Functional connectivity and microstructural white matter changes in phenocopy frontotemporal dementia

Objectives: Phenocopy frontotemporal dementia (phFTD) is a rare and poorly understood clinical syndrome. PhFTD shows core behavioural variant FTD (bvFTD) symptoms without associated cognitive deficits and brain abnormalities on conventional MRI and without progression. In contrast to phFTD, functional connectivity and white matter (WM) microstructural abnormalities have been observed in bvFTD. We hypothesise that phFTD belongs to the same disease spectrum as bvFTD and investigated whether functional connectivity and microstructural WM changes similar to bvFTD are present in phFTD. Methods: Seven phFTD patients without progression or alternative psychiatric diagnosis, 12 bvFTD patients and 17 controls underwent resting state functional MRI (rs-fMRI) and diffusion tensor imaging (DTI). Default mode network (DMN) connectivity and WM measures were compared between groups. Results: PhFTD showed subtly increased DMN connectivity and subtle microstructural changes in frontal WM tracts. BvFTD showed abnormalities in similar regions as phFTD, but had lower increased DMN connectivity and more extensive microstructural WM changes. Conclusions: Our findings can be interpreted as neuropathological changes in phFTD and are in support of the hypothesis that phFTD and bvFTD may belong to the same disease spectrum. Advanced MRI techniques, objectively identifying brain abnormalities, would therefore be potentially suited to improve the diagnosis of phFTD. Key points: • PhFTD shows brain abnormalities that are similar to bvFTD.• PhFTD shows increased functional connectivity in the parietal default mode network.• PhFTD shows microstructural white matter abnormalities in the frontal lobe.• We hypothesise phFTD and bvFTD may belong to the same disease spectrum

Resting-state functional MRI in behavioral variant of frontotemporal dementia

Abstract Frontotemporal lobar degeneration (FTLD) is the second most common neurodegenerative disease leading to early-onset dementia with an estimated worldwide prevalence of 10 to 30 cases per 100000 individuals in the age group of 46 to 65 years. Behavioral variant frontotemporal dementia (bvFTD) is the most common FTLD subtype. It is characterized by a progressive deterioration of behavior and personality as well as executive dysfunction. In Finland, almost 50 % of familial FTLD cases are attributable to the C9ORF72 mutation. bvFTD is associated with a characteristic pattern of brain atrophy detectable in structural MRI. However, these changes are typically not visible in the early stages of the disease. Resting-state functional MRI (RS-fMRI) is being increasingly used to evaluate changes in functional connectivity within neuronal networks in the brain but only a few RS-fMRI investigations of bvFTD patients have been published with inconsistent results. The object of this thesis was to investigate functional connectivity changes detected in the salience (SLN) and default mode networks (DMN) in bvFTD. Another aim was to clarify the role of other cognitive resting-state networks in this disease. A cohort of 26 bvFTD patients was studied, with 8 of these patients carrying the C9ORF72 expansion. Connectivity changes were detected in multiple clinically relevant cognitive networks. Decreased functional connectivity was observed in the SLN, which is associated with guiding of behavior. Increased activity was present in the DMN and the dorsal attention network (DAN). In C9ORF72 associated bvFTD, there was an abnormal linkage detected between the DMN and the thalamus. Currently, fMRI is generally used as a research tool and in a group setting. Different study methods have been used in the literature and also in the studies of this thesis, the analysis procedures differed to some extent. The variety of analysis methods may explain the heterogeneity in fMRI findings in bvFTD patients. There is a need for standardization of the fMRI methodology, larger study groups and also in the future the methodology should be improved so that single patient analysis would provide results to allow a confident diagnosis of this disease.Tiivistelmä Otsa-ohimolohkorappeuma (Frontotemporal lobar degeneration, FTLD) on toiseksi yleisin etenevä dementiaan johtava sairaus, joka ilmaantuu usein jo työikäisenä. Otsalohkodementia on otsa-ohimolohkorappeuman yleisin alamuoto, jonka oireisto painottuu persoonan ja käyttäytymisen muutoksiin sekä toiminnan ohjauksen ongelmiin. Suomessa C9ORF72-toistojaksomutaatio selittää lähes 50 % perinnöllisistä otsa-ohimolohkorappeumista. Aivojen rakenteellisella magneettikuvauksella (MK) voidaan havaita rakenteellisia muutoksia, jotka ilmaantuvat kuitenkin vasta taudin edettyä vaikeampaan vaiheeseen. Aivojen lepotilan toiminnallinen magneettikuvaus (TMK) mahdollistaa aivojen hermoverkkojen toiminnan eli konnektiviteetin kartoituksen. Aiemmin TMK:a on tutkittu esim. Alzheimerin taudissa. Otsalohkodementiassa TMK:sta on julkaistu ainoastaan yksittäisiä tutkimuksia ja tulokset ovat olleet osin ristiriitaisia. Väitöskirjatutkimuksen tarkoituksena on ollut selvittää valve-lepotilan hermoverkossa ja olennaisen tunnistavassa hermoverkossa tapahtuvia muutoksia otsalohkodementiaa sairastavilla potilailla. Toisena tavoitteena on ollut tutkia muissa kognitiivisissa hermoverkoissa tapahtuvia muutoksia. Otsalohkodementiaa sairastaville potilaille (n= 26) sekä ikä- ja sukupuolivakioiduille kontrolleille on tehty kliininen tutkimus ja rakenteellinen sekä toiminnallinen aivojen magneettikuvaus. Kahdeksalla potilaalla todettiin C9ORF72-toistojaksomutaatio. Useiden kognitiivisten hermoverkkojen toiminnassa havaittiin muutoksia, jotka korreloivat potilaiden kliinisiin oireisiin. Alentunutta konnektiviteettia todettiin olennaisen tunnistavassa hermoverkossa, joka osallistuu käyttäytymisen säätelyyn. Lisääntynyttä konnektiviteettia esiintyi valve-lepotilan hermoverkossa ja tarkkaavaisuus hermoverkossa. Potilailla, joilla on C9ORF72-mutaatio, havaittiin epänormaali yhteys valve-lepotilan hermoverkon ja talamuksen välillä. TMK:ta käytetään tällä hetkellä lähinnä tutkimustyökaluna. Analyysityökaluissa on ollut vaihtelevuutta eri julkaisuissa ja osin myös tämän väitöskirjan osatöissä. Julkaistut TMK-löydökset otsalohkodementiassa ovat osin ristiriitaisia ja se saattaa selittyä erilaisilla analyysimenetelmillä. Metodologiaa tulisi standardisoida ja lisäksi tarvitaan suurempia potilasryhmiä ja menetelmien kehittämistä, jotta TMK:n käyttö yksilötason kliinisessä diagnostiikassa olisi jatkossa mahdollista

The effect of gray matter ICA and coefficient of variation mapping of BOLD data on the detection of functional connectivity changes in Alzheimer’s disease and bvFTD

Abstract Resting-state fMRI results in neurodegenerative diseases have been somewhat conflicting. This may be due to complex partial volume effects of CSF in BOLD signal in patients with brain atrophy. To encounter this problem, we used a coefficient of variation (CV) map to highlight artifacts in the data, followed by analysis of gray matter voxels in order to minimize brain volume effects between groups. The effects of these measures were compared to whole brain ICA dual regression results in Alzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD). 23 AD patients, 21 bvFTD patients and 25 healthy controls were included. The quality of the data was controlled by CV mapping. For detecting functional connectivity (FC) differences whole brain ICA (wbICA) and also segmented gray matter ICA (gmICA) followed by dual regression were conducted, both of which were performed both before and after data quality control. Decreased FC was detected in posterior DMN in the AD group and in the Salience network in the bvFTD group after combining CV quality control with gmICA. Before CV quality control, the decreased connectivity finding was not detectable in gmICA in neither of the groups. Same finding recurred when exclusion was based on randomization. The subjects excluded due to artifacts noticed in the CV maps had significantly lower temporal signal-to-noise ratio than the included subjects. Data quality measure CV is an effective tool in detecting artifacts from resting state analysis. CV reflects temporal dispersion of the BOLD signal stability and may thus be most helpful for spatial ICA, which has a blind spot in spatially correlating widespread artifacts. CV mapping in conjunction with gmICA yields results suiting previous findings both in AD and bvFTD

Differences in structural covariance brain networks between behavioral variant frontotemporal dementia and Alzheimer's disease

Disease‐specific patterns of gray matter atrophy in Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) overlap with distinct structural covariance networks (SCNs) in cognitively healthy controls. This suggests that both types of dementia target specific structural networks. Here, we study SCNs in AD and bvFTD. We used structural magnetic resonance imaging data of 31 AD patients, 24 bvFTD patients, and 30 controls from two centers specialized in dementia. Ten SCNs were defined based on structural covariance of gray matter density using independent component analysis. We studied group differences in SCNs using F‐tests, with Bonferroni corrected t‐tests, adjusted for age, gender, and study center. Associations with cognitive performance were studied using linear regression analyses. Cross‐sectional group differences were found in three SCNs (all P < 0.0025). In bvFTD, we observed decreased anterior cingulate network integrity compared with AD and controls. Patients with AD showed decreased precuneal network integrity compared with bvFTD and controls, and decreased hippocampal network and anterior cingulate network integrity compared with controls. In AD, we found an association between precuneal network integrity and global cognitive performance (P = 0.0043). Our findings show that AD and bvFTD target different SCNs. The comparison of both types of dementia showed decreased precuneal (i.e., default mode) network integrity in AD and decreased anterior cingulate (i.e., salience) network integrity in bvFTD. This confirms the hypothesis that AD and bvFTD have distinct anatomical networks of degeneration and shows that structural covariance gives valuable insights in the understanding of network pathology in dementia