Variant Of Frontotemporal Lobar Degeneration Research Articles

IPSC-induced neurons with the V337M MAPT mutation are selectively vulnerable to caspase-mediated cleavage of tau and apoptotic cell death

BackgroundTau post-translational modifications (PTMs) result in the gradual build-up of abnormal tau and neuronal degeneration in tauopathies, encompassing variants of frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). Tau proteolytically cleaved by active caspases, including caspase-6, may be neurotoxic and prone to self-aggregation. Also, our recent findings show that caspase-6 truncated tau represents a frequent and understudied aspect of tau pathology in AD in addition to phospho-tau pathology. In AD and Pick's disease, a large percentage of caspase-6 associated cleaved-tau positive neurons lack phospho-tau, suggesting that many vulnerable neurons to tau pathology go undetected when using conventional phospho-tau antibodies and possibly will not respond to phospho-tau based therapies. Therefore, therapeutic strategies against caspase cleaved-tau pathology could be necessary to modulate the extent of tau abnormalities in AD and other tauopathies. MethodsTo understand the timing and progression of caspase activation, tau cleavage, and neuronal death, we created two mAbs targeting caspase-6 tau cleavage sites and probed postmortem brain tissue from an individual with FTLD due to the V337M MAPT mutation. We then assessed tau cleavage and apoptotic stress response in cortical neurons derived from induced pluripotent stem cells (iPSCs) carrying the FTD-related V337M MAPT mutation. Finally, we evaluated the neuroprotective effects of caspase inhibitors in these iPSC-derived neurons. ResultsFTLD V337M MAPT postmortem brain showed positivity for both cleaved tau mAbs and active caspase-6. Relative to isogenic wild-type MAPT controls, V337M MAPT neurons cultured for 3 months post-differentiation showed a time-dependent increase in pathogenic tau in the form of caspase-cleaved tau, phospho-tau, and higher levels of tau oligomers. Accumulation of toxic tau species in V337M MAPT neurons was correlated with increased vulnerability to pro-apoptotic stress. Notably, this mutation-associated cell death was pharmacologically rescued by the inhibition of effector caspases. ConclusionsOur results suggest an upstream, time-dependent accumulation of caspase-6 cleaved tau in V337M MAPT neurons promoting neurotoxicity. These processes can be reversed by caspase inhibition. These results underscore the potential of developing caspase-6 inhibitors as therapeutic agents for FTLD and other tauopathies. Additionally, they highlight the promise of using caspase-cleaved tau as biomarkers for these conditions.

The graded multidimensional geometry of phenotypic variation and progression in neurodegenerative syndromes.

Clinical variants of Alzheimer's disease and frontotemporal lobar degeneration display a spectrum of cognitive-behavioural changes varying between individuals and over time. Understanding the landscape of these graded individual-/group-level longitudinal variations is critical for precise phenotyping; however, this remains challenging to model. Addressing this challenge, we leverage the National Alzheimer's Coordinating Center database to derive a unified geometric framework of graded longitudinal phenotypic variation in Alzheimer's disease and frontotemporal lobar degeneration. We included three time-point, cognitive-behavioural and clinical data from 390 typical, atypical and intermediate Alzheimer's disease and frontotemporal lobar degeneration variants (114 typical Alzheimer's disease; 107 behavioural variant frontotemporal dementia; 42 motor variants of frontotemporal lobar degeneration; and 103 primary progressive aphasia patients). On this data, we applied advanced data-science approaches to derive low-dimensional geometric spaces capturing core features underpinning clinical progression of Alzheimer's disease and frontotemporal lobar degeneration syndromes. To do so, we first used principal component analysis to derive six axes of graded longitudinal phenotypic variation capturing patient-specific movement along and across these axes. Then, we distilled these axes into a visualisable 2D manifold of longitudinal phenotypic variation using Uniform Manifold Approximation and Projection. Both geometries together enabled the assimilation and inter-relation of paradigmatic and mixed cases, capturing dynamic individual trajectories, and linking syndromic variability to neuropathology and key clinical end-points such as survival. Through these low-dimensional geometries, we show that (i) specific syndromes (Alzheimer's disease and primary progressive aphasia) converge over time into a de-differentiated pooled phenotype, while others (frontotemporal dementia variants) diverge to look different from this generic phenotype; (ii) phenotypic diversification is predicted by simultaneous progression along multiple axes, varying in a graded manner between individuals and syndromes; and (iii) movement along specific principal axes predicts survival at 36 months in a syndrome-specific manner and in individual pathological groupings. The resultant mapping of dynamics underlying cognitive-behavioural evolution potentially holds paradigm-changing implications to predicting phenotypic diversification and phenotype-neurobiological mapping in Alzheimer's disease and frontotemporal lobar degeneration.

Distinctive whole-brain cell types predict tissue damage patterns in thirteen neurodegenerative conditions

For over a century, brain research narrative has mainly centered on neuron cells. Accordingly, most neurodegenerative studies focus on neuronal dysfunction and their selective vulnerability, while we lack comprehensive analyses of other major cell types’ contribution. By unifying spatial gene expression, structural MRI, and cell deconvolution, here we describe how the human brain distribution of canonical cell types extensively predicts tissue damage in 13 neurodegenerative conditions, including early- and late-onset Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, amyotrophic lateral sclerosis, mutations in presenilin-1, and 3 clinical variants of frontotemporal lobar degeneration (behavioral variant, semantic and non-fluent primary progressive aphasia) along with associated three-repeat and four-repeat tauopathies and TDP43 proteinopathies types A and C. We reconstructed comprehensive whole-brain reference maps of cellular abundance for six major cell types and identified characteristic axes of spatial overlapping with atrophy. Our results support the strong mediating role of non-neuronal cells, primarily microglia and astrocytes, in spatial vulnerability to tissue loss in neurodegeneration, with distinct and shared across-disorder pathomechanisms. These observations provide critical insights into the multicellular pathophysiology underlying spatiotemporal advance in neurodegeneration. Notably, they also emphasize the need to exceed the current neuro-centric view of brain diseases, supporting the imperative for cell-specific therapeutic targets in neurodegeneration.

The Diagnostic Challenge of Frontal Alzheimer's Disease: Case Report and Literature Review

Atypical forms of Alzheimer's disease (AD) have long been described, but it's only recently that the aphasic, frontal, and visuospatial variants have been included in the clinical diagnostic and research criteria for AD. The frontal form, also known as the behavioral and/or dysexecutive form of AD, is still a poorly understood and poorly defined entity. Patients present with either behavioral or executive disorders, or both. It is now possible to establish, in vivo, a diagnosis of frontal variant AD (fv-AD) with a high degree of probability by comparing the neuropsychological profile and biomarkers. However, the neuropsychological and behavioral profile of patients with fv-AD is still poorly understood, often leading to diagnostic difficulties and confusion with the behavioral variant of frontotemporal lobar degeneration (bv-FTLD), which is the main differential diagnosis. We will illustrate the difficulties sometimes encountered in practice in the differential diagnosis between these pathologies through a clinical observation.

Neuropsychiatric Symptoms and Neuropathological diagnoses of Alzheimer’s Disease and Related Dementias

AbstractBackgroundThe associations of Alzheimer’s disease (AD) and related dementias (ADRD) pathologies with common neuropsychiatric symptoms (NPS) is not well‐established.MethodThis retrospective cohort study used 1,808 brains from 39 sites in the National Alzheimer’s Coordinating Center (NACC) V.10 collection for participants with the Neuropsychiatric Interview‐Questionnaire (NPI‐Q) administered annually and without consideration of clinical diagnosis. Brain autopsy diagnoses of AD, Lewy Body Disease (LBD), cerebral amyloid angiopathy, frontotemporal lobar degeneration (FTLD), cerebrovascular disease (CVD), hippocampal sclerosis, and “no known pathology” were examined. NPI‐Q domain score if present at any timepoint was the primary outcome and average NPI‐Q domain score during follow‐up was secondary. The associations of ADRD diagnoses with twelve NPI‐Q symptom domains were examined in regression analyses, correcting for multiple comparisons.ResultThe study sample of 1,808 adults had a mean [SD] age 80.0 [11.0] years and 54.6% were male. Apathy was the most prevalent NPS, reaching 80% in hippocampal sclerosis. CVD showed few NPS associations. FTLD was associated with increased apathy, increased disinhibition, and decreased psychosis and agitation compared to AD. Hippocampal sclerosis was associated with increased apathy (OR 2.60, 95%CI 1.86‐3.66, pfdr<.05) and disinhibition (OR 2.15, 95% CI 1.63‐2.84, pfdr<.05). In multiple regression analyses that included concomitant neuropathologies, the main findings remained. More severe pathology was associated consistently with increased NPS, e.g., LBD showed increase in hallucinations from brainstem (β=0.23, 95% CI 0.07‐0.76, p<.05) to limbic (β=1.69, 95% CI 1.27‐2.27, p<.01) to neocortical (β=4.49, 95% CI 3.27‐6.16, p<.001) pathology. Hallucinations were more common in participants with AD+LBD (168/534=31.5%) compared to AD without LBD (152/704=21.6%) and LBD without AD (23/119=19.6%).ConclusionVisual hallucinations may characterize LBD with AD more than LBD without AD. NPS criteria of apathy and disinhibition in behavioral variant frontotemporal lobar degeneration were supported. In hippocampal sclerosis, the novel findings of increased apathy and disinhibition merit further investigation. Severity of neuropathology was related to NPS severity, indicating that NPS reflect underlying ADRD pathology and highlight the importance of diagnosing and treating NPS.

Idiopathic normal pressure hydrocephalus and frontotemporal dementia: an unexpected association.

Idiopathic normal pressure hydrocephalus has a complex multifactorial pathogenesis and is associated with Alzheimer's disease in many patients. To date, it is not well known if a similar association exists with behavioural variant of frontotemporal lobar degeneration. In a first step, we compare the prevalence of idiopathic normal pressure hydrocephalus in two groups of patients, one with behavioural variant of frontotemporal lobar degeneration (n = 69) and the other with Alzheimer's disease (n = 178). In the second step, we describe more precisely the phenotype of patients with the association of idiopathic normal pressure hydrocephalus and behavioural variant of frontotemporal lobar degeneration. Firstly, we report that the prevalence of idiopathic normal pressure hydrocephalus was far higher in the group of patients with behavioural variant of frontotemporal lobar degeneration than in the group of patients with Alzheimer's disease (7.25% and 1.1%, respectively, P = 0.02). Secondly, we show that patients with the double diagnosis share common clinical and para-clinical features of both idiopathic normal pressure hydrocephalus and behavioural variant of frontotemporal lobar degeneration patients, including CSF shunting efficacy in real-life experience. Overall, our results suggest a link between these two conditions and should encourage neurologists to look for idiopathic normal pressure hydrocephalus in their behavioural variant of frontotemporal lobar degeneration patients in the event of gait disturbances; the benefit/risk balance could indeed be in favour of shunt surgery for selected patients with this newly described entity.

Disfluency patterns in Alzheimer’s disease and frontotemporal lobar degeneration

ABSTRACT Disfluencies may reflect various mechanisms: word-finding difficulties, planning strategies, inter-individual cognitive variability, etc. In the current paper, we examined disfluency production in patients with a behavioural variant of Frontotemporal lobar degeneration (bvFTLD), compared to patients with Alzheimer’s disease (AD) and healthy older adults. We showed that bvFTLD participants have lower speech rate and produce more incomplete utterances. However, those measures were not correlated with naming and fluency tasks. On the contrary, AD participants did not differ from healthy controls on disfluency production, but discourse measures were correlated with the participants’ lexical-semantic impairment. This provides evidence for different causes of disfluency in AD and FTLD, and a distinct role of each disfluency phenomenon.

Functional Connectivity Rearrangements Propagating from Disease Epicenters in Frontotemporal Lobar Degeneration Variants (P12-3.001)

Functional Connectivity Rearrangements Propagating from Disease Epicenters in Frontotemporal Lobar Degeneration Variants (P12-3.001)

Associations Between Neuropsychiatric Symptoms and Neuropathological Diagnoses of Alzheimer Disease and Related Dementias

Understanding associations of Alzheimer disease (AD) and related dementias (ADRD) pathologies with common neuropsychiatric symptoms (NPS) may have implications for diagnosis and management. To evaluate ADRD neuropathological diagnoses and NPS without consideration of clinical diagnosis. This retrospective cohort study evaluated 1808 brains from 39 sites in the US National Alzheimer Coordinating Center v. 10 collection for participants among whom the Neuropsychiatric Inventory Questionnaire (NPIQ) was administered annually. Brain autopsy diagnoses of AD, Lewy body disease (LBD), cerebral amyloid angiopathy, frontotemporal lobar degeneration, cerebrovascular disease, hippocampal sclerosis, and no known pathology were examined. Autopsy data collected from January 2012 to January 2018 were deidentified and compiled into the publicly available v. 10 database. Data were analyzed from February 2021 to August 2021. The primary outcome was NPIQ domain score, if present at any time point, and mean NPIQ domain score during follow-up was secondary. Associations of ADRD diagnoses with 12 NPIQ symptom domains were examined in regression analyses, correcting for multiple comparisons. The study sample of 1808 adults had a mean (SD) age of 80.0 (11.0) years, and 987 participants (54.6%) were male. Apathy was the most prevalent NPS, reaching 80% (203 of 254 individuals) in those with hippocampal sclerosis. Cerebrovascular disease showed few NPS associations. Frontotemporal lobar degeneration was associated with increased apathy, increased disinhibition, and decreased psychosis and agitation compared with AD. Hippocampal sclerosis was associated with increased apathy (odds ratio, 2.60; 95% CI; 1.86-3.66, false discovery rate controlled P < .001) and disinhibition (odds ratio, 2.15; 95% CI, 1.63-2.84; false discovery rate controlled P < .001). In multiple regression analyses that included concomitant neuropathologies, the main findings remained. More severe pathology was consistently associated with increased NPS (eg, LBD was associated with an increase in hallucinations from brain stem [β, 0.23; 95% CI, 0.07-0.76; P = .02] to limbic [β, 1.69; 95% CI, 1.27-2.27; P < .001] to neocortical [β, 4.49; 95% CI, 3.27-6.16; P < .001] pathology). Hallucinations were more common in participants with AD and LBD (168 of 534 [31.5%]) compared with those with AD without LBD (152 of 704 [21.6%]) and those with LBD without AD (23 of 119 [19.6%]). In this cohort study of 1808 brains from the US National Alzheimer Coordinating Center, patients with LBD and AD showed a higher prevalence of hallucinations compared with those with LBD without AD. Neuropsychiatric symptom criteria of apathy and disinhibition in behavioral variant frontotemporal lobar degeneration were supported in this study. In hippocampal sclerosis, the findings of increased apathy and disinhibition merit further investigation. Severity of neuropathology was associated with NPS severity, indicating that NPS may reflect underlying ADRD pathology and highlighting the importance of diagnosing and treating NPS.

Converging longitudinal patterns of atrophy in clinical variants of frontotemporal lobar degeneration

AbstractBackgroundThe aim of this study was to assess longitudinal patterns of atrophy shown by magnetic resonance imaging (MRI) in the whole‐brain GM of patients affected by different clinical variants of the FTLD spectrum.MethodFifty‐nine patients, including 26 with behavioral variant of frontotemporal dementia (bvFTD), 10 non‐fluent/agrammatic variant of primary progressive aphasia (nfvPPA), 12 semantic variant of PPA (svPPA), and 11 MND, in the absence of known pathogenic mutations, underwent MRI on a 3T scanner at 6‐month intervals for one year. Thirty‐three healthy controls underwent the same protocol. 3D T1‐weighted MRI sequences were analyzed using voxel‐based morphometry to assess the longitudinal evolution of GM atrophy in patients, compared with HC.ResultAt baseline, severe diffuse atrophy of frontotemporal cortical regions and basal ganglia was found in bvFTD, nfvPPA and svPPA groups, whereas MND did not show significant GM atrophy. At 6‐month follow‐up, bvFTD and PPA groups showed significant progression of atrophy in the insular (bvFTD, nfvPPA and svPPA) and anterior cingulate cortex (bvFTD and nfvPPA), bilaterally, as well as in the left caudate nucleus and middle temporal cortex (svPPA). At 12‐month follow‐up, similar patterns of atrophy progression were found, with the additional involvement of the superior frontal cortical gyri in nfvPPA, bilaterally, and the right hippocampus in svPPA. No significant progression of atrophy was found in MND patients.ConclusionOur data suggest that atrophy of insular and anterior cingulate cortical regions closely reflects the progression of neurodegeneration across the behavioral and linguistic presentations of frontotemporal dementia (FTD), in contrast with a substantial sparing of GM in MND. Supported by: European Research Council (StG‐2016_714388_NeuroTRACK).

Converging longitudinal patterns of atrophy in clinical variants of frontotemporal lobar degeneration

We aimed to assess longitudinal patterns of atrophy shown by magnetic resonance imaging (MRI) in the cortical and subcortical GM of patients affected by different clinical variants of the FTLD spectrum.

Caregiver burden in patients with behavioural variant frontotemporal dementia and non-fluent variant and semantic variant primary progressive aphasia

Studies on caregiver burden in patients with frontotemporal lobar degeneration are rare, differ methodologically and show variable results. Single center longitudinal pilot study on caregiver burden and potential risk factors in patients with behavioural variant frontotemporal dementia (bvFTD) and semantic (svPPA) and non-fluent variants (nfvPPA) primary progressive aphasia. Forty-six bvFTD, nine svPPA, and six nfvPPA patients and caring relatives were analysed for up to 2 years using the Mini-Mental State Examination as global measure for cognitive performance, Frontal Assessment Battery (frontal lobe functions), Frontal Behavioural Inventory (personality and behaviour), Neuropsychiatric Inventory (dementia-related neuropsychiatric symptoms), Barthel Index and Lawton IADL Scale (basic and instrumental activities of daily living), the Caregiver Strain Index (CSI), and in most participants also the Zarit Burden Interview (ZBI). CSI baseline sum scores were highest in bvFTD (mean ± SD 5.5 ± 3.4, median 5, IQR 6), intermediate in svPPA (2.9 ± 2.3; 3; 3.5) and low in nfvPPA (1.6 ± 2.1; 1; 2). Similar differences of caregiver burden were found using the ZBI. During follow-up, CSI and ZBI sum scores deteriorated in svPPA, not in bvFTD and nfvPPA, and correlated significantly with personality and behaviour, neuropsychiatric symptoms, caregiver age, and instrumental, but not basic activities of daily living, Mini-Mental State Examination scores or frontal lobe functions. This study reveals differences in caregiver burden in variants of frontotemporal lobar degeneration. Caregivers should be systematically asked for caregiver burden from the time of the diagnosis to provide comprehensive support in time.

Validation de la mini-SEA dans une population française variée : données de référence pour la pratique clinique

Social cognition, referring to humans’ abilities to process social information in order to efficiently interact with each other, is impaired in a wide range of clinical groups. Among them, patients with behavioral variant frontotemporal lobar degeneration (bvFTD) have been found to present deficits in emotion recognition and mental state inference. Based on these components of social cognition, the mini-SEA battery was developed a dozen years ago and is widely used today with patients suffering from a variety of conditions. However, national normative studies are still lacking. The aim of the present study is to provide such normative reference data for French participants and to evaluate the psychometric qualities of the mini-SEA. 150 healthy participants were assessed with the mini-SEA. We found that performance decreased with the age of participants, and we observed a general, though small, advantage for women participants. Sensitivity analyses revealed that both sub-tests are relatively easy for healthy participants. However, emotion recognition performance appeared to depend on the type of emotions displayed. Internal consistency and reliability both appeared to be satisfactory, although these dimensions should be investigated in greater depth in future studies. Finally, the mini-SEA showed good clinical validity, as reflected by excellent specificity and sensitivity values.

A case suspected of Alzheimer type dementia showing multimodal (face and voice) person recognition disorder from face and voice

A 90-year-old woman presented with a multimodal (face and voice) person recognition disorder. Although she had moderate general cognitive impairment, her visual cognitive capacity, other than face recognition, was well preserved. She could identify the faces and voices of family members but could not recall the names and voices of relatives whom she met infrequently, famous individuals, or the medical staff. She could remember the first names and some information about prominent individuals when supplied with their surnames. Therefore, we thought that her person-specific semantic memory was intact but she was unable to access it through their faces and voices. MRI revealed predominantly right-sided bilateral anterior temporal lobe and hippocampal atrophy. SPECT images showed decreased blood flow in the bilateral anterior temporal lobes and inferior parietal lobule (heavily and predominantly right-sided), right posterior cingulate gyrus, and precuneus. Progressive person recognition disorder or prosopagnosia has been considered a right temporal variant of frontotemporal lobar degeneration because abnormal behaviors and psychiatric symptoms frequently coexist. However, no such symptoms were observed in this case, therefore we suspected dementia of the Alzheimer type.

Klüver‐Bucy syndrome due to stroke in the left temporal lobe

AbstractBackgroundKlüver‐Bucy syndrome (KBS) comprises: 1) hyperorality, 2) hypermetamorphosis, 3) hypersexuality, 4) eating disorder, 5) placidity, 6) visual agnosia (psychic blindness) and 7) amnesia (at least three components are described as partial KBS). The classic description involves bilateral injuries to the anterior temporal lobes, but it has been reported that unilateral lesions can also lead to KBS.MethodCase report and analyses of MR Images (T1, Flair and Tractography) of a patient presenting partial KBS due to stroke in the left temporal lobe.ResultMale patient, 69 years‐old, with cognitive deficits that have begun after a left frontotemporal stroke in 2003, with remarkable changes in the temporal pole. In the first months after the stroke, he used to get lost when out of home and had difficulty remembering names and recognizing well known persons due to psychic blindness. During the next years, the patient developed impairment in declarative memory, but preserved visuospatial skills (many times coming to the medical appointments alone, using public transportation). Over time, he developed binge eating (once eating 1 kilogram of cheese, for instance), inability to deal with money (unnecessary loans in banks) and bizarre sexual behavior (such as excessive addiction to porn movies, public masturbation, flirting with women in his neighborhood, and an episode of inappropriate sexual behavior with his daughter‐in‐law). The patient still resists taking bath and changing clothes.ConclusionThe exact anatomic basis of KBS is still controversial. What is remarkable is the main role of the amygdala in the syndrome. However, periamygdalar lesions can cause disconnection syndromes and damage the limbic network that involves the uncus, the hippocampus, the insular cortex, orbitofrontal and cingulate gyri. Patients with KBS can mimic behavioral variant frontotemporal lobar degeneration (bvFTLD) – particularly regarding eating and sexual disorders, probably due to the connections between the amygdala and the orbitofrontal gyri. The integrity of these two regions and their connections probably play an important role in emotional continence, modulating basic desires in the human species. Lesions in the uncinate fasciculus can predispose to KBS. Our patient exhibits lack of fibers connecting temporal lobe and orbitofrontal cortex showed in the tractography.

Zinc Binds to RRM2 Peptide of TDP-43.

Transactive response DNA and RNA binding protein 43 kDa (TDP-43) is a highly conserved heterogeneous nuclear ribonucleoprotein (hnRNP), which is involved in several steps of protein production including transcription and splicing. Its aggregates are frequently observed in motor neurons from amyotrophic lateral sclerosis patients and in the most common variant of frontotemporal lobar degeneration. Recently it was shown that TDP-43 is able to bind Zn2+ by its RRM domain. In this work, we have investigated Zn2+ binding to a short peptide 256–264 from C-terminus of RRM2 domain using isothermal titration calorimetry, electrospray ionization mass spectrometry, QM/MM simulations, and NMR spectroscopy. We have found that this peptide is able to bind zinc ions with a Ka equal to 1.6 × 105 M−1. Our findings suggest the existence of a zinc binding site in the C-terminal region of RRM2 domain. Together with the existing structure of the RRM2 domain of TDP-43 we propose a model of its complex with Zn2+ which illustrates how zinc might regulate DNA/RNA binding.

DOUBLE JEOPARDY: UNTANGLING DEPRESSION, PARKINSON'S DISEASE & FRONTOTEMPORAL DEMENTIA IN CLINICAL PRACTICE WITH BEDSIDE COGNITIVE TESTING

Introduction Progressive supranuclear palsy is a taupathy disorder often mistaken on diagnosis by other neurocognitive disorders such as Parkinson's (PD) and Alzheimer's (AD) disease amongst other. PSP tends to be diagnosed in the later course of the disease and by time of diagnosis, individuals have a median survival of 7?years. PSP is a disease in which a diagnosis and treatment is done in a multidisiplinary approach involving collaboration of Psychiatry and Neurology. As it was seen in this clinical case which describes a patient with undetected progressive supranuclear palsy who were referred to a university hospital psychiatric emergency services facility for treatment of late onset symptoms and signs attributed to primary psychopathology related to behavioral variant of frontotemporal lobar degeneration (FTLDbv). Methods The patient described in the clinical vignette underwent a comprehensive neuropsychiatric assessment, given that the accuracy of the diagnosis of FTLDbv was in doubt. The clinical interview identified no significant prior developmental, medical, neurological, psychiatric, or substance use disorders; no family history of neuropsychiatric disturbance; and no significant psychosocial stressor before the onset of his neuropsychiatric condition at age 59. Bedside cognitive testing showed a Geriatric Depression Scale (GDS) score suggestive of mild symptoms of depression, and would be unlikely to explain his new onset psychosis. His subclinical Executive Interview 25 (EXIT 25) score and normal Mini Mental State Examination (MMSE) were not indicative of a dementia syndrome. Given the strong temporal relationship between the onset of his behavioral changes and perceptual disturbances and the start of levodopa/carbidopa, this medication was discontinued. He was admitted to the inpatient psychiatric service for observation. He was started initially on an atypical antipsychotic, but had this medication discontinued, as he no longer exhibited symptoms of psychosis. His citalopram was titrated to 40mg daily to optimize treatment of his major depressive disorder. Patient was discharge with complete resolution of psychotic symptoms and with diagnosis of Depressive disorder, unspecified and medication-induced psychotic disorder with delusions and hallucinations. A dopamine transporter (DaT) protein scan, a marker for presynaptic terminals in dopaminergic nigrostriatal neuros (marker for PD) and or iodine-123-metaiodobenzylguanadine (MIBG) myocardial scintigraphy (marker for DLB), was not performed. Results CASE REPORT: A 59-year-old, left handed, previously healthy gentleman was brought by police to a university hospital psychiatry emergency services for evaluation of acute safety concerns, regarding behavioral and personality changes. Patient was admitted to the hospital displaying motor symptoms with appearance of jaw tremor, ataxia, and urinary incontinence. After a negative brain MRI and head CT scan, the neurology team concluded that he had Parkinson`s disease and patient was discharged on levodopa/carbidopa (25?mg/?100 mg) QID and citalopram 20?mg daily for associated depressive symptoms with no benefit. After discharge from the hospital, he had become increasingly impulsive, hypersexual and engaging in risky behaviors with firearms. Persistent and progressive change in personality and behavior were the earliest displayed signs and they remained the most prominent features of his condition. All of these disturbances worsened after patient was started on levodopa/carbidopa. After evaluation by the psychiatry consultation and liaison service, a Mental status examination revealed cognitive and neurovegetative symptoms of depression as well as auditory illusions and concerns that a stranger had invaded his home. He denied manic symptoms. No suicidal and homicidal thoughts. Despite extensive neurological and neuropsychological evaluation 10-months later, surprisingly, it was established the diagnosis of progressive supranuclear palsy (PSP), as at that visit the patient presented with predominantly delay axial Parkinsonism, supranuclear gaze palsy, and increased falls due to postural instability. A neuropsychological assessment provided evidence of an executive syndrome of subcortical frontal type. Conclusions Progressive supranuclear palsy is a debilitating taupathy disorder that often is mistaken on diagnosis by other neurocognitive disorders such as Parkinson's dementia, Alzheimer's dementia and Frontotemporal lobar degeneration amongst others. Thus, making PSP diagnosis difficult at initial presentation and often presenting later in life. PSP diagnosis requires a multidisciplinary approach, a collaboration between Psychiatry and Neurology to piece together the complex problems that often manifest in challenging neuropsychiatric syndromes. The possibility of PSP should be considered in the differential diagnosis of late onset psychiatric syndromes. Early PSP diagnosis is imperative for both patients and physicians, as proper treatment will be started without delay to address PSP symptomatology. Thus, reducing the burden of patient and family, as well as reducing unnecessary diagnostic tests, hospitalizations and sub-optimal psychiatric treatment. It is imperative that providers from all specialties be aware of PSP early presentation and how it can be mistaken, specially in early stages, with other neurocognitive disorders in order to make proper referrals for the most effective treatment available. This research was funded by: N/A

A novel homozygous mutation in TREM2 found in a Chinese early-onset dementia family with mild bone involvement

Variants in triggering receptor expressed on myeloid cells 2 (TREM2) are associated with both behavioral variant frontotemporal lobar degeneration and Alzheimer's disease. TREM2 homozygous mutations cause Nasu-Hakola disease, an early-onset recessive form of dementia preceded by bone cysts and fractures. The same type of mutations has been shown to cause frontotemporal dementia without the presence of any bone phenotype. Herein, we report a Chinese Han consanguineous family carrying a novel TREM2 mutation, presenting with early-onset dementia similar to behavioral variant frontotemporal dementia with mild radiological bone involvement. Minigene reporter assay showed the variant disturbed splicing by preservation of intron 2 in transcription. In our investigation, the clinical and genetic spectra of Chinese early-onset dementia patients were expanded; TREM2 mutations should be screened in familial and Chinese early-onset dementia patients.

Apraxia profiles—A single cognitive marker to discriminate all variants of frontotemporal lobar degeneration and Alzheimer's disease

IntroductionApraxia is common in neurodegenerative dementias but underrepresented in clinical workup for differential diagnoses. MethodsPraxis-profiles were assessed with the Dementia Apraxia Test in 93 patients with early stages of biologically supported Alzheimer's disease or frontotemporal lobar degeneration: semantic primary-progressive aphasia, nonfluent primary-progressive aphasia, and behavioral variant frontotemporal dementia. Associations with core cognitive deficits of the dementia subtypes (i.e., visuospatial, sociocognitive, and semantic-linguistic) were explored. ResultsPatients showed significant apraxia compared with healthy controls but also disease-specific praxis-profiles. Using only the Dementia Apraxia Test, all four dementia subtypes could be correctly discriminated in 64.4% of cases, and in 78.2% when only distinguishing Alzheimer's disease versus frontotemporal lobar degeneration. Praxis-profiles showed consistent associations with core cognitive impairments of the different dementia subtypes. DiscussionThe Dementia Apraxia Test is a valid, time-efficient and versatile cognitive marker to delineate variants of frontotemporal lobar degeneration and Alzheimer's disease in clinical routine, facilitating differential diagnoses of dementia subtypes in early disease stages.

SCREENING FOR C9ORF72 EXPANSION MUTATION IN SERBIAN PATIENTS WITH EARLY ONSET DEMENTIA

Early-onset dementia (EOD) is a neurological syndrome conventionally considered to include patients with disease onset before 65 years of age. It has been shown that hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of both familial and sporadic behavioral variant of frontotemporal lobar degeneration (bvFTLD), amyotrophic lateral sclerosis (ALS) as well as combined syndrome FTLD-motor neuron disease (FTLD-MND). To determine the frequency of C9ORF72 expansion mutation (C9+) in cohort of 117 consecutive EOD patients who attended Neurology Clinic, Clinical Centre of Serbia between april 2012 and april 2014. Sizing PCR across the hexanucleotide repeats was performed using previously published primers. Subsequently, all apparently normal homozygous samples were screened for the C9ORF72 GGGGCC expansion using repeat-primed PCR. Fragment length analysis was performed on an ABI 3500 genetic analyzer and analyzed using ABI GeneMapper v4.1. In our cohort, we identified 4 out of 117 (3,4%) EOD patients with C9ORF72 expansion mutation. All C9+ patients were classified in FTLD disease spectrum group 4/49 (8,2%) where 3 patients fulfilled criteria for FTLDbv and 1 patient had FTLD-MND overlap. None of the C9+ patients fulfilled diagnostic criteria for FTLD language variants, FTD-Progressive supranuclear palsy overlap, dementia with Lewy bodies and Alzheimer's dementia. Our findings are consistent with literature data that around 90% of C9ORF72 repeat expansions are associated with clinical presentation of FTDbv, ALS or combined syndrome FTD-MND.