset primary psychiatric disorders (PPD), diagnostic biomarkers reflecting the different underlying pathophysiologies are urgently needed. Thus far, elevated cerebrospinal fluid (CSF) levels of neurofilament light chain (NfL) have been reported in various neurological conditions. Furthermore, recent advancements in ultrasensitive analytical methods (e.g., single molecule array, Simoa) have enabled sensitive and less invasive NfL detection also from blood samples. In this study, we evaluated the potential of serum NfL (sNfL) as a diagnostic tool between FTLD and PPD. We analyzed sNfL levels with Simoa from 125 participants including patients from FTLD (n = 91) and PPD (n = 34) spectra. Our results show that sNfL levels are higher in the FTLD group compared to the PPD group as well as in separate clinical subtypes of FTLD compared to different psychiatric manifestations (i.e., mood or psychotic disorders). At single-subject level, discrimination between FTLD and PPD was possible with 80% sensitivity and 85% specificity (AUC = 0.850, 95% CI 0.776–0.923), and between behavioral variant frontotemporal dementia (bvFTD) and PPD with 79% sensitivity and 85% specificity (AUC = 0.830, 95% CI 0.732–0.908). These findings highlight the potential of sNfL as a discriminating biomarker for FTLD over PPD in patients with wide-ranging behavioral, psychiatric and cognitive symptoms.

Elevated YKL-40 and low sAPPβ:YKL-40 ratio in antemortem cerebrospinal fluid of patients with pathologically confirmed FTLD

ObjectivesThe combination of high YKL-40 (a glial inflammatory marker) and low sAPPβ (a soluble β fragment of amyloid precursor protein) in cerebrospinal fluid (CSF) has been associated with frontotemporal lobar...

A 2-Step Cerebrospinal Algorithm for the Selection of Frontotemporal Lobar Degeneration Subtypes

Cerebrospinal fluid (CSF) core Alzheimer disease (AD) biomarkers have shown an excellent capacity for the in vivo detection of AD. Previous studies have shown that CSF levels of phosphorylated tau (p-tau) also correlate with tau pathology in frontotemporal lobar degeneration (FTLD) after accounting for AD copathology. To develop an algorithm based on core AD CSF measures to exclude cases with AD pathology and then differentiate between FTLD-tau and FTLD transactive response DNA-binding protein of approximately 43kDa (FTLD-TDP). A case-control study at the University of Pennsylvania. Participants were selected from a database of 1796 patients included between 1992 and 2016 with different neurodegenerative diseases with available CSF. Three patient cohorts were included: a cohort of patients with sporadic, autopsy-confirmed FTLD and AD (n = 143); a cohort of patients with frontotemporal degeneration (FTD) with TDP-associated or tau-associated mutations (n = 60); and a living cohort of patients with syndromes highly predictive of FTLD (progressive supranuclear palsy and FTD-amyotrophic lateral sclerosis; n = 62). Cerebrospinal fluid values of amyloid β1-42 (Aβ1-42), total tau (t-tau), and p-tau obtained using the INNO-BIA AlzBio3 (xMAP; Luminex) assay or INNOTEST enzyme-linked immunosorbent assay transformed using a previously validated algorithm. Sensitivities and specificities for differentiating AD from FTLD groups were calculated. This autopsy cohort included FTLD-tau (n = 27; mean [SD] age at onset, 60.8 [9.7] years), FTLD-TDP (n = 13; mean [SD] age at onset, 62.4 [8.5] years), AD (n = 89, mean [SD] age at onset, 66.5 [9.7] years); and mixed FTLD-AD (n = 14, mean [SD] age at onset, 70.6 [8.5] years).The p-tau/Aβ1-42 ratio showed an excellent diagnostic accuracy to exclude AD cases in the autopsy cohort with single neurodegenerative pathologies (area under the curve [AUC], 0.98; 95% CI, 0.96-1.00). Cerebrospinal fluid p-tau levels showed a good AUC (0.87; 95% CI, 0.73-1.00) for discriminating pure FTLD-TDP from pure FTLD-tau. The application of an algorithm using cutpoints of CSF p-tau to Aβ1-42 ratio and p-tau allowed a good discrimination of pure FTLD-TDP cases from the remaining FTLD-tau and mixed FTLD cases. The diagnostic value of this algorithm was confirmed in an independent cohort of living patients with progressive supranuclear palsy and FTD-amyotrophic lateral sclerosis (AUC, 0.9; 95% CI, 0.81-0.99). However, the algorithm was less useful in FTD cases carrying a pathogenic mutation (AUC, 0.58; 95% CI, 0.38-0.77) owing to elevated p-tau levels in TDP-associated mutation carriers. Alzheimer disease CSF core biomarkers can be used with high specificity for the in vivo identification of patients with pure FTLD-TDP and FTLD-tau when accounting for comorbid AD and genetic status.

Low Prevalence of Cancer in Patients withFrontotemporal Lobar Degeneration.

Several studies have reported reduced risk of cancer in patients with Alzheimer's disease (AD) or Parkinson's disease. The relationship between cancer and frontotemporal lobar degeneration (FTLD) has not been previously reported. Here, our aim was to evaluate the occurrence of cancer in Finnish FTLD patients with a high proportion of C9ORF72 repeat expansion carriers in comparison to age- and sex-matched group of AD patients and control subjects classified as not cognitively impaired (NCI). The prevalence of cancer was 9.7% in FTLD, 18.7% in AD, and 17.4% in NCI (FTLD versus AD p = 0.012, FTLD versus NCI p = 0.029) groups. No differences were observed between C9ORF72 repeat expansion carriers and non-carriers inside the FTLD group. To our knowledge, this is the first study showing significantly lower prevalence of cancer in FTLD patients compared to patients with AD or NCI subjects. Our data suggest an inverse association between neurodegeneration and cancer and that FTLD-specific mechanisms may underlie the especially strong inverse association observed in this study.

Serum C-Peptide, Visfatin, Resistin, and Ghrelin are Altered in Sporadic and GRN-Associated Frontotemporal Lobar Degeneration.

Frontotemporal lobar degeneration (FTLD) is a group of complex neurodegenerative disease characterized by progressive deterioration of the frontal and anterior temporal lobes of the brain resulting in different heterogeneous conditions, mainly characterized by personality changes, behavioral disturbances, such as binge eating, and deficits in language and executive functions. Null mutations in progranulin gene (GRN) are one of the most frequent genetic determinants in familial frontotemporal dementia. Recently, progranulin was recognized as an adipokine involved in diet-induced obesity and insulin resistance revealing its metabolic function. Increasing evidence suggests that neurodegenerative dementias are associated with a higher prevalence of metabolic changes than in the general population. According to these findings, the aim of this study is to investigate putative alterations in markers linked to metabolic functions (i.e., C-peptide, ghrelin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide-1, glucagon, insulin, resistin, and three adipokines as visfatin, leptin, and plasminogen activator inhibitor-1 total) in sporadic and GRN-related FTLD. We found that 1) C-peptide is increased in sporadic and GRN-mutated FTLD patients; in addition, we demonstrated an anticipation of the disease in patients with the highest C-peptide concentrations; 2) visfatin is slightly reduced in the whole FTLD group; 3) resistin, an adipokine involved in inflammatory-related diseases, is specifically increased in FTLD due to GRN null mutations; 4) ghrelin concentration is specifically increased in pre-symptomatic subjects and FTLD patients with GRN mutations. These findings support the hypothesis that alterations in metabolic pattern are involved in FTLD progression highlighting novel putative targets for the development of preventive and personalized therapies.

Topographic distribution of brain iron deposition and small cerebrovascular lesions in amyotrophic lateral sclerosis and in frontotemporal lobar degeneration: a post-mortem 7.0-tesla magnetic resonance imaging study with neuropathological correlates.

Amyotrophic lateral sclerosis (ALS) is associated with frontotemporal lobar degeneration (FTLD) in 15% of the cases. A neuropathological continuity between ALS and FTLD-TDP is suspected. The present post-mortem 7.0-tesla magnetic resonance imaging (MRI) study compares the topographic distribution of iron (Fe) deposition and the incidence of small cerebrovascular lesions in ALS and in FTLD brains. Seventy-eight post-mortem brains underwent 7.0-tesla MRI. The patients consisted of 12 with ALS, 38 with FTLD, and 28 controls. Three ALS brains had minor FTLD features. Three coronal sections of a cerebral hemisphere were submitted to T2 and T2* MRI sequences. The amount of Fe deposition in the deep brain structures and the number of small cerebrovascular lesions was determined in ALS and the subtypes of FTLD compared to control brains, with neuropathological correlates. A significant increase of Fe deposition was observed in the claustrum, caudate nucleus, globus pallidus, thalamus, and subthalamic nucleus of the FTLD-FUS and FTLD-TDP groups, while in the ALS one, the Fe increase was only observed in the caudate and the subthalamic nuclei. White matter changes were only significantly more severe in the FTLD compared to those in ALS and in controls brains. Cortical micro-bleeds were increased in the frontal and temporal lobes of FTLD as well as of ALS brains compared to controls. Cortical micro-infarcts were, on the other hand, more frequent in the control compared to the ALS and FTLD groups. The present study supports the assumption of a neuropathological continuity between ALS and FTLD and illustrates the favourable vascular risk profile in these diseases.

CSF sAPPβ, YKL-40, and neurofilament light in frontotemporal lobar degeneration.

To analyze the clinical utility of 3 CSF biomarkers and their structural imaging correlates in a large cohort of patients with different dementia and parkinsonian syndromes within the spectrum of frontotemporal lobar degeneration (FTLD). We analyzed 3 CSF biomarkers (YKL-40, soluble β fragment of amyloid precursor protein [sAPPβ], neurofilament light [NfL]) and core Alzheimer disease (AD) biomarkers (β-amyloid1-42, total tau, phosphorylated tau) in patients with FTLD-related clinical syndromes (n = 159): behavioral variant of frontotemporal dementia (n = 68), nonfluent (n = 23) and semantic (n = 19) variants of primary progressive aphasia, progressive supranuclear palsy (n = 28), and corticobasal syndrome (n = 21). We also included patients with AD (n = 72) and cognitively normal controls (CN; n = 76). We compared cross-sectional biomarker levels between groups, studied their correlation with cortical thickness, and evaluated their potential diagnostic utility. Patients with FTLD-related syndromes had lower levels of sAPPβ than CN and patients with AD. The levels of sAPPβ showed a strong correlation with cortical structural changes in frontal and cingulate areas. NfL and YKL-40 levels were high in both the FTLD and AD groups compared to controls. In the receiver operating characteristic analysis, the sAPPβ/YKL-40 and NfL/sAPPβ ratios had areas under the curve of 0.91 and 0.96, respectively, distinguishing patients with FTLD from CN, and of 0.84 and 0.85, distinguishing patients with FTLD from patients with AD. The combination of sAPPβ with YKL-40 and with NfL in CSF could be useful to increase the certainty of the diagnosis of FTLD-related syndromes in clinical practice. This study provides Class III evidence that CSF levels of sAPPβ, YKL-40, and NfL are useful to identify patients with FTLD-related syndromes.

Patterns of Microglial Cell Activation in Alzheimer Disease and Frontotemporal Lobar Degeneration

Aims: Microglia-driven neuroinflammation can play an important role in the pathophysiology of neurodegenerative disorders. In this study, we sought to characterize the distribution of microglial cell activation in 2 neurodegenerative dementias with distinct protein signatures, Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD) of the TDP subtype, and to determine if there was an anatomical correlation with the phenotypes most commonly associated with these conditions. Methods: The distribution and extent of microglial cell activation was assessed semiquantitatively in the hippocampal formation, cortical gray matter, and subcortical white matter of CD68-immunostained sections of the frontal, temporal, parietal, and occipital cortices from 15 pathologically confirmed cases of AD, 13 cases of FTLD, and 18 controls. Results: Significantly higher levels of microglial cell activation occurred in the subiculum in AD and FTLD than in controls. Additionally, AD had higher microglial activation in the CA1 and FTLD in the hippocampal white matter than the controls. Microglial activation was greater in the dentate gyrus molecular layer in AD than in FTLD. In the cortical regions, the 2 pathological groups differed only in frontal white matter, with the FTLD group showing higher microglial scores. FTLD showed higher microglial activation in the white matter compared to the respective gray matter in the entorhinal, temporal, and frontal regions. Conclusions: Our work expands the knowledge of the distribution and magnitude of microglial activation in these disorders. Additionally, we found some microglial circuit-specific patterns that could help to explain some of the clinical overlap between AD and FTLD-TDP, namely in memory deficits.

Evolution of autobiographical memory impairments in Alzheimer's disease and frontotemporal dementia – A longitudinal neuroimaging study

Compromised autobiographical memory (ABM) retrieval is well established in dementia, attributable to degeneration of a core memory brain network. It remains unclear, however, how the progressive spread of atrophy with advancing disease severity impacts ABM retrieval across life epochs. To this end, we conducted a longitudinal study of recent and remote ABM in Alzheimer's disease (AD, n =11), and a frontotemporal lobar degeneration group (FTD, n =13) comprising 7 behavioral variant FTD and 6 semantic dementia patients, in comparison with 23 healthy older Controls. Patients were re-assessed approximately one year following their initial visit and underwent repeat testing and brain imaging. Linear mixed modeling neuroimaging analyses explored disease-specific cortical changes driving ABM alterations over time. AD patients showed comparable ABM profiles across assessment periods however, follow-up performance correlated strongly with lateral temporal lobe integrity. In contrast, recent ABMs were disproportionately disrupted at follow-up relative to baseline in the FTD group, attributable to cortical thinning in posterior brain regions, including the right posterior cingulate cortex. Our findings offer new insights regarding the potential time-specific role of discrete cortical regions in ABM retrieval and the differential fate of formerly evocative memories with advancing disease severity in dementia syndromes.